Compositions of multiple aripiprazole prodrugs

Patent metadata

Field	Value
Publication number	US-10159671-B2
Application number	US-201715435170-A
Country	US
Kind code	B2
Filing date	Feb 16, 2017
Priority date	Feb 17, 2016
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

Described herein is a composition comprising: (a) a first population of particles of a first aripiprazole prodrug; and (b) a second population of particles of a second aripiprazole prodrug, different to the first aripiprazole prodrug. At least one of the first and second prodrug populations has a volume based particle size (Dv50) of less than about 1000 nm. Also described herein are methods of treatment using the aforementioned composition, and methods of making the aforementioned composition.

First claim

What is claimed is:

1. A composition comprising:
(a) a first population of particles of a first aripiprazole prodrug, said first population of prodrug particles having at least one surface stabilizer adsorbed on the surface thereof, and
(b) a second population of particles of a second aripiprazole prodrug, said second population of prodrug particles having at least one surface stabilizer adsorbed on the surface thereof,
wherein said first and second aripiprazole prodrug each have the formula:

where n is zero or an integer from 1 to 20, and the first aripiprazole prodrug has a different value for n to that of the second aripiprazole prodrug, and
wherein at least one of the first and second populations of particles has a volume based particle size (Dv50) of less than about 1000 nm.

2. The composition of claim 1 , wherein the first and second population of particles are provided in a relative amount such that the ratio of the weight of the first prodrug to the weight of the second prodrug is between 1:3 and 3:1.

3. The composition of claim 1 , wherein the first and second population of particles are provided in a relative amount such that the ratio of the weight of the first prodrug to the weight of the second prodrug is between 1:1 and 1:4.

4. The composition of claim 1 , wherein the n value for the first aripiprazole prodrug is equal to 4.

5. The composition of claim 1 , wherein the n value for the second aripiprazole prodrug is equal to 10.

6. The composition of claim 1 , wherein the n value for the first aripiprazole prodrug is equal to 4 and the n value for the second aripiprazole prodrug is equal to 10.

7. The composition of claim 1 , wherein the volume based particle distribution size (Dv50) of the first and second population of aripiprazole prodrug particles is between about 50 nm and about 700 nm.

8. The composition of claim 1 , wherein the volume based particle distribution size (Dv50) of the first population of aripiprazole prodrug particles is between about 175 nm and about 350 nm.

9. The composition of claim 1 , wherein the volume based particle size (Dv50) of the first aripiprazole prodrug is between abut 100 and about 300 nm and the volume based particle size of the second aripiprazole prodrug population is between about 200 and about 700 nm.

10. The composition of claim 1 , wherein the at least one surface stabilizer is selected from the group consisting of: a polyoxyethylene sorbitan fatty acid ester, low molecular weight povidones, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, dioctyl sodium sulfosuccinate (or docusate sodium), methyl and propyl parabens, sorbitan monolaurate, carboxymethyl cellulose, hydroxypropylcellulose, sodium deoxycholate, akylsaccharides, difunctional block copolymers, gelatin, albumin, lysozyme, cyclodextrins, gel forming polymers, a polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycols.

11. The composition of claim 1 , wherein the at least one surface stabilizer is selected from the group consisting of polyoxyethylene sorbitan monolaurate, a polyoxyethylene-polyoxypropylene block copolymer having an average molecular weight of about 8,400 and the polyethylene glycol PEG4000.

12. The composition of claim 1 , wherein the ratio of the first and second prodrug to surface stabilizer is within the range from about 0.1:1 to about 40:1.

13. The composition of claim 1 , further comprising a dispersion medium in which the first aripiprazole prodrug population of particles and the second aripiprazole prodrug population of particles is dispersed.

14. The composition of claim 1 , wherein the composition is provided in an injection device selected from the group consisting of a pre-filled syringe, an auto-injector, a needleless syringe and a dual chambered syringe.

15. A method of treating a condition in a mammal comprising administering to a mammal in need the composition of claim 1 , wherein the condition is selected from the group consisting of schizophrenia, bipolar I disorder, major depressive disorder (MDD), autistic disorder, and agitation associated with schizophrenia or bipolar I disorder,
wherein the composition of claim 1 has a first population of particles of a first aripiprazole prodrug and a second population of particles having a second aripiprazole prodrug, wherein at least one of the populations has a volume based particle size (Dv50) of less than about 1000 nm.

16. A method for preparing a composition according to claim 1 , the method comprising the following steps:
(a) calculating a quantity of at least one stabilizer to be added to the composition,
(b) producing a first population of aripiprazole prodrug particles having a volume based particle size (Dv50) of less than about 1000 nm,
(c) producing a second population of a second aripiprazole prodrug, different to the first aripiprazole prodrug, having a volume based particle size (Dv50) of greater or less than about 1000 nm, and
(d) combining a quantity of at least one surface stabilizer with the first and second populations of aripiprazole prodrug particles, such that the at least one surface stabilizer is adsorbed to the surface of the particles of the first and second particle populations.

17. A composition comprising:
a mixture of: (i) a population of particles of a first aripiprazole prodrug; and (ii) a population of particles of a second aripiprazole prodrug, wherein the ratio of the first aripiprazole prodrug to the second aripiprazole prodrug is between about 1:99 and 99:1, and wherein at least one of the first and/or second population of particles has a volume based particle size (Dv50) of less than about 1000 nm, and wherein said first and second aripiprazole prodrug have the formula:

wherein n is zero or an integer less than 20.

18. The composition of claim 17 , wherein in the first aripiprazole prodrug formula n is equal to 4 and in the second aripiprazole prodrug formula n is equal to 10.

19. The composition of claim 17 , wherein the volume based particle distribution size (Dv50) of the first and second population of aripiprazole prodrug particles is between about 50 and about 700 nm.

20. The composition of claim 19 , wherein the volume based particle distribution size (Dv50) of the first and second population of aripiprazole prodrug particles is between about 175 nm and about 350 nm.

21. The composition of claim 17 , wherein the volume based particle size (Dv50) of the first aripiprazole prodrug is between about 100 and about 300 nm and the Dv50 of the second aripiprazole prodrug population is between about 200 and about 700 nm.

22. The composition of claim 17 , wherein said mixture of first and second aripiprazole prodrugs further comprises at least one surface stabilizer.

23. The composition of claim 22 , wherein the at least one surface stabilizer is selected from the group consisting of a polyoxyethylene sorbitan fatty acid ester, low molecular weight povidones, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, dioctyl sodium sulfosuccinate (or docusate sodium), methyl and propyl parabens, sorbitan monolaurate, carboxymethyl cellulose, hydroxypropylcellulose, sodium deoxycholate, akylsaccharides, difunctional block copolymers, d-alpha tocopheryl polyethylene

Assignees

• Alkermes Pharma Ireland Ltd

Inventors

• Zeidan Tarek A
• Manser David
• Perkin Kristopher
• Cresswell Philip
• Hickey Magali
• Steinberg Brian

Classifications

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title

• A61K9/14

  Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} · CPC title

• A61K9/145

  with organic compounds · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title