Spray-dried compositions comprising cgrp receptor antagonists

Abstract

According to the invention, there is provided a pharmaceutically-acceptable composition in the form of a solid, amorphous, mono-particulate powder comprising a mixture of: (a) a pharmacologically-effective dosage amount of a small molecule CGRP receptor antagonist, or a pharmaceutically-acceptable salt thereof; and (b) a pharmaceutically-acceptable carrier material, which carrier material comprises a maltodextrin with a dextrose equivalent (DE) that is above 15. Compositions are suitable for, for example, transmucosal drug delivery, including nasal delivery, by which said compositions may be loaded into a single-use nasal applicator. Compositions are preferably made by way of spray drying and may further include a disaccharide, such as lactose or trehalose which, along with the active ingredient and maltodextrin, which may be spray-dried together in combination. Compositions may further comprise one or more alkyl saccharides. Preferred alkyl saccharides include sucrose esters, such as sucrose monolaurate. Preferred CGRP receptor antagonists include the gepants, such as ubrogepant, atogepant, rimegepant and zavegepant. The compositions are thus particularly useful in the treatment of migraine related conditions.

Description

Abstract According to the present invention, a pharmaceutically acceptable composition is provided in the form of a solid amorphous single-particle powder comprising a mixture of: (a) a pharmacologically effective dose of a small molecule CGRP receptor antagonist or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier material comprising maltodextrin with a glucose equivalent (DE) greater than 15. The composition is suitable for, for example, mucosal drug delivery, including nasal delivery, wherein the composition can be loaded into a single-use nasal applicator via nasal delivery. The composition is preferably prepared by spray drying and may further comprise disaccharides, such as lactose or trehalose, which may be spray-dried together with the active ingredient and maltodextrin. The composition may further comprise one or more alkyl sugars. Preferred alkyl sugars include sucrose esters, such as sucrose monolaurate. Preferred CGRP receptor antagonists include gibberellic acid, such as ubugigpa, atogigpa, remegipa, and zavigipa. Therefore, the composition is particularly useful for treating migraine-related conditions.

Claims

Claims 1. A pharmaceutically-acceptable composition in the form of a solid, amorphous, mono-particulate powder comprising a mixture of: (a) a pharmacologically-effective dosage amount of a small molecule calcitonin gene-related peptide receptor antagonist, or a pharmaceutically-acceptable salt thereof; and (b) a pharmaceutically-acceptable carrier material, which carrier material comprises a maltodextrin with a dextrose equivalent (DE) that is above 15.

2. A composition as claimed in Claim 1, wherein the carrier material further comprises a disaccharide, selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose and lactose.

3. A composition as claimed in Claim 2, wherein the disaccharide comprises lactose and / or trehalose.

4. A composition as claimed in Claim 2 or Claim 3, wherein the carrier material comprises a combination of lactose and maltodextrin 19DE.

5. A composition as claimed in any one of Claims 2 to 4, wherein the ratio of disaccharide:maltodextrin by weight, based on the total weight of the composition, is in the range of about 10:1 to about 1:

8.

6. A composition as claimed in any one of the preceding claims, wherein the lowest measurable glass transition temperature of the composition is at least about 35ºC when measured at a relative humidity of up to about 35%.

7. A composition as claimed in any one of the preceding claims, wherein the composition further comprises a sucrose ester.

8. A composition as claimed in Claim 7, wherein the sucrose ester comprises sucrose monolaurate.

9. A composition as claimed in any one of the preceding claims which is suitable and / or adapted for nasal delivery.

10. A composition as claimed in Claim 9, wherein the particle size distribution includes a D10 that is above about 3 μm, above about 5 μm or above about 10 μm.

11. A composition as claimed in Claims 9 or Claim 10, wherein the powder has a particle size distribution that includes a volume-based mean diameter within the range of DERXW^^^^NjP^DQG^DERXW^^^^^NjP^ 12. A composition as claimed in any one of Claims 9 to 11, wherein the particle size distribution includes a D90 that is below about 500 μm, below about 200 μm, or below about 100 μm.

13. A composition as claimed in any one of the preceding claims wherein the pharmacologically-effective dosage amount of the small molecule calcitonin gene- related peptide receptor antagonist or salt thereof is between about 5 mg and about 150 mg.

14. A composition as claimed in any one of the preceding claims, wherein the small molecule calcitonin gene-related peptide receptor antagonist is selected from ubrogepant, atogepant, rimegepant and zavegepant.

15. A composition as claimed in Claim 14, wherein the small molecule calcitonin gene- related peptide receptor antagonist is rimegepant.

16. A composition as claimed in Claim 14, wherein the small molecule calcitonin gene- related peptide receptor antagonist is zavegepant.

17. A process for the manufacturing of a composition as defined in any one of the preceding claims, wherein said process comprises the steps of: i) mixing together the small molecule calcitonin gene-related peptide receptor antagonist or pharmaceutically-acceptable salt thereof and the pharmaceutically-acceptable carrier material, in an appropriate volatile solvent, ii) spray-drying the mixture from step i).

18. A composition obtainable by a process as defined in Claim 17.

19. A nasal applicator device suitable and / or adapted for delivery of a composition as defined in any one of Claims 1 to 16 or 18 to the nose, which comprises, or is adjunct and / or attached to, a reservoir, within which reservoir said composition is contained.

20. The nasal applicator as claimed in Claim 19, which is configured such that said device, upon actuation, is capable of depositing said pharmacologically-effective dosage amount of the small molecule calcitonin gene-related peptide receptor antagonist, or a pharmaceutically-acceptable salt thereof, to the nasal mucosa.

21. A process for the manufacturing of an applicator device as claimed in Claim 19 or Claim 20, which comprises a process as claimed in Claim 17 followed by loading the composition so formed into a reservoir within, or adjunct or attached to, said applicator device.

22. A container that substantially prevents ingress of atmospheric water by comprising thermoformed plastics and / or molecular sieves with a pore size of 3Å or 4Å, which container contains, or is capable of receiving, a nasal applicator device as defined in Claim 19 or Claim 20.

23. The container as claimed in Claim 22, which comprises a material selected from the group: heat-sealed aluminium pouches and thermoformed plastics and / or a desiccant selected from the group: silica gel and molecular sieves with a pore size of 3Å or 4Å.

24. A composition as defined in any one of Claims 1 to 16 or 18 for use in the treatment of a migraine related condition.

25. The use of a composition as defined in any one of Claims 1 to 16 or 18 for the manufacture of a medicament for the treatment of a migraine related condition.

26. A method of treatment of a migraine related condition, which method comprises the administration of a composition as defined in any one of Claims 1 to 16 or 18 to a patient suffering from, or susceptible to, said condition.

27. A composition for use as claimed in Claim 24, a use as claimed in Claim 25, or a method as claimed in Claim 26, wherein the migraine related condition comprises acute migraine, episodic migraine or chronic migraine, each or which may be with or without aura.

28. A composition for use, as use, or a method, as claimed in Claim 27, wherein the composition is administered to the nose by way of an applicator as defined in Claim 19 or Claim 20.

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