WO2017076987A1 - Composition comprenant de l'aprémilast sous forme aqueuse - Google Patents

Composition comprenant de l'aprémilast sous forme aqueuse Download PDF

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Publication number
WO2017076987A1
WO2017076987A1 PCT/EP2016/076589 EP2016076589W WO2017076987A1 WO 2017076987 A1 WO2017076987 A1 WO 2017076987A1 EP 2016076589 W EP2016076589 W EP 2016076589W WO 2017076987 A1 WO2017076987 A1 WO 2017076987A1
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Prior art keywords
compound
polymer
disease
melt
solid solution
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PCT/EP2016/076589
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English (en)
Inventor
Henrike FRANEK
Konstantin Holfinger
Hans-Jürgen MIKA
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Ratiopharm Gmbh
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Publication of WO2017076987A1 publication Critical patent/WO2017076987A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to N-[2-[1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- 1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]acetamide (also referred to as compound (I)).
  • the invention relates to compositions comprising compound (I) or a pharmaceutically acceptable salt thereof and processes for the preparation thereof.
  • N-[2-[1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1 ,3-dioxo-2,3-dihydro-1 H- isoindol-4-yl]acetamide is an experimental inhibitor of phosphodiesterase (PDE) 4, interferon gamma antagonist; IL-2 gene inhibitor; leukotriene synthesis inhibitor; TNF alpha synthesis inhibitor; IL-6 antagonist; IL-17 gene inhibitor; angiogenesis inhibitor; NO-synthase inhibitor; and IL-23 gene inhibitor.
  • PDE phosphodiesterase
  • Enantiomerically pure compound (I) has low solubility in aqueous solution. In aqueous buffer pH 7.4 the solubility measured at room temperature is about 0.01 mg/ml. Poor solubility typically leads to poor oral bioavailability, fed/fasted variations in bioavailability, cumbersome and inconvenient dosage forms, and may necessitate the use of harsh solubilising agents that are associated with adverse side effects.
  • WO201 1/059931 describes a method for preparing a nanosuspension of a poorly soluble drug in order to improve bioavailability. Said method comprises stirring the drug, which has been micronized, in an aqueous polymeric excipient solution in the absence of surfactants and passing the concentrate through a high-shear microfluidizer processor to obtain the nanosuspension.
  • WO2009/120167 describes solid forms of (+)-N-[2-[1 -(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]acetamide (also known as apremilast). However, there is no enabling disclosure of an amorphous form.
  • US 2015/0283249 relates to amorphous apremilast and a process for the preparation thereof.
  • a solid form of compound (I) should exhibit at least one of the following properties: adequate dissolution properties; storage stability at ambient conditions, preferably avoiding the requirement of desiccants in the packages; and be easily preparable with good content uniformity.
  • compositions of the invention have advantageous properties over compositions comprising crystalline forms of compound (I).
  • dissolution studies have shown that a composition comprising a solid solution or solid dispersion or melt of compound (I) according to the present invention exhibits at least a similar rate of dissolution to a composition comprising crystalline compound (I).
  • compositions comprising a solid solution or dispersion or melt of compound (I) according to the invention have been shown to retain at least 80% dissolution within 30 minutes in dissolution tests after being subjected to accelerated storage conditions.
  • the present invention relates to a solid solution or solid dispersion comprising compound (I)
  • the present invention relates to a process for preparing a solid solution or solid dispersion comprising compound (I) comprising spray drying compound (I), together with at least one pharmaceutically acceptable excipient.
  • the present invention relates to a process for preparing a solid solution or solid dispersion of compound (I) comprising freeze drying compound (I), together with at least one pharmaceutically acceptable excipient.
  • the present invention relates to a solid solution or solid dispersion comprising compound (I) obtainable by a process according to the second and third aspects of the invention.
  • the present invention relates to a melt consisting essentially of compound (I).
  • the present invention relates to a melt consisting of compound (I).
  • the present invention relates to a process for preparing a melt consisting essentially of compound (I) comprising melting compound (I).
  • the present invention relates a process for preparing a melt consisting of compound (I) comprising melting compound (I).
  • the present invention relates to a melt obtainable by a process according to the sixth aspect of the invention.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a solid solution or solid dispersion according to the above aspects of the invention, or a melt according to the above aspects of the invention, and a pharmaceutically acceptable excipient.
  • the present invention relates to a method of treating or preventing a disease or disorder ameliorated by the inhibition of TNF-[alpha] production, wherein the method comprises administering a therapeutically or prophylactically effective amount of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the present invention also relates to the solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment of a disease or disorder ameliorated by the inhibition of TNF-[alpha] production.
  • the present invention also relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a disease or disorder ameliorated by the inhibition of TNF-[alpha] production.
  • the present invention relates to a method of treating or preventing a disease or disorder ameliorated by the inhibition of PDE4, wherein the method comprises administering a therapeutically or prophylactically effective amount of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the present invention also relates to the solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment of a disease or disorder ameliorated by the inhibition of PDE4.
  • the present invention also relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a disease or disorder ameliorated by the inhibition of PDE4.
  • the present invention relates to a method of treating or preventing a cancer, wherein the method comprises administering a therapeutically or prophylactically effective amount of an amorphous form of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the present invention also relates to the solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment or prevention of cancer.
  • the present invention also relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment or prevention of cancer.
  • Figure 1 shows the XRPD pattern of the product of preparative example 1 .
  • the diffraction pattern of reference standard corundum (ASTM standard ref) is superimposed.
  • Figure 2 shows the HPLC chromatogram for the product of preparative example 1 .
  • Figure 3 shows the DSC and TGA pattern for the product of preparative example 1 .
  • Figure 4 shows the XRPD pattern of crystalline Form B of apremilast.
  • compound (I) refers to N-[2-[1 -(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]acetamide, which has the following structure:
  • a solid solution or solid dispersion refers to dissolution or molecular dispersion of compound (I) or (la) within an excipient matrix which is in the solid state at ambient temperature and pressure (e.g. at 20 ⁇ ⁇ and a pressure of 101 kPa).
  • a melt refers to the material which results when pure, or essentially pure, compound (I) or (la) is heated at least to about its melting point and optionally allowed to cool, preferably to ambient temperature.
  • pure refers to compound (I) or (la) which has a purity of 99% or more, as determined by UV-HPLC for instance.
  • Essentially pure refers to compound (I) or (la) which has a purity of 95% or more, as determined by UV-HPLC for instance.
  • the invention includes, where appropriate all enantiomers of compound (I).
  • the person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms).
  • the corresponding enantiomers may be isolated/prepared by methods known in the art.
  • compound (I) both the (+) and (-)-enantiomers of compound (I) separately, or mixtures thereof in any ratio, including a racemic mixture of enantiomers for example, are encompassed.
  • compound (I) is substantially all in the (+)-enantiomeric form and is also known as apremilast; preferably compound (I) is 80% or more in the (+)-enantiomeric form, more preferably compound (I) is 90% or more in the (+)-enantiomeric form, more preferably compound (I) is 95% or more in the (+)-enantiomeric form, more preferably compound (I) is 99% or more in the (+)-enantiomeric form.
  • Pharmaceutically acceptable salts of compound (I) may include, without limitation, non-toxic acid addition salts such as those derived from organic and inorganic acids, e.g. without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.
  • non-toxic acid addition salts such as those derived from organic and inorganic acids, e.g. without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid
  • the present invention relates to a solid solution or solid dispersion comprising compound (I)
  • the solid solution or solid dispersion comprises amorphous compound (I).
  • the solid solution or solid dispersion compound (I) is substantially free of any crystalline forms.
  • the solid solution or solid dispersion of compound (I) contains 20% or less of any crystalline form, preferably 10% or less, more preferably 5% or less, more preferably 2% or less, more preferably 1 % or less.
  • the crystalline proportion can be determined by means of quantitative X-ray diffractometry according to the method of Hermans and Weidinger.
  • the solid solution or solid dispersion of compound (I) comprises at least one pharmaceutically acceptable excipient.
  • the solid solution or solid dispersion consists essentially of compound (I) and at least one pharmaceutically acceptable excipient.
  • the solid solution or solid dispersion consists of compound (I) and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient has a softening point (Ts) or a glass transition temperature (Tg) of about 20 °C or higher, preferably about 20 °C to about 220 °C, more preferably about 20 °C to about 200 °C, even more preferably about 40 °C to about 180 ⁇ ⁇ , most preferably about 60 °C to about 140 ⁇ ⁇ .
  • Ts softening point
  • Tg glass transition temperature
  • the softening point and the glass transition temperature can be determined by any known means.
  • the softening point and glass transition temperature can be determined by means of differential scanning calorimetry (DSC). Suitable methods of determining softening points and glass transition temperatures are as described in the European Pharmacopoeia 7 (Ph. Eur., chapter 2.2.34) and the United States Pharmacopoeia (USP, chapter 891 ), the content of which is incorporated herein by reference.
  • the pharmaceutically acceptable excipient is selected from the group consisting of a polymer, a saccharide, an oligosaccharide, a polysaccharide, a sugar alcohol, a lipid, and a wax.
  • the pharmaceutically acceptable excipient is selected from the group consisting of a saccharide, an oligosaccharide, a polysaccharide, a sugar alcohol, a lipid, and a wax.
  • the pharmaceutically acceptable excipient is a polymer.
  • the polymer has a number-average molecular weight of 1 ,000 to 4,000,000 g/mol, more preferably from 1 ,000 to 3,500,000 g/mol, even more preferably from 1 ,500 to 3,000,000 g/mol, and particularly preferably from 3,500 to 2,500,000 g/mol.
  • the polymer has a viscosity of 150,000 mPa « s or less, more preferably 100,000 mPa « s or less, and especially 75,000 mPa « s or less when dissolved in (distilled) water (if the polymer is insoluble in water any other suitable solvent as described in "Handbook of Pharmaceutical Excipients" Sixth Edition, Edited by Raymond C Rowe, Paul J Sheskey and Marianne E Quinn, Pharmaceutical Press and American Pharmacists Association 2009 is to be used) in an amount of 2 % by weight, and measured at 25 °C in accordance with the European Pharmacopoeia (Ph. Eur.), 6th edition, section 2.2.10. Hydrophilic and amphiphilic polymers may be used.
  • Hydrophilic refers to polymers which possess hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulphonate, carboxylate and quaternary ammonium groups. Hydroxy groups are preferable.
  • Suitable polymers are, for example, cellulosic polymers and non-cellulosic polymers, such as methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxyethyl cellulose acetate succinate (HECAS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxyethyl methyl cellulose acetate succinate (HEMCAS) ,carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC), carboxymethyl ethyl cellulose (
  • the polymer may be selected from one or more of methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxyethyl cellulose acetate succinate (HECAS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxyethyl methyl cellulose acetate succinate (HEMCAS) ,carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), polyvinyl methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl
  • the polymer may be selected from one or more of methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxyethyl methyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxyethyl cellulose acetate succinate (HECAS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxyethyl methyl cellulose acetate succinate (HEMCAS) ,carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), polyvinyl methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl
  • the pharmaceutical composition of the invention may in particular comprise the following polymers: polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), polyethylene oxide hydroxylpropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinylcaprolactam- polyvinylacetat-polytethylene glycol graft copolymer (Soluplus®) and mixtures thereof.
  • polymers such as polypropylene glycol or preferably poly
  • the pharmaceutical composition of the invention may in particular comprise the following polymers: polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polyacrylamide, polymethacrylates, vinyl pyrrolidone/vinyl acetate copolymers (such as Kollidon® VA64, BASF), polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), polyethylene oxide, polyvinylcaprolactam- polyvinylacetat-polytethylene glycol graft copolymer (Soluplus®) and mixtures thereof.
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • polyacrylamide polymethacrylates
  • vinyl pyrrolidone/vinyl acetate copolymers such as Kollidon® VA64, BASF
  • the pharmaceutical composition of the invention may in particular comprise the following polymers: polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polyacrylamide, polymethacrylates, polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF), polyethylene oxide, polyvinylcaprolactam-polyvinylacetat-polytethylene glycol graft copolymer (Soluplus®) and mixtures thereof.
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • polyacrylamide polymethacrylates
  • polyalkylene glycols such as polypropylene glycol or preferably polyethylene glycol
  • co-block polymers of polyethylene glycol especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic®, BASF)
  • the polymer is a cellulosic polymer.
  • the polymer is a non-ionizable cellulosic polymer.
  • MC methyl cellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HEMC hydroxyethyl methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • the polymer is selected from methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxyethyl methyl cellulose (HEMC) and hydroxypropyl cellulose (HPC.
  • MC methyl cellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HEMC hydroxyethyl methyl cellulose
  • HPC hydroxypropyl cellulose
  • the polymer is an ionizable cellulosic polymer.
  • HPMCP hydroxypropyl methyl cellulose phtalate
  • HPMCA hydroxypropyl methyl cellulose acetate
  • HPCAS hydroxypropyl methyl cellulose acetate succinate
  • HPCAS hydroxypropyl cellulose acetate succinate
  • HECAS hydroxyethyl cellulose acetate succinate
  • HMCS hydroxyethyl methyl cellulose succinate
  • HEMCAS hydroxyethyl methyl cellulose acetate succinate
  • CMC carboxymethyl cellulose
  • CEC carboxyethyl cellulose
  • CMEC carboxymethyl ethyl cellulose
  • the polymer is selected from hydroxypropyl methyl cellulose phtalate (HPMCP), hydroxypropyl methyl cellulose acetate (HPMCA), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxyethyl cellulose acetate succinate (HECAS) hydroxyethyl methyl cellulose succinate (HEMCS), hydroxyethyl methyl cellulose acetate succinate (HEMCAS), carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC) and carboxymethyl ethyl cellulose (CMEC).
  • HPMCP hydroxypropyl methyl cellulose phtalate
  • HPMCA hydroxypropyl cellulose acetate
  • HPCAS hydroxypropyl cellulose acetate succinate
  • HECAS hydroxyethyl cellulose acetate succinate
  • HMCS hydroxyethyl methyl cellulose succinate
  • HEMCAS hydroxyethyl methyl cellulose acetate succinate
  • the polymer is an amphiphilic cellulosic polymer.
  • cellulose acetate phtalate (CAP) and cellulose acetate trimellitate (CAT) where the cellulosic repeat units that have one or more acetate substituents are hydrophobic relative to those that have no acetate substituents, or hydroxypropyl methyl cellulose acetate phthalate (HPMCAP) and hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) which have one or more ionized phtalate or trimellitate substituents.
  • the polymer is a non-cellulosic polymer.
  • the polymer is a non-ionizable, non-cellulosic polymer.
  • vinyl polymers and copolymers having hydroxyl, alkylacyloxy, or cyclicamido substituents; and polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), vinylpyrrolidon vinylacetat copolymer (VP/VAc copolymer), polyvinylacetat polyvinylpyrollidon copolymer (PVAc/PVP copolymer, Povidon), polyvinyl polypyrrolidon (PVPP copolymer, Crospovidon), polyvinyl alcohol polyethylene glycol copolymer (PVA/PEG copolymer), poly propylen glycols (PPGs), poly ethylen glycols (PPG
  • the polymer is selected from vinyl polymers and copolymers having hydroxyl, alkylacyloxy, or cyclicamido substituents; and polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form, polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), vinylpyrrolidon vinylacetat copolymer (VP/VAc copolymer), polyvinyl alcohol polyethylene glycol copolymer (PVA/PEG copolymer), poly propylen glycols (PPGs), poly ethylen glycols (PEGs 1500, 3000, 3350, 4000, 6000, 8000, 10000, 12000, 20000) and polyoxyethylene polyoxypropylene copolymers (Poloxamers).
  • PVA polyvinyl alcohol
  • PVAc polyvinyl acetate
  • VP/VAc copolymer vinylpyrrolidon vinylacetat
  • the polymer is selected from vinyl polymers and copolymers having hydroxyl, alkylacyloxy, or cyclicamido substituents; and polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form, polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl alcohol polyethylene glycol copolymer (PVA/PEG copolymer), poly propylen glycols (PPGs), poly ethylen glycols (PEGs 1500, 3000, 3350, 4000, 6000, 8000, 10000, 12000, 20000) and polyoxyethylene polyoxypropylene copolymers (Poloxamers).
  • PVA polyvinyl alcohol
  • PVAc polyvinyl acetate
  • PVA/PEG copolymer polypropylen glycols
  • PPGs poly ethylen glycols
  • the polymer is an ionizable, non-cellulosic polymer.
  • carboxylic acid-functionalized vinyl polymers polymethacrylates (such as the EU DRAG ITS®), carboxylic acid functionalized polyacrylates (such as the EU DRAG ITS®), amine-functionalized polyacrylates and/or polymethacrylates.
  • the polymer is an amine-functionalized polyacrylate and/or polymethacrylates.
  • the polymer is an amphiphilic non-cellulosic polymer.
  • copolymers of a relatively hydrophilic and a relatively hydrophobic monomer such as the EUDRAGITS®), polyoxyethylene-polyoxypropylene copolymers (such as the PLURONICS®), Polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft Co-polymer (such as the Soluplus).
  • the polymer is selected from polyoxyethylene-polyoxypropylene copolymers (such as the PLURONICS®) and Polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft Co-polymer (such as the Soluplus).
  • the polymer is selected from copovidone, PEG 6000, Polyoxyethylene- polyoxypropylene block copolymer (e.g. Pluronic F68), Isomalt and Polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft Co-polymer (Soluplus). Even more preferably the polymer is copovidone.
  • the polymer is selected from PEG 6000, Polyoxyethylene-polyoxypropylene block copolymer (e.g. Pluronic F68), Isomalt and Polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft Co-polymer (Soluplus).
  • the polymer is selected from HPMCAS, Polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft Co-polymer (Soluplus), HPMC or copovidone. Even more preferably the polymer is copovidone.
  • the polymer is selected from Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Co-polymer (Soluplus) or copovidone.
  • the polymer comprises copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the polymer consists essentially of copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :1 0. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the polymer consists of copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5. In another embodiment, the polymer is copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the solid dispersion or solid solution comprises compound (I) and copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the solid dispersion or solid solution consists essentially of compound (I) and copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the solid dispersion or solid solution consists of compound (I) and copovidone and the weight ratio of compound (I) to copovidone may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • polymers examples include HPMCAS, carboxymethyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC); microcrystalline cellulose, and mixtures of the polymers mentioned; or mixtures of the polymers mentioned with polymers listed above.
  • the polymers may be selected from carboxymethyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC); microcrystalline cellulose, and mixtures of the polymers mentioned; or mixtures of the polymers mentioned with polymers listed above.
  • CMC carboxymethyl cellulose
  • HPC hydroxypropyl cellulose
  • natural gum can be used as the polymer, e.g. gum traganth, alginates, gum Arabic and gum guar.
  • the pharmaceutically acceptable excipient is a non-polymeric compound which preferably contains polar side groups.
  • examples include sugar alcohols and sugars.
  • sugar alcohols are glycerol, xylitol, sorbitol, mannitol, isomalt and maltitol.
  • sugars are aldoses, such as glucose and galactose, ketoses such as fructose, acetales, such as saccarose and trehalose, and hemiacetales, such as maltose and lactose.
  • the pharmaceutically acceptable excipients include substances which behave like polymers, in particular semisolid excipients. Examples of these are fats and waxes.
  • Waxes suitable for use in the present invention include cetyl palmitate, carnauba wax or bees' wax. It is likewise possible to use fats, such as glycerol fatty acid esters (e.g. glycerol palmitate, glycerol behenate, glycerollaurate, glycerol stearate), PEG glycerol fatty acid esters or vegetable oils or hydrogenated vegetable oils. Further examples are glycerol, stearyl alcohol, salts of fatty acids (e.g. aluminium monostearate).
  • semisolid excipients are PEG 400, poly(oxy-1 ,2-ethanediyl) (Solutol HS 15), poloxamer 407 (Pluronic F127), macrogolglycerolhydroxystearat 40 (Cremophor RH 40), ceteareth - 6 and stearyl alcohol (Cremophor A6), lauroyl macrogol-32 glycerides (Gelucire 44/14), stearoyi macrogol-32 glycerides (Gelucire 50/13) and macrogol-20-glycerolmono-stearat (Tagat S2).
  • the type and quantity of the excipient should be selected such that the resulting matrix or solid solution has a glass transition temperature (Tg) of 20 °C or higher, preferably of 25 °C or higher.
  • the ratio of compound (I) to pharmaceutically acceptable excipient is not particularly limited. The ratio can be adjusted to obtain the desired dilution effect or to allow for the solubility of the active substance in the suitable excipient.
  • the weight ratio of compound (I) to excipient may be in the range of 1 :1 to 1 :1 ,000. Preferred ranges are for example 1 :1 to 1 :500, 1 :1 to 1 :150, 1 :1 to 1 :100, 1 :10 to 1 :50, and in particular about 1 :50. In one embodiment, the ratio is about 1 :1 . All of the above-mentioned upper and lower limits can also be combined with each other in order to form additional preferred ranges.
  • the weight ratio of compound (I) to excipient may be in the range of 1 :1 to 1 :10. Preferred ranges are for example 1 :2 to 1 :8, 1 :3 to 1 :6 and 1 :3 to 1 :5. A preferred ratio is about 1 :5.
  • the solid solution or solid dispersion is comminuted, for example by crushing, milling, grinding etc. Comminuting can be carried out by any known method in the art.
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 1 ⁇ .
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 800 nm.
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 500 nm.
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 300 nm.
  • the solid solution or solid dispersion contains substantially no particles, in particular no particles of compound (I), having a particle size of more than 300 nm, based on the total weight of the active ingredient present in the solid solution or solid dispersion.
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 200 nm.
  • the solid solution or solid dispersion contains 15% by weight or less of particles of compound (I) with a particle size of more than 100 nm.
  • particle size may refer to particle diameter.
  • the particle size may be determined by means of confocal Raman spectroscopy. For example, pressed disks can be made of the samples, and a mapping measurement can be performed on the surface of the samples along a quadratic raster of 15 x 15 points, spaced by 2 ⁇ in both directions. The measurements can be performed with a INTEGRA-Spectra Nanofinder of the company NT-MDT or a Senterra Raman microscope (Bruker Optics) at 785 nm (100 mW) using a 50x objective (laser beam diameter approx. 2 ⁇ ).
  • the solid solution is a "single-phase" solid solution.
  • the solid solution is defined by reference to a common glass transition point of the excipient and the active ingredient. This can be determined by means of DSC.
  • the present invention relates to a process for preparing a solid solution or solid dispersion comprising compound (I) comprising spray drying compound (I), together with at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipients may be selected from any of the embodiments described above.
  • the present invention relates to a process for preparing a solid solution or solid dispersion of compound (I) comprising freeze drying compound (I), together with at least one pharmaceutically acceptable excipient.
  • the process comprises the steps of:
  • step (i) i. dissolving compound (I) and at least one pharmaceutically acceptable excipient, preferably a polymer as described above, in a solvent; and ii. freeze drying the solution provided in step (i).
  • the process comprises the steps of:
  • step (i) i. dissolving compound (I) and at least one pharmaceutically acceptable excipient, preferably a polymer as described above, in a solvent; and ii. spray drying the solution provided in step (i).
  • the starting form of compound (I) which is dissolved with excipient can be any form of compound (I).
  • the starting form of compound (I) is crystalline Form B.
  • the starting form of compound (I) is Form B with a purity of 90% or more; more preferably 95% or more; most preferably 99% or more.
  • Form B may be characterised by XRPD peaks located at 10.1 , 13.5, 20.7, 22.5, 24.7 and 26.9 degrees 2theta.
  • Form B may be further characterised by XRPD peaks located at 10.1 , 12.4, 13.5, 15.7, 16.3, 18.1 , 20.7, 22.5, 24.7, 26.2, 26.9, and 29.1 degrees 2theta.
  • the XRPD of Form B is provided in Figure 4.
  • Form B can be prepared according to the procedure of WO2000/025777, which is incorporated herein by reference.
  • the solvent is selected from water, alcohol (e.g. methanol, ethanol, isopropanol, butanol, pentanol), dimethyl sulphoxide (DMSO), acetone, ethyl acetate, heptane, dichloromethane or mixtures thereof.
  • alcohol e.g. methanol, ethanol, isopropanol, butanol, pentanol
  • DMSO dimethyl sulphoxide
  • acetone ethyl acetate
  • heptane heptane
  • dichloromethane dichloromethane or mixtures thereof.
  • the solvent is selected from water, dimethyl sulphoxide (DMSO), acetone, ethyl acetate, heptane, dichloromethane or mixtures thereof.
  • DMSO dimethyl sulphoxide
  • acetone ethyl acetate
  • heptane heptane
  • dichloromethane dichloromethane
  • the solvent is selected from water, dimethyl sulphoxide (DMSO), acetone, ethyl acetate, heptane or mixtures thereof.
  • DMSO dimethyl sulphoxide
  • the solvent is selected from water, dimethyl sulphoxide (DMSO), and heptane or mixtures thereof.
  • the solvent comprises a hydrocarbon solvent, such as hexane or heptane.
  • the solvent comprises heptane.
  • the solvent is selected from a methanol/dichloromethane mixture.
  • the volume ratio of methanokdichloromethane is 1 :1 to 1 :99 (v/v), more preferably the ratio is in the range of 1 :50 (v/v), more preferably the ratio is in the range of 1 :10 (v/v), more preferably the ratio is in the range of 1 :5 (v/v).
  • the inlet temperature in spray drying step (ii) is between about 60 °C to about 200 °C, preferably between about 60 °C to about 160 ⁇ ⁇ .
  • the inlet temperature in spray drying step (ii) is between about 101 °C to about 200 °C, preferably between about 121 °C to about 160 °C, more preferably between about 130 °C to about 160 °C.
  • the spray rate in spray drying step (ii) is about 7% to about 20%, preferably the spray rate is about 16%.
  • the aspirator in spray drying step (ii) runs at about 80% to about 100%.
  • the spray-drying may be carried out in a spray tower.
  • a Buchi B-290 is suitable (Buchi Labortechnik GmbH, Germany).
  • Spray-drying has the advantage of being a continuous method, which enhances the reproducibility and hence also the homogeneity and uniformity of content of active agent.
  • step (ii) are preferably selected such that the resulting particles have a volume-average particle diameter (D 50 ) of 1 to 250 ⁇ , more preferably 2 to 150 ⁇ , especially 3 to 100 ⁇ .
  • D 50 volume-average particle diameter
  • step (ii) are preferably selected such that the resulting particles have a volume-average particle diameter (D 50 ) of 51 to 250 ⁇ , more preferably 51 to 150 ⁇ , especially 51 to 100 ⁇ .
  • D 50 volume-average particle diameter
  • volume-average particle diameter relates in the context of this invention to the D 50 value of the volume average particle diameter determined by means of laser diffractometry.
  • a Malvern Instruments Mastersizer 2000 may be used to determine the diameter (wet measurement with ultrasound for 5 min., 2,500 rpm, the evaluation using the Fraunhofer method, and preferably using sun flower oil as dispersant).
  • the average particle diameter which is also referred to as the D 50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50 % by volume of the particles have a smaller diameter than the diameter which corresponds to the D 50 value. Similarly, 50 % by volume of the particles then have a larger diameter than the D 50 value.
  • the process may further comprise comminuting the solid solution or solid dispersion resulting from step (ii).
  • Comminuting can be carried out by any suitable technique known in the art, for instance crushing, milling or grinding.
  • the process comprises the following steps:
  • step (b) freeze drying or spray drying the solution provided in step (a); and .
  • the process consists essentially of the following steps:
  • step (b) freeze drying or spray drying the solution provided in step (a); and .
  • the process consists of the following steps:
  • step (b) freeze drying or spray drying the solution provided in step (a); and .
  • the present invention relates to a solid solution or solid dispersion comprising compound (I) obtainable by any of the processes described above.
  • the present invention relates to a melt consisting essentially of compound (I).
  • the melt consists essentially of amorphous compound (I).
  • the present invention relates to a melt consisting of compound (I).
  • the melt consists of amorphous compound (I).
  • the melt of compound (I) is substantially free of any crystalline forms. In another embodiment, the melt of compound (I) contains 20% or less of any crystalline form, preferably 10% or less, more preferably 5% or less, more preferably 2% or less, more preferably 1 % or less.
  • the melt is comminuted, for example by crushing, milling or grinding etc.
  • Comminuting can be carried out by any known method in the art.
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 1 ⁇ .
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 800 nm.
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 500 nm.
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 300 nm.
  • the melt contains substantially no particles, in particular no particles of compound (I), having a particle size of more than 300 nm, based on the total weight of the active ingredient present in the melt.
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 200 nm.
  • the melt contains 15% by weight or less of particles of compound (I) with a particle size of more than 100 nm.
  • the particle size may be determined by means of confocal Raman spectroscopy using an INTEGRA-Spectra Nanofinder of the company NT-MDT.
  • the present invention relates to a process for preparing a melt consisting essentially of compound (I) comprising melting compound (I).
  • the process of the sixth aspect is for preparing a melt consisting essentially amorphous compound (I).
  • the present invention relates a process for preparing a melt consisting of compound (I) comprising melting compound (I).
  • the process of the sixth aspect is for preparing a melt consisting of amorphous compound (I).
  • the starting form of compound (I) which is melted can be any form of compound (I).
  • the starting form of compound (I) is crystalline Form B.
  • the starting form of compound (I) is Form B with a purity of 90% or more; more preferably 95% or more; most preferably 99% or more.
  • Form B may be characterised by XRPD peaks located at 10.1 , 13.5, 20.7, 22.5, 24.7 and 26.9 degrees 2theta.
  • Form B may be further characterised by XRPD peaks located at 10.1 , 12.4, 13.5, 15.7, 16.3, 18.1 , 20.7, 22.5, 24.7, 26.2, 26.9, and 29.1 degrees 2theta.
  • the XRPD of Form B is provided in Figure 4.
  • Form B can be prepared according to the procedure of WO2000/025777, which is incorporated herein by reference.
  • compound (I) is heated to a temperature of between about 150°C and about 200 °C, preferably a temperature of between about 160°C and about ⁇ ⁇ ' ⁇ , more preferably a temperature of between about 165°C and about ⁇ ⁇ ' ⁇ , more preferably a temperature of between about 165°C and about M5 °C, more preferably a temperature of about 170 ⁇ ⁇ .
  • the process further comprises cooling the melt of compound (I).
  • the melt may be cooled by allowing it to cool passively to room temperature.
  • the melt can be left to cool to room temperature by standing open to atmosphere.
  • the melt may be left to cool to room temperature under an inert atmosphere, such as a nitrogen or argon blanket.
  • the melt is cooled actively.
  • the melt may be quenched cooled. Quench cooling may take place by immersing the vessel that the melt is in a water bath.
  • the melt may be cooled by exposing it to a stream of air or inert gas, such as nitrogen or argon.
  • the process may further comprise comminuting the melt.
  • Comminuting can be carried out by any suitable technique known in the art, for instance crushing, milling or grinding.
  • the process may further comprise extrusion of the melt. Extrusion can be carried out using any technique known in the art.
  • suitable techniques include those described in "Pharmaceutical Extrusion Technology" by Isaac Ghebre-Sellassie, Charles Martin, ISBN 0824740505, Informa Healthcare Verlag, 2003, the content of which is incorporated herein by reference.
  • the process comprises the following steps:
  • the process consists essentially of the following steps:
  • the process consists of the following steps:
  • pure refers to compound (I) which has a purity of 99% or more as determined by UV-HPLC.
  • Essentially pure refers to compound (I) which has a purity of 95% or more as determined by UV-HPLC.
  • the present invention relates to a melt obtainable by any of the processes described above.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a solid solution or solid dispersion according to the invention, or a melt according to the invention, and a pharmaceutically acceptable excipient.
  • Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermal ⁇ , buccally, or nasally.
  • Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups, and suspensions.
  • Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration, suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle.
  • the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery, there are provided suitable aerosol delivery systems known in the art.
  • compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
  • Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and die.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the die.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • flavouring agents and flavour enhancers make the dosage form more palatable to the patient.
  • Common flavouring agents and flavour enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be dried using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention the active ingredient and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin, and, optionally, contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient and severity of the condition.
  • the dosages below are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
  • compositions (or component parts thereof) of the present invention may be administered orally.
  • the compositions (or component parts thereof) of the present invention may be administered by direct injection.
  • the compositions (or component parts thereof) of the present invention may be administered topically.
  • the compositions (or component parts thereof) of the present invention may be administered by inhalation.
  • the compositions (or component parts thereof) of the present invention may also be administered by one or more of: parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular or transdermal administration means, and are formulated for such administration.
  • the pharmaceutical composition of the present invention may be administered in accordance with a regimen of 1 to 10 times per day, such as once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • administered also includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
  • the pharmaceutical composition of the present invention may be administered by one or more of the following routes: oral administration, injection (such as direct injection), topical, inhalation, parenteral administration, mucosal administration, intramuscular administration, intravenous administration, subcutaneous administration, intraocular administration or transdermal administration.
  • oral administration such as direct injection
  • parenteral administration such as topical, inhalation
  • mucosal administration intramuscular administration, intravenous administration, subcutaneous administration, intraocular administration or transdermal administration.
  • the present invention relates to a method of treating or preventing a disease or disorder ameliorated by the inhibition of TNF-[alpha] production, wherein the method comprises administering a therapeutically or prophylactically effective amount of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the disease or disorder ameliorated by the inhibition of TNF-[alpha] production is selected from psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's Disease; prurigo nodularis; lichen planus; complex apthosis; Behcet's Disease; lupus; hepatitis; uveitis; Sjogren's Disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B cell lymphoma; polymysoitis; dermatomyositis; constituiuon body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and pyoderma gangrenosum.
  • the ninth aspect relates to a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment of any of following: psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's Disease; prurigo nodularis; lichen planus; complex apthosis; Behcet's Disease; lupus; hepatitis; uveitis; Sjogren's Disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B cell lymphoma; polymysoitis; dermatomyositis; constituiuon body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and pyoderma gangrenosum
  • the ninth aspect relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of any of following: psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's Disease; prurigo nodularis; lichen planus; complex apthosis; Behcet's Disease; lupus; hepatitis; uveitis; Sjogren's Disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B cell lymphoma; polymysoitis; dermatomyositis; constituiuon body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and p
  • the present invention relates to a method of treating or preventing a disease or disorder ameliorated by the inhibition of PDE4, wherein the method comprises administering a therapeutically or prophylactically effective amount of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the disease or disorder ameliorated by the inhibition of PDE4 is selected from HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythrematosus; erythema nodosum leprosum in leprosy; radiation damage; asthma;
  • the tenth aspect relates to a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment of any of following: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lup
  • the tenth aspect relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of any of following: HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple
  • the present invention relates to a method of treating or preventing a cancer, wherein the method comprises administering a therapeutically or prophylactically effective amount of an amorphous form of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention.
  • the eleventh aspect relates to a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention for use in the treatment of cancer.
  • the eleventh aspect relates to the use of a solid solution or solid dispersion according to the invention, a melt according to the invention, or a pharmaceutical composition according to the invention in the preparation of a medicament for the treatment of cancer.
  • the cancer is selected from multiple myeloma, malignant melanoma, malignant glioma, leukaemia and a solid tumour.
  • XPRD patterns were generated on a Bruker-AXS D8 Advance powder X-ray diffractometer (Bruker-AXS, Düsseldorf, Germany), equipped with a Vantec-1 detector (3 ° opening angle). The sample holder was rotated in a plane parallel to its surface at 20 rpm during measurement. The measurement conditions were as follows: Radiation: Cu K-alpha, Source 38 kV / 40 mA, divergence slit (variable V6, antiscattering slit 5.59 mm, detector slit 10.28 mm, start angle 2 °, end angle 55°, Step 0.016 ° 2 ⁇ ).
  • DSC measurements were performed using a Mettler Toledo DSC 1 apparatus. The work was performed at a heating rate of 1 to 20 °C/min, preferably 5 to 15°C/min, and at a cooling rate of 5 to 25 °C/min, preferably 10 to 20 °C/min.
  • TGA measurements may be performed on a suitable instrument (e.g. a SEIKO Instrument) in a nitrogen atmosphere and platinum pans.
  • the temperature range may be 30 °C to 600 °C at a rate of between 10°C/min.
  • Dissolution conditions were 900 ml. buffer and 0.5% SDS, 37°C, 100 rpm paddle (USP app.ll).
  • the preparation of the buffers employed is provided below:
  • pH 4.5 (50 mM) buffer weigh about 29.9 g of CH 3 COONa x 3H 2 0 into a 10 litre vessel. Fill up with purified water to 10kg. Adjust the pH with CH 3 COOH to 4.5.
  • pH 6.8 (50 mM) buffer weigh 68.05 g of KH 2 P0 4 x H 2 0 and 9.6 g of NaOH pellets into a 10 litre vessel. Fill up with purified water to 10kg. Adjust the pH with NaOH or H 3 P0 4 to 6.8.
  • An oil bath with silicon oil was heated to 170 - 175 °C 175 °C, a PT100 temperature sensor was placed into the oil bath to regulate and control its temperature.
  • a 250 mL 3-necked round bottomed flask was tare weighed and Apremilast (10.03 g) was weighed into it.
  • the flask was evaporated and vented with inert gas (Ar) three times and evacuated again (100 mbar).
  • the flask was immersed into the thermo-regulated bath, while the bath was stirred slowly.
  • a temperature sensor in the inner of the flask reached 167°C, when the solid powder becomes coalescent. A greenish-lemon coloured melt had been formed at this temperature after 15 min, and little bubbles are expelled. When the bubbling had come to an end after 5- 10 minutes a clear melt had been obtained.
  • the flask was taken from heating bath, and immersed to cold water bath at 15°C. Immediately the melt becomes a solid and brittle glass. The flask with the residual glass had been weighed, a net weight of 9.9622 g was found. The brittle glass was broken from the inner walls of the flask by means of a spatula and transferred to a mortar of agate. The glass was finely ground to obtain a nearly white, light green shining powder (recovery 99.6%). A weight loss of 0.71 % (LOD) was calculated.
  • a solid solution or solid dispersion according to any preceding paragraph comprising/ essentially consisting of/ consisting of a pharmaceutically acceptable excipient selected from the group consisting of a polymer, a saccharide, an oligosaccharide, a polysaccharide, a sugar alcohol, a lipid, and a wax.
  • Ts softening point
  • Tg glass transition temperature
  • polymer is vinylpyrrolidone vinylacetate copolymer (VP/VAc copolymer, copovidone), PEG 6000, Polyoxyethylene-polyoxypropylene block copolymer (e.g. Pluronic F68), Isomalt and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Copolymer (Soluplus), preferably the polymer is copovidone.
  • VP/VAc copolymer, copovidone polyoxyethylene-polyoxypropylene block copolymer
  • Pluronic F68 Polyoxyethylene-polyoxypropylene block copolymer
  • Isomalt and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Copolymer (Soluplus)
  • the polymer is copovidone.
  • Compound (I) A process for preparing a solid solution or solid dispersion comprising compound (I) comprising freeze drying compound (I), together with at least one pharmaceutically acceptable excipient.
  • Ts softening point
  • Tg glass transition temperature
  • MC methyl cellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HEMC hydroxyethyl methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC hydroxypropyl methyl cellulose phthalate
  • HPMCP hydroxypropyl methyl cellulose acetate
  • HPMCA hydroxypropyl methyl cellulose acetate succinate
  • HPCAS hydroxypropyl cellulose acetate succinate
  • HPCAS hydroxyethyl cellulose acetate succinate
  • HECAS hydroxyethyl methyl cellulose succinate
  • HEMCAS hydroxyethyl methyl cellulose acetate succinate
  • CMC carboxyethyl cellulose
  • CEC carboxymethyl ethyl cellulose
  • CMEC hydroxypropyl methyl cellulose acetate phthalate
  • HPMCAP hydroxypropyl methyl cellulose acetate trimellitate
  • HPCAT polyvinyl alcohol
  • PVP polyvinyl pyrrolidone
  • PVAC polyvinyl acetate
  • PVAC vinylpyrrolidon vinylacetat copolymer
  • VP/VAc copolymer such as Copovidon Kollidon
  • polymer is vinylpyrrolidone vinylacetate copolymer (VP/VAc copolymer, copovidone), PEG 6000, Polyoxyethylene-polyoxypropylene block copolymer (e.g. Pluronic F68), Isomalt and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Co-polymer (Soluplus), preferably the polymer is copovidone.
  • VP/VAc copolymer, copovidone polyoxyethylene-polyoxypropylene block copolymer
  • Pluronic F68 Polyoxyethylene-polyoxypropylene block copolymer
  • Isomalt and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft Co-polymer (Soluplus)
  • the polymer is copovidone.
  • a process according to any preceding paragraph comprising the steps of:
  • step (i) spray drying or freeze drying the solution provided in step (i).
  • the solvent is selected from water, alcohol (e.g. methanol, ethanol, isopropanol, butanol, pentanol), dimethyl sulphoxide (DMSO), acetone, ethyl acetate, heptane, dichloromethane or mixtures thereof.
  • alcohol e.g. methanol, ethanol, isopropanol, butanol, pentanol
  • DMSO dimethyl sulphoxide
  • acetone ethyl acetate
  • heptane heptane
  • dichloromethane dichloromethane or mixtures thereof.
  • the inlet temperature in step (ii) is between about 60 °C to about 160 °C.
  • step (ii) is about 7% to about 20%, preferably the spray rate is about 16%.
  • a solid solution or solid dispersion comprising compound (I) obtainable by a process according to any one of paragraphs 12 to 29.
  • a process for preparing a melt consisting of compound (I) comprising melting compound (I).
  • Compound (I) A process according to any one of paragraphs 34 and 35 wherein compound (I) is heated to a temperature of between about 150°C and about 200 °C, preferably a temperature of between about ⁇ ⁇ ' ⁇ and about ⁇ ⁇ ' ⁇ , more preferably a temperature of between about 165°C and about 185°C, more preferably a temperature of between about 165°C and about 175°C, more preferably a temperature of about M0 °C. 37.
  • a process according to any one of paragraphs 34 to 36 further comprising cooling the melt of compound (I).
  • a melt obtainable by a process according to any one of paragraphs 34 to 43.
  • a pharmaceutical composition comprising a solid solution or solid dispersion according to any one of paragraphs 1 to 1 1 and 30, or a melt according to any one of paragraphs 31 to 33 and 44, and a pharmaceutically acceptable excipient.
  • a method of treating or preventing a disease or disorder ameliorated by the inhibition of TNF-[alpha] production comprises administering a therapeutically or prophylactically effective amount of a solid solution or solid dispersion according to any one of paragraphs 1 to 1 1 and 30, or a melt according to any one of paragraphs 31 to 34 and 44, or a pharmaceutical composition according to paragraph 45.
  • the disease or disorder is selected from psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's Disease; prurigo nodularis; lichen planus; complex apthosis; Behcet's Disease; lupus; hepatitis; uveitis; Sjogren's Disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B cell lymphoma; polymysoitis; dermatomyositis; consistiuon body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and pyoderma gangrenosum.
  • the disease or disorder is selected from HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythrematosus; erythema nodosum leprosum in leprosy; radiation damage; asthma; and hyperoxic al
  • a method of treating or preventing a cancer comprising administering a therapeutically or prophylactically effective amount of an amorphous form of a solid solution or solid dispersion according to any one of paragraphs 1 to 1 1 and 30, or a melt according to any one of paragraphs 31 to 34 and 44, or a pharmaceutical composition according to paragraph 45.
  • the method of paragraph 50 wherein the cancer is selected from multiple myeloma, malignant melanoma, malignant glioma, leukemia and a solid tumor.
  • the disease or disorder is selected from psoriasis; psoriatic arthritis; rheumatoid arthritis; chronic cutaneous sarcoid; giant cell arteritis; Parkinson's Disease; prurigo nodularis; lichen planus; complex apthosis; Behcet's Disease; lupus; hepatitis; uveitis; Sjogren's Disease; depression; interstitial cystitis; vulvodynia; prostatitis; osteoarthritis; diffuse large B cell lymphoma; polymysoitis; dermatomyositis; constituiuon body myositis; erosive osteoarthritis; interstitial cystitis; hepatitis; endometriosis; radiculopathy; and pyoderma gangrenosum.
  • the disease or disorder is selected from HIV; hepatitis; adult respiratory distress syndrome; bone resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythrematosus; erythema nodosum leprosum in leprosy; radiation damage; asthma; and hyperoxic al
  • the cancer is selected from multiple myeloma, malignant melanoma, malignant glioma, leukemia and a solid tumor.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des solutions solides ou des dispersions solides comprenant un composé (I) : et leurs procédés de préparation.
PCT/EP2016/076589 2015-11-03 2016-11-03 Composition comprenant de l'aprémilast sous forme aqueuse WO2017076987A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020249505A1 (fr) * 2019-06-13 2020-12-17 Evonik Operations Gmbh Composition pulvérulente comprenant un mélange de copolymères et une cellulose hydrosoluble
EP4183389A1 (fr) 2021-11-18 2023-05-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'aprémilast

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WO2009120167A1 (fr) * 2008-03-27 2009-10-01 Celgene Corporation Formes solides comprenant de la (+)-2-[1-(3-éthoxy-4-méthoxyphényl)-2-méthylsulfonyléthyl]-4-acétylaminoisoindoline-1,3-dione, leurs compositions, et utilisations associées
WO2014204825A1 (fr) * 2013-06-17 2014-12-24 Celgene Corporation Formulations de comprime de (+)-2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
CN104523574A (zh) * 2015-02-08 2015-04-22 长沙佰顺生物科技有限公司 一种阿普斯特固体分散体及其制备方法
CN104546831A (zh) * 2014-12-30 2015-04-29 杭州新博思生物医药有限公司 一种含阿普斯特的药物组合物
US20150283249A1 (en) * 2014-04-04 2015-10-08 Cadila Healthcare Limited Amorphous form of apremilast
WO2016135755A1 (fr) * 2015-02-27 2016-09-01 Mylan Laboratories Limited Aprémilast amorphe, pré-mélanges correspondant et nouvelles formes cristallines d'aprémilast

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WO2009120167A1 (fr) * 2008-03-27 2009-10-01 Celgene Corporation Formes solides comprenant de la (+)-2-[1-(3-éthoxy-4-méthoxyphényl)-2-méthylsulfonyléthyl]-4-acétylaminoisoindoline-1,3-dione, leurs compositions, et utilisations associées
WO2014204825A1 (fr) * 2013-06-17 2014-12-24 Celgene Corporation Formulations de comprime de (+)-2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US20150283249A1 (en) * 2014-04-04 2015-10-08 Cadila Healthcare Limited Amorphous form of apremilast
CN104546831A (zh) * 2014-12-30 2015-04-29 杭州新博思生物医药有限公司 一种含阿普斯特的药物组合物
CN104523574A (zh) * 2015-02-08 2015-04-22 长沙佰顺生物科技有限公司 一种阿普斯特固体分散体及其制备方法
WO2016135755A1 (fr) * 2015-02-27 2016-09-01 Mylan Laboratories Limited Aprémilast amorphe, pré-mélanges correspondant et nouvelles formes cristallines d'aprémilast

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020249505A1 (fr) * 2019-06-13 2020-12-17 Evonik Operations Gmbh Composition pulvérulente comprenant un mélange de copolymères et une cellulose hydrosoluble
CN113950321A (zh) * 2019-06-13 2022-01-18 赢创运营有限公司 包含共聚物混合物和水溶性纤维素的粉末组合物
EP4183389A1 (fr) 2021-11-18 2023-05-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'aprémilast
WO2023089101A1 (fr) 2021-11-18 2023-05-25 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant de l'aprémilast

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