Pharmaceutical composition for nasal delivery
According to the invention, there is provided a solid pharmaceutical composition formulation for nasal delivery of an opioid antagonist, comprising a pharmacologically-effective amount of an opioid antagonist and a pharmaceutically-acceptable carrier. The compositions are preferably in the form of a powder produced by spray-drying, which are subsequently loaded into single use nasal applicators. Preferred pharmaceutically-acceptable carriers in this regard include disaccharides (e.g. lactose or trehalose) and dextrins (e.g. cyclodextrins or maltodextrins), preferably spray-dried together in combination. Compositions may further comprise an alkyl saccharide, preferably a sucrose ester, such as sucrose monolaurate. The compositions and applicators may be employed in the treatment of opioid overdose in subjects.
1. A solid pharmaceutical composition in the form of a spray-dried powder comprising:
a pharmacologically-effective amount of naloxone or a pharmaceutically-acceptable salt thereof; and
a pharmaceutically-acceptable carrier material comprising a combination of:
(i) a disaccharide selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose, and lactose; and
(ii) a dextrin;
wherein the composition is essentially free of water and is suitable for nasal delivery of naloxone or the pharmaceutically-acceptable salt thereof, and the naloxone or pharmaceutically-acceptable salt thereof is less than about 15% chemically degraded after storage for 3 months at 75% relative humidity and 40° C.
2. The composition as claimed in claim 1 , wherein the lowest measurable glass transition temperature of the composition is at least about 40° C. when measured at a relative humidity of about 35%.
3. The composition as claimed in claim 1 , wherein the particle size distribution of the spray-dried powder includes a Dv(10) that is above about 3 μm.
4. The composition as claimed in claim 1 , wherein the disaccharide comprises lactose and/or trehalose.
5. The composition as claimed in claim 1 , which further comprises an alkyl saccharide.
6. The composition as claimed in claim 5 wherein the alkyl saccharide comprises a sucrose ester.
7. The composition as claimed in claim 6 , wherein the sucrose ester comprises sucrose monolaurate.
8. The composition as claimed in claim 1 , wherein the dextrin comprises a cyclodextrin or a maltodextrin.
9. The composition as claimed in claim 1 , wherein the carrier material comprises α-D-lactose monohydrate as the disaccharide and one or more of 2-hydroxypropyl-β-cyclodextrin and/or maltodextrin 12DE as the dextrin.
10. The composition as claimed in claim 1 , wherein the dextrin comprises a maltodextrin.
11. The composition as claimed in claim 10 , wherein the carrier material comprises α-D-lactose as the disaccharide, and a maltodextrin.
12. The composition as claimed in claim 1 , wherein the disaccharide is present in an amount of between about 10% and about 30% by weight based on the total weight of the composition.
13. The composition as claimed in claim 1 , wherein the ratio of disaccharide:dextrin is between about 10:1 and about 1:10 by weight based on the total weight of the composition.
14. The composition as claimed in claim 1 , wherein the powder has a particle size distribution that includes a volume-based mean diameter within the range of about 10 μm and about 100 μm.
15. A process for the manufacturing of a pharmaceutical composition as defined in claim 1 , wherein said process comprises the steps of:
(a) mixing together in a volatile solvent, naloxone, or a pharmaceutically-acceptable salts thereof, and pharmaceutically-acceptable carrier materials comprise a combination of:
and
(b) spray-drying the mixture from step (a) to form the pharmaceutical composition comprising spray-dried particles.
16. A composition obtainable by the process as defined in claim 15 .
17. A nasal applicator device suitable and/or adapted for delivery of the pharmaceutical composition as defined in claim 1 to the nose, which comprises, or is adjunct and/or attached to, a reservoir, within which reservoir said composition is contained.
18. A process for the manufacturing of the applicator device as claimed in claim 17 , the process comprising the steps of:
i) mixing together naloxone or salt thereof and the pharmaceutically-acceptable carrier materials in a volatile solvent;
ii) spray-drying the mixture from step i) to form the pharmaceutical composition comprising spray-dried particles; and
iii) loading the pharmaceutical composition formed in step ii) into the reservoir within or adjunct or attached to said applicator device.
19. A method of treating opioid overdose, which method comprises administering the composition as defined in claim 1 to a subject in need of such treatment.
20. The method as claimed in claim 19 , wherein the composition is administered to said subject by way of an applicator that comprises, or is adjunct and/or attached to, a reservoir, within which reservoir said composition is contained.
21. The composition as claimed in claim 1 , which comprises less than about 5% of water.
22. The composition as claimed in claim 1 , which comprises less than about 2% of water.
23. The composition as claimed in claim 1 , which comprises less than about 1% of water.
24. The nasal applicator device as claimed in claim 17 , which is packaged within a container that substantially prevents the ingress of atmospheric water under the storage conditions of 75% relative humidity and 40° C.
25. The nasal applicator device as claimed in claim 17 , which is packaged within a container that comprises a material selected from the group of heat-sealed aluminum pouches and thermoformed plastics.
26. A process for the manufacturing of an applicator device as claimed in claim 24 , the process comprising:
i) mixing together naloxone or salt thereof and the pharmaceutically-acceptable carrier materials in a volatile solvent;
ii) spray-drying the mixture from step i) to form the pharmaceutical composition comprising spray-dried particles;
iii) loading the pharmaceutical composition formed in step ii) into the reservoir within or adjunct or attached to said applicator device; and
iv) loading the applicator device from step iii) into the container that substantially prevents the ingress of atmospheric water.
27. A process for the manufacturing of an applicator device as claimed in claim 25 , the process comprising:
i) mixing together naloxone or salt thereof and the pharmaceutically-acceptable carrier materials in a volatile solvent;
ii) spray-drying the mixture from step i) to form the pharmaceutical composition comprising spray-dried particles;
iii) loading the pharmaceutical composition formed in step ii) into the reservoir within or adjunct or attached to said applicator device; and
iv) loading the applicator device from step iii) into the container that comprises a material selected from the group of heat-sealed aluminum pouches and thermoformed plastics.
28. The composition as claimed in claim 1 , wherein the naloxone or pharmaceutically-acceptable salt thereof is less than about 10% chemically degraded after storage for 3 months at 75% relative humidity and 40° C.
29. A nasal applicator device suitable and/or adapted for delivery of the composition as defined in claim 28 to the nose, which comprises, or is adjunct and/or attached to, a reservoir, within which reservoir said composition is contained.
30. The nasal applicator device as claimed in claim 29 , which is packaged within a container that substantially prevents the ingress of atmospheric water under the storage conditions of 75% relative humidity and 40° C.
31. The nasal applicator device as claimed in claim 29 , which is packaged within a container that comprises a material selected from the group of heat-sealed aluminum pouches and thermoformed plastics.
32. The composition as claimed in claim 1 , wherein the naloxone or pharmaceutically-acceptable salt thereof is less than about 5% chemically degraded after storage for 3 months at 75% relative humidity and 40° C.
33. A nasal applicator device suitable and/or adapted for delivery of the composition as defined in claim 32 to the nose, which comprises, or is adjunct and/or attached to, a reservoir, within which reservoir said composition is contained.
34. The nasal applicator device as claimed in claim 33 , which is packaged within a container that substantially prevents the ingress of atmospheric water under the storage conditions of 75% relative humidity and 40° C.
35. The nasal applicator device as claimed in claim 33 , which is packaged within a container that comprises a material selected from the group of heat-sealed aluminum pouches and thermoformed plastics.