WO2025003437A1 - Composition pharmaceutique comprenant un sel d'acide fumarique de (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine - Google Patents

Composition pharmaceutique comprenant un sel d'acide fumarique de (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine Download PDF

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Publication number
WO2025003437A1
WO2025003437A1 PCT/EP2024/068305 EP2024068305W WO2025003437A1 WO 2025003437 A1 WO2025003437 A1 WO 2025003437A1 EP 2024068305 W EP2024068305 W EP 2024068305W WO 2025003437 A1 WO2025003437 A1 WO 2025003437A1
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Prior art keywords
disorder
pharmaceutical composition
disease
tablet
formula
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Clas Sonesson
John CROALL
Richard Bell
Nicola PETERS
Matthew Ling
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Integrative Research Laboratories Sweden AB
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Integrative Research Laboratories Sweden AB
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Priority to EP24737952.2A priority Critical patent/EP4734984A1/fr
Priority to CN202480041747.3A priority patent/CN121511083A/zh
Publication of WO2025003437A1 publication Critical patent/WO2025003437A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a fumaric acid salt of the compound (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine.
  • the present disclosure also relates to a method for preparing the pharmaceutical composition and uses thereof. Further, the present disclosure relates to an oral medicinal capsule or tablet prepared from the pharmaceutical composition.
  • the compound (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine is a pharmaceutical drug being developed for the treatment of Parkinson 's disease. In particular, it is being developed for preventing impaired balance and falls in patients suffering from Parkinson 's disease.
  • WO 2010/058018 discloses 3-phenyl-3-methoxy derivatives useful for modulating extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders.
  • the compound 3-(2,3-difluorophenyl)-3- methoxypyrrolidine is disclosed in the form of a racemate, and as the corresponding (+)- and (-)-enantiomers, respectively.
  • the racemate is disclosed in its non-salt form (Preparation 19) and in the form of a hydrochloric acid salt (Example 12).
  • the two enantiomers are disclosed in the non-salt form as well as in the form of an oxalic acid salt (Examples 5 and 7, respectively). Tablet and capsule formulations for oral administration are described.
  • WO 2018/211080 Al discloses the fumaric acid salt of compound (+)-3-(2,3- difluorophenyl)-3-methoxypyrrolidine, a method for preparation thereof as well as uses thereof. It is described that the fumaric acid salt of compound (+)-3-(2,3- difluorophenyl)-3-methoxypyrrolidine may be a combination of fumaric acid and (+)- 3-(2,3-difluorophenyl)-3-methoxypyrrolidine in a ratio of 1: 1, which exhibits properties of high crystallinity, not being hygroscopic, not changing in its crystalline phase at any tested relative humidity, high melting point and/or aqueous solubility profile.
  • One of the most common dosage forms is solid oral dosage forms such as oral medicinal capsules or tablets due to inter alia the ease of manufacturing, packaging, transportation and accurate dosing.
  • the capsules or tablets should therefore have an acceptable size and/or shape for all strengths of the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • a specific amount of the excipient(s) may be required.
  • an increase of the amount of API will be accompanied by a decrease of the amount of excipient(s) so that there is a risk for a decrease of the characteristics provided by excipient(s).
  • capsules or tablets of the same size and/or shape but with varying amounts of API and excipient(s) may have different characteristics with respect to e.g. hardness and disintegration time to an extent that may result in a different and possibly undesired experience for the patient being treated.
  • an object of the present disclosure to overcome or at least mitigate some of the problems described herein. Further, it is an object of the present disclosure to provide an oral dosage form such as an oral medicinal capsule or tablet in a single size and/or shape comprising the fumaric acid salt of compound (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine suitable for varying amounts of API. Moreover, it is an object of the present disclosure to provide aspects and/or advantages not provided by hitherto known technique.
  • Figure 1A shows the compact tensile strength as a function of the ejected solid fraction for compositions comprising the salt of Formula II and microcrystalline cellulose in an amount from 20 wt% to 60 wt%.
  • Figure IB shows the compact tensile strength as a function of the ejected solid fraction for compositions comprising the salt of Formula II and a 1 : 1 mixture of microcrystalline cellulose and Lactose in an amount from 20 wt% to 60 wt%.
  • Figure 1C shows the compact tensile strength as a function of the ejected solid fraction for compositions comprising the salt of Formula II and a 3: 1 ratio of microcrystalline cellulose and anhydrous calcium phosphate in an amount from 20 wt% to 60 wt%.
  • Figure 2 shows the tablet hardness as a function of compression force for compositions comprising the salt of Formula II and microcrystalline cellulose of grade PH102 and PH105, respectively.
  • Figure 3 shows tablet hardness as a function of compression force for tablets comprising 30.86 wt% of the salt of Formula II.
  • composition for an oral medicinal capsule or tablet comprising:
  • Formula II said salt being a combination of a compound of Formula I and fumaric acid:
  • a diluent comprising or consisting of microcrystalline cellulose and optionally a further diluent
  • a method for preparing the pharmaceutical composition as described herein comprising the steps of: a) co-milling the salt of Formula II and the microcrystalline cellulose optionally followed by sieving thereby providing a first mixture, b) optionally adding a disintegrant to the first mixture optionally followed by mixing and/or sieving thereby providing a second mixture, c) optionally adding a lubricant to the second mixture optionally followed by mixing thereby providing a third mixture, d) forming the mixture from step a), b) or c) into granules, and e) optionally adding a flow aid to the granules.
  • compositions as described herein, or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for use as a medicament.
  • a pharmaceutical composition as described herein, or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for use in the treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in
  • a pharmaceutical composition as described herein, or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for the manufacture of a medicament for use in the treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders,
  • a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, movement disorder, Parkinson's disease, Parkinsonism, parkinsonia
  • compositions for an oral medicinal capsule or tablet comprising:
  • Formula II said salt being a combination of a compound of Formula I and fumaric acid:
  • a diluent comprising or consisting of microcrystalline cellulose and optionally a further diluent
  • the granules and the flow aid agent may be present as a mixture such as a homogenous or a heterogenous mixture.
  • the flow aid agent is adsorbed onto and/or absorbed into the granules.
  • the salt of Formula II may be present in the pharmaceutical composition in an amount within the range of from about 10 wt% to about 40 wt%, such as from about 20 wt% to about 40 wt%, based on the total weight of (i) and, if present, (ii).
  • the salt of Formula II may be present in an amount of about 20 wt% based on the total weight of (i) and, if present, (ii).
  • the salt of Formula II may be present in an amount of about 30 wt% based on the total weight of (i) and, if present, (ii).
  • the salt of Formula II may be present in an amount of about 40 wt% based on the total weight of (i) and, if present, (ii).
  • the diluent comprises or consists of microcrystalline cellulose.
  • the microcrystalline cellulose may have a mean particle size from about 10 micrometers to about 150 micrometers, such as from about 20 micrometers to about 100 micrometers. In an example, the microcrystalline cellulose may have a mean particle size of about 20 micrometers or about 100 micrometers.
  • the diluent may also comprise a further diluent which may comprise or consist of phosphate, such as anhydrous phosphate, such as dicalcium phosphate, such as anhydrous dicalcium phosphate.
  • the granules contain no further microcrystalline cellulose in addition to that provided by the diluent.
  • the diluent may be present as balance such as balance in the granules.
  • the diluent may be added in an amount to reach the intended total weight of the granule(s).
  • granule(s) comprising 30 wt% of the salt of Formula II, 2 wt% of a disintegrant and 0.5 wt% of a lubricant may include an amount of 67.5 wt% of the diluent as balance.
  • the granules may comprise a disintegrant or be free from a disintegrant.
  • the disintegrant may be one or more of the following: crospovidone, croscarmellose sodium, sodium starch glycolate.
  • the diluent may comprise or consist of sodium starch glycolate. The presence of a disintegrant may help achieving a desired time for disintegration in the dosage form where the granules are included.
  • the dosage form may be a capsule or tablet as described herein.
  • the disintegrant may be present in an amount within the range of from about 0.5 wt% to about 5 wt%, such as about 3 wt%, based on the total weight of (i) and, if present, (ii).
  • the disintegrant may be present in an amount of about 1 wt%, about 2 wt%, about 3 wt% or about 4 wt% such as about 2 wt% or about 4 wt% based on the total weight of (i) and, if present, (ii).
  • the disintegrant may be present in an amount of about 2 wt% or 4 wt% based on the total weight of (i) and, if present, (ii).
  • the lubricant may comprise or consist of one or more of the following: magnesium stearate, talc, stearic acid.
  • the lubricant may comprise or consist of magnesium stearate.
  • the presence of a lubricant may improve the flowability of the powder blend and/or prevent the powder from sticking during transfer between equipment and during tabletting.
  • the lubricant may be present in an amount within the range of from about 0.5 wt% to about 2 wt%, such as about 0.5 wt%, based on the total weight of (i) and, if present, (ii).
  • the granules may be free from lubricant.
  • the pharmaceutical composition may comprise a flow aid such as magnesium stearate in order to improve the flowability of the resulting composition.
  • the flow aid may be present in an amount within the range of from about 0.5 wt% to about 1 wt%, such as about 0.5 wt%, based on the total weight of (i) and, if present, (ii).
  • the pharmaceutical composition may be free from flow aid.
  • the pharmaceutical composition exhibits good flowability properties and does so for varying amounts of the salt of Formula II such as amounts varying from 10 wt% to 40 wt% such as from 20 wt% to 40 wt% based on the total weight of (i) and, if present, (ii).
  • the pharmaceutical composition has been found to allow for producing oral medicinal capsules and tablets of the same size for dosages of the salt of Formula II varying from about 10 wt% to about 40 wt%, such as from 20 wt% to about 40 wt%, based on the total weight of the oral medicinal capsules and tablets.
  • an oral medicinal capsule or an oral medicinal tablet such as a caplet comprising the pharmaceutical composition.
  • the oral medicinal tablet may have an oblong shape, i.e. it may be a caplet.
  • the oral medicinal tablet such as a caplet or the oral medicinal capsule may have a size measuring about 17.5 mm x about 8.5 mm x 5 mm.
  • the capsule may comprise a pharmaceutically acceptable material such as gelatin or hydroxypropyl methyl cellulose.
  • the oral medicinal tablet may be prepared by compressing the pharmaceutical composition into a tablet which may subsequently be provided with a coating.
  • the pharmaceutical composition may be prepared by forming granules comprising the salt of Formula II, optionally a disintegrant and/or a lubricant which may subsequently be mixed with a flow aid.
  • a method for preparing a pharmaceutical composition as described herein comprising the steps of: a) co-milling the salt of Formula II and the microcrystalline cellulose and optionally the further diluent optionally followed by sieving thereby providing a first mixture, b) optionally adding a disintegrant to the first mixture optionally followed by mixing and/or sieving thereby providing a second mixture, c) adding a lubricant to the second mixture optionally followed by mixing thereby providing a third mixture, d) forming the third mixture into granules, and e) optionally adding a flow aid to the granules.
  • step a) of the method comprises co-milling the salt of Formula II and the microcrystalline cellulose and the further diluent as described herein optionally followed by sieving thereby providing a first mixture.
  • the method may further comprise a further step f): f) filling an oral medicinal capsule with the granules or compressing the capsules into an oral medicinal tablet.
  • 5% or less such as from 1% to 5%, such as 2% or 4% of the microcrystalline cellulose
  • a disintegrant changes the compressibility and/or flowability of the first, second or third mixture by 10% or less, such as by 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. This is advantageous as it allows for adjusting the composition as desired without negatively impacting the compressibility and/or flowability.
  • the compressibility and/or flowability may be measured using a Carr index:
  • the first mixture, second mixture and/or third mixture of the method described herein may have a Carr index from about 20 to about 30, such as from about 20 to about 25 or from about 25 to about 30. These values provide acceptable compressibility and/or flowability.
  • compositions as described herein or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for use as a medicament.
  • a pharmaceutical composition as described herein, or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for use in the treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains
  • a pharmaceutical composition as described herein, or an oral medicinal capsule or a medicinal tablet comprising the pharmaceutical composition for the manufacture of a medicament for use in the treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders
  • a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson 's disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, movement disorder, Parkinson's disease, Parkinsonism, parkinsonia
  • terapéuticaally effective amount refers to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • the term prevention includes references to the prophylaxis of (and, similarly, preventing) the disease or disorder (and vice-versa).
  • the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
  • the disease, disorder and/or condition described herein may be Parkinson 's disease dementia, behavioural and/or psychological symptoms of dementia.
  • the disease, disorder and/or condition described herein comprises a movement disorder such as impaired balance.
  • the oral medicinal capsule or tablet described herein may be administered to a patient such as a human from 1 to 3 times daily, such as 3 times daily.
  • the medicinal capsule or tablet is administered to a patient once or twice daily.
  • the oral medicinal capsule or a medicinal tablet may be administered to a patient to provide a dosage of 100 mg based on the compound of Formula I, or a dosage of 200 mg based on the compound of Formula I.
  • a dosage of 100 mg based on the compound of Formula I may be administered by providing an oral medicinal tablet comprising about 20 wt% of the salt of Formula II.
  • the present disclosure also provides the following aspects.
  • a pharmaceutical composition for an oral medicinal capsule or tablet comprising:
  • Formula II said salt being a combination of a compound of Formula I and fumaric acid: in a ratio of 1: 1, said salt being present in an amount within the range of from 10 wt% to 40 wt% based on the total weight of (i) and, if present, (ii),
  • composition according to aspect 1 or 2 wherein the microcrystalline cellulose is present as balance.
  • composition according to any one of aspects 1-3, wherein the disintegrant is one or more of the following: crospovidone, croscarmellose sodium, sodium starch glycolate.
  • composition according to any one of the preceding aspects, wherein the disintegrant is present in an amount within the range of from 0.5 wt% to 5 wt%, such as 3 wt%, based on the total weight of (i) and, if present, (ii).
  • lubricant comprises one or more of the following: magnesium stearate, talc, stearic acid.
  • composition according to any one of the preceding aspects, wherein the lubricant is present in an amount within the range of from 0.5 wt% to 2 wt%, such as 0.5 wt%, based on the total weight of (i) and, if present, (ii).
  • composition according to any one of the preceding aspects, wherein the flow aid is present in an amount within the range of from 0.5 wt% to 1 wt%, such as 0.5 wt%, based on the total weight of (i) and, if present, optionally (ii).
  • An oral medicinal capsule or an oral medicinal tablet such as a caplet comprising the pharmaceutical composition according to any one of aspects 1-9.
  • a method for preparing the pharmaceutical composition according to any one of aspects 1-9 comprising the steps of: a) co-milling the salt of Formula II and the microcrystalline cellulose optionally followed by sieving thereby providing a first mixture, b) optionally adding a disintegrant to the first mixture optionally followed by mixing and/or sieving thereby providing a second mixture, c) optionally adding a lubricant to the second mixture optionally followed by mixing thereby providing a third mixture, d) forming the mixture from step a), b) or c) into granules, and e) optionally adding a flow aid to the granules.
  • the oral medicinal capsule or a medicinal tablet according to aspect 10 which is administered to a patient from 1 to 3 times daily such as 3 times daily.
  • the salt of Formula II was prepared as described in WO 2018/211080 Al.
  • the salt of Formula II was crystalline, had a melting point of 163 °C and was not hygroscopic.
  • the properties of the salt of Formula II were examined in order to find out if it was suitable for use in the preparation of tablets and capsules. To this end particles of the salt of Formula II having a size from about 10 pm to about 100 pm were subjected to SEM. It was observed that the particles had a ruler like plate morphology which is likely to result in poor flow properties.
  • the salt of Formula II was tested in amounts of 20 wt%, 40 wt% and 60 wt% based on the total weight of the composition.
  • Three filling materials were tested, namely (i) microcrystalline cellulose (grade PH102), (ii) a 1 : 1 mixture of microcrystalline cellulose (grade PH102) and Lactose (grade FastFlo Lactose) and (iii) a 3: 1 ratio of microcrystalline cellulose (grade PH102) and anhydrous calcium phosphate.
  • Starch glycolate was selected as disintegrant.
  • Magnesium stearate was selected as lubricant.
  • the salt of Formula II was screened through a 500 pm sieve.
  • the sieved salt of Formula II was then blended with the filler(s) and disintegrant for 10 minutes using a mixer from Turbula TC2 followed by addition of magnesium stearate and further blending for 3 minutes at 34 rpm.
  • the resulting compositions are shown in Table 2.
  • compositions were granulated using a compaction simulator from Merlin Powder Characterisation Ltd. A profile was selected to mimic Gerteis Minipactor (Roller Diameter 250 mm) at a roll speed of 2.5 rpm. The output from the simulator was an assessment of how the tensile strength of the ribbons varied with the porosity. As used herein, the solid fraction is the bulk density divided by the absolute density.
  • the compact tensile strength and ejected solid fraction for each composition is shown in Figures 1A-C.
  • the tensile strength should reach the criterion of a pressure of 2 MPa such as equal to or approximately 2 MPa at a solid fraction of 0.8.
  • the compositions of Examples 3A and 3B comprising microcrystalline cellulose at loadings of 20 wt% and 40 wt% met the above criterion.
  • the compositions of Examples 3G and 3H comprising microcrystalline cellulose and anhydrous dicalcium phosphate at loadings of 20 wt% and 40 wt% met the above criterion.
  • Example 4 Flowability of a powder comprising the salt of Formula II
  • a powder comprising the salt of Formula II had suitable flowability for manufacturing of a pharmaceutical capsule or tablet.
  • the fillers were microcrystalline cellulose and a combination of microcrystalline cellulose and anhydrous dicalcium phosphate, respectively.
  • Crospovidone i.e. water insoluble cross-linked polyvinylpyrrolidine, was added as disintegrant.
  • Magnesium stearate was added as lubricant.
  • the compositions were prepared by blending all excipients except for magnesium stearate at 34 rpm for 10 minutes. The magnesium stearate was then added followed by blending at 34 rpm for 3 minutes.
  • the flow properties were determined using a jolting volumeter at 0, 10, 500 and 1250 taps.
  • the Carr index (which may also be denominated Carr's index) was calculated and used for assessing the flowability. As used herein, the Carr index is calculated using equation 1 :
  • pl250 is the freely settled bulk density and p0 is the tapped bulk density.
  • a Carr index from 20 to 30 is considered acceptable.
  • a Carr index from 20 to 25 is considered acceptable.
  • Table 4 shows the Carr index for the two compositions.
  • Example 4A had a Carr index of 32.5 while the composition of Example 4B had a Carr index of 33.3.
  • both compositions had a Carr index that was considered too high for allowing consistent filling of a die with a fixed volume with the same amount of powder each time.
  • the manufacturing of the granules and tablets was as follows. Batches were manufactured at 20 g scale. The salt of Formula II was screened through a 500 mm sieve prior to use. Intragranular materials with the exception of the magnesium stearate were blended together at 34 rpm for 10 minutes using a Turbula C2 blender. The intragranular magnesium stearate was then added and blended for 3 minutes at 34 rpm. Roller compaction of the intragranular blend was performed on a Vector TFC- lab roller compactor at a roll pressure of 10 kN/cm, roll speed of 2.0 rpm and a screw feeder of 30 rpm.
  • Table 6 show that all tablets had an acceptable disintegration time. As used herein, an acceptable disintegration time is 15 minutes or less. Further, Table 6 shows that the using a filler comprising microcrystalline cellulose and anhydrous dibasic calcium phosphate increased the disintegration time compared to using a filler consisting of microcrystalline cellulose only.
  • Example 6 Flowability of tablettabilitv blends
  • compositions comprising granules and extragranular material, i.e. tablettability blends.
  • the compositions were as shown in Table 7. Table 7
  • Compositions 6A-6D were prepared as follows.
  • the salt of Formula II was sieved through a 500 mm sieve.
  • the thus sieved salt of Formula II, filler(s) and sodium starch glycolate were blended for 10 minutes at 34 rpm using a Turbula TC2 blender.
  • Intragranular magnesium stearate was then added and blending continued for 3 minutes at 34 rpm.
  • the resulting intragranular blends were then slugged on a Riva minipress fitted with 16 mm round normal concave tooling. Compression was performed at a thickness allowing to achieve a solid fraction of about 0.75.
  • the resulting compacts were then crushed and passed through a 1 mm screen to form granules.
  • Example 6A and Example 6C in Table 8 show that including dicalcium phosphate in the filler increases the flowability as evidenced by the Carr index.
  • a comparison of Example 6B and Example 6D in Table 8 shows that including dicalcium phosphate in the filler increases the Carr index.
  • a comparison of Example 6A and Example 6B in Table 8 shows that increasing the amount of the salt of Formula II leads to a higher Carr index.
  • a comparison of Example 6C and Example 6D in Table 8 shows that including dicalcium phosphate in the filler increases the Carr index.
  • the Carr index was below 30 which was considered acceptable.
  • a tablettability blend such as a tablettability blend in this example provided an acceptable flowability.
  • the tablet hardness as a function of the grade of microcrystalline cellulose was investigated.
  • the tested blends had the compositions shown in Table 9.
  • the blends were prepared as follows: a) the salt of Formula II was screened through a 500 pm sieve b) the components with the exception of magnesium stearate were blended at 30 rpm for 10 minutes using a Turbula TC2 blender c) the intragranular magnesium stearate was added the blend resulting from step b) and blending was performed during 3 minutes at 34 rpm d) roller compaction took place on a Vector TFC-Lab roller compactor: roll speed 1 rpm, screw feeder speed 40 rpm and roll pressure 12 kNcm 1 e) ribbons obtained in step d) were passed through a granulator fitted with 1 mm screen f) the extragranular magnesium stearate was added to the blend obtained in step e) and blending took place for 3 minutes at 34 rpm g) tablets were prepared on a Riva Minipress using 14 mm tooling with a target weight of 750 mg at a compression speed of approximately 30 r
  • the tested blends had the compositions shown in Table 10.
  • Sodium starch glycolate was used as disintegrant.
  • Magnesium stearate was used as lubricant. Table 10
  • the tested blends were prepared as follows.
  • the salt of Formula II was passed through a 500 pm sieve.
  • the intragranular excipients except for magnesium stearate were blended together at 34 rpm for 10 minutes using a Turbula TC2 mixer.
  • the intragranular magnesium stearate was then added and blended using the same parameters for 3 minutes.
  • Roller compaction with two passes was performed with two passes through a Vector TFC-lab micro at screw feeder speed 40 rpm, roll speed 1.0 and roll pressure 12 kN/cm.
  • Granulation of ribbons was performed through a 1 mm screen.
  • the extragranular magnesium stearate was then added followed by blending at 34 rpm for 3 minutes. Carr Index testing was performed on all blends.
  • Tablets were compressed using a Riva Minipress using (i) 14 mm round normal concave tooling for an amount of the salt of Formula II of 30.86 % w/w, and (ii) 12 mm round normal concave tooling for an amount of the salt of Formula II of 38.58 % w/w.
  • a force versus hardness measurement was performed on each tablet.
  • Disintegration testing was performed on tablets prepared at a hardness (kP) of lx tablet diameter in millimeters in purified water at 37 °C with discs.

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Abstract

L'invention concerne une composition pharmaceutique comprenant un sel de formule II. La composition pharmaceutique comprend des granules et est appropriée pour préparer une capsule ou un comprimé médicinal oral.
PCT/EP2024/068305 2023-06-28 2024-06-28 Composition pharmaceutique comprenant un sel d'acide fumarique de (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine Ceased WO2025003437A1 (fr)

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EP24737952.2A EP4734984A1 (fr) 2023-06-28 2024-06-28 Composition pharmaceutique comprenant un sel d'acide fumarique de (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine
CN202480041747.3A CN121511083A (zh) 2023-06-28 2024-06-28 包含(+)-3-(2,3-二氟苯基)-3-甲氧基吡咯烷的富马酸盐的药物组合物

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058018A1 (fr) 2008-11-24 2010-05-27 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Dérivés de 3-phényl-3-méthoxy-pyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale
WO2018211080A1 (fr) 2017-05-19 2018-11-22 Integrative Research Laboratories Sweden Ab (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine ou ses sels pharmaceutiquement acceptables, son procédé de préparation et ses utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058018A1 (fr) 2008-11-24 2010-05-27 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Dérivés de 3-phényl-3-méthoxy-pyrrolidine en tant que modulateurs de la neurotransmission catécholaminergique corticale
WO2018211080A1 (fr) 2017-05-19 2018-11-22 Integrative Research Laboratories Sweden Ab (+)-3-(2,3-difluorophényl)-3-méthoxypyrrolidine ou ses sels pharmaceutiquement acceptables, son procédé de préparation et ses utilisations

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, vol. 10, no. 12, 12 June 2021 (2021-06-12), pages 1485 - 1494
HJORTH S. ET AL: "(3 S )-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 374, no. 3, September 2020 (2020-09-01), US, pages 404 - 419, XP093102672, ISSN: 0022-3565, DOI: 10.1124/jpet.120.000037 *
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 374, no. 3, 1 September 2020 (2020-09-01), pages 404 - 419
REIN-HEDIN ERIK ET AL: "First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Pirepemat, a Cortical Enhancer, in Healthy Volunteers", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, vol. 10, no. 12, 12 June 2021 (2021-06-12), GB, pages 1485 - 1494, XP093102322, ISSN: 2160-763X, DOI: 10.1002/cpdd.959 *

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