Search

EP-4734984-A1 - A PHARMACEUTICAL COMPOSITION COMPRISING A FUMARIC ACID SALT OF (+)-3-(2,3-DIFLUOROPHENYL)-3-METHOXYPYRROLIDINE

EP4734984A1EP 4734984 A1EP4734984 A1EP 4734984A1EP-4734984-A1

Abstract

The disclosure relates to a pharmaceutical composition comprising a salt of Formula II. The pharmaceutical composition comprises granules and is suitable for preparing an oral medicinal capsule or tablet.

Inventors

  • SONESSON, CLAS
  • CROALL, John
  • BELL, RICHARD
  • PETERS, Nicola
  • LING, MATTHEW

Assignees

  • Integrative Research Laboratories Sweden AB

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A pharmaceutical composition for an oral medicinal capsule or tablet, said pharmaceutical composition comprising: (i) granules, and (ii) optionally a flow aid agent, said granules comprising: (a) a salt of Formula II: Formula II said salt being a combination of a compound of Formula I and fumaric acid: Formula I 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), (b) a diluent comprising microcrystalline cellulose and optionally a further diluent, (c) optionally a disentegrant, and (d) optionally a lubricant.
  2. 2. The pharmaceutical composition according to claim 1, wherein (i) and (ii) are provided as a mixture.
  3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the flow aid agent is adsorbed onto and/or absorbed into the granules.
  4. 4. The pharmaceutical composition according to any one of claims 1-3, wherein the diluent comprises microcrystalline cellulose and a further diluent.
  5. 5. The pharmaceutical composition according to claim 4, wherein the further diluent comprises or consists of phosphate, such as anhydrous phosphate, such as dicalcium phosphate, such as anhydrous dicalcium phosphate.
  6. 6. The pharmaceutical composition according to any one of claims 1-5, wherein the disintegrant is one or more of the following: crospovidone, croscarmellose sodium, sodium starch glycolate.
  7. 7. The pharmaceutical composition according to any one of the preceding claims, 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).
  8. 8. The pharmaceutical composition according to any one of the preceding claims, wherein the lubricant comprises one or more of the following: magnesium stearate, talc, stearic acid.
  9. 9. The pharmaceutical composition according to any one of the preceding claims, 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).
  10. 10. The pharmaceutical composition according to any one of the preceding claims, wherein the flow aid agent comprises or consists of magnesium stearate.
  11. 11. The pharmaceutical composition according to any one of the preceding claims, wherein the flow aid agent 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).
  12. 12. An oral medicinal capsule or an oral medicinal tablet such as a caplet comprising the pharmaceutical composition according to any one of claims 1-11.
  13. 13. A method for preparing the pharmaceutical composition according to any one of claims 1-11, said method comprising the steps of: a) co-milling the salt of Formula II and the diluent comprising microcrystalline cellulose and optionally a 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) 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 agent to the granules.
  14. 14. The method according to claim 13, wherein the diluent in step a) comprises microcrystalline cellulose and a further diluent.
  15. 15. The method according to claim 13 or 14, wherein the further diluent comprises or consists of phosphate, such as anhydrous phosphate, such as dicalcium phosphate, such as anhydrous dicalcium phosphate.
  16. 16. The method according to any one of claims 13-15, further comprising the step of: f) filling an oral medicinal capsule with the granules or compressing the capsules into an oral medicinal tablet.
  17. 17. The method according to any one of claims 13-16, wherein replacement of 33 wt% or less such from 20 wt% to 30 wt% or 25 wt% of the microcrystalline cellulose with the further diluent changes the compressibility and/or flowability of the first, second or third mixture by 10% or less, such as from 1% to 10 % or by 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.
  18. 18. The method according to any one of claims 13-17, wherein replacement of 5% or less, such as from 1% to 5%, such as 2% or 4% of the microcrystalline cellulose with 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%.
  19. 19. The method according to claim 17 or 18, wherein the compressibility and/or flowability is measured using a Carr index: Carr Index = 100 X P 1 p 2 l^250/ 0 wherein pl250 is the freely settled bulk density and p0 is the tapped bulk density.
  20. 20. The method according to any one of claims 13-19, wherein the first, second or third mixture has a Carr index from 20 to 30, such as from 20 to 25 or from 25 to 30.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING A FUMARIC ACID SALT OF (+)-3-(2,3-DIFLUOROPHENYL)-3-METHOXYPYRROLIDINE Technical field The present disclosure relates to 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. Background 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. Clinical Pharmacology in Drug Development, vol. 10, no. 12, 12 June 2021, pages 1485-1494 describes a First-in -Human Study to Assess the Safety, Tolerability, and Pharmacokineteics of Pirepemat, A cortical Enhancer, in healthy Volunteers. It is described that pirepemat (fumarate salt) and placebo were administered as oral capsules. Journal of Pharmacology and Experimental Therapeutics, vol. 374, no. 3, 1 September 2020, pages 404-419 discloses the distinctive pharmacological profile for (3S)-3-(2,3- difluorophenyl)-3-methoxypyrrolidine (IR.L752) and its regioselective central nervous system transmission-enhancing properties. It is stated that the cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IR.L752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. The diseases for which (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine is being developed mainly affect older people. Therefore, it is important that the administration dosage form being chosen is convenient for this patient group in order to avoid misuse or non-adherence to the treatment. 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. Unfortunately, older patients often have problems swallowing capsules or tablets due to e.g dysphagia (i.e. swallowing disorder). In order to facilitate oral intake, the capsules or tablets should therefore have an acceptable size and/or shape for all strengths of the active pharmaceutical ingredient (API). However, in order to achieve the desired characteristics of the dosage form containing the API a specific amount of the excipient(s) may be required. For a capsule or tablet of a specific size and/or shape 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). In other words, 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. Additionally, from a manufacturing and/or dosing point of view it may be desirable to be able to produce capsules or tablets of the same size and/or shape regardless of the amount of active pharmaceutical ingredient (API) being included since, for instance, the same processing equipment may be used. It is an object of the present disclosu