CHEMICAL COMPOSITION

• US 20190321310A1
• Filed: 06/15/2017
• Published: 10/24/2019
• Est. Priority Date: 06/16/2016
• Status: Abandoned Application

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University, University of Liverpool
• Inventors: Rannard, Steven Paul, Owen, Andrew, Savage, Alison, Tatham, Lee, Shapiro, Theresa, Bakshi, Rahul P., Mlambo, Godfree, Tripathi, Abhai
• Application Number:
  US16/310,199
• Publication Number:
  US 20190321310A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/08 for Pneumocystis carinii
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A solid composition comprising nanoparticles of atovaquone dispersed within one or more carrier materials, wherein the atovaquone is present in an amount of at least 10 wt %. Also described is an intramuscularly- or subcutaneously-injectable formulation of nanoparticles of atovaquone.

Claims

1. A solid composition comprising nanoparticles of atovaquone dispersed within one or more carrier materials, wherein the atovaquone is present in an amount of at least 10 wt %.

2. A solid composition as claimed in claim 1 wherein the one or more carrier materials provide hydrophilic polymeric and surfactant activity, and are preferably selected from the group consisting of:

polyvinyl alcohol-polyethylene glycol graft copolymer;

polyvinyl alcohol;

polyvinylpyrrolidone k30;

polyoxyethylene (20) sorbitan monolaurate;

polyoxyethylene (20) sorbitan monooleate;

sodium deoxycholate;

D-α

-tocopherol polyethylene glycol 1000 succinate; and

polyethylene glycol (15)-hydroxystearate.

3. A solid composition as claimed in claim 2, wherein the one or more carrier materials are provided in any one or more of the following combinations:

polyvinyl alcohol-polyethylene glycol graft copolymer AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate;

polyvinylpyrrolidone k30 AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate;

polyvinylpyrrolidone k30 AND polyethylene glycol (15)-hydroxystearate;

polyvinyl alcohol AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol AND sodium deoxycholate;

polyvinyl alcohol AND polyethylene glycol (15)-hydroxystearate.

4. A solid composition as claimed in claim 2, wherein the one or more carrier materials are selected from the group consisting of:

polyvinyl alcohol-polyethylene glycol graft copolymer;

polyvinyl alcohol;

polyvinylpyrrolidone k30;

polyoxyethylene (20) sorbitan monolaurate;

polyoxyethylene (20) sorbitan monooleate;

sodium deoxycholate; and

D-α

-tocopherol polyethylene glycol 1000 succinate.

5. A solid composition as claimed in claim 4, wherein the one or more carrier materials are provided in any one or more of the following combinations:

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate;

polyvinylpyrrolidone k30 AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol AND sodium deoxycholate.

6. A solid composition as claimed in any one of claims 1 to 5, wherein the nanoparticles of atovaquone have an average particle size between 100 and 800 nm.

7. A solid composition as claimed in any one of claims 1 to 6, wherein the polydispersity of the nanoparticles of atovaquone is less than or equal to 0.8.

8. A process for preparing a solid composition according to any one of claims 1 to 7, the process comprising:

(i) preparing an oil-in-water emulsion comprising;

an oil phase comprising atovaquone; and

an aqueous phase comprising one or more selected carrier materials, the one or more selected carrier materials being defined in any of claims 2 to 5; and

(ii) removing the oil and water from the oil-in-water emulsion to form the solid composition.

9. A process for preparing a solid composition according to any one of claims 1 to 7, the process comprising:

(i) preparing a single phase solution comprising atovaquone and one or more selected carrier materials, the one or more selected carrier materials being defined in any one of claims 2 to 5, in one or more solvents; and

(ii) remove the one or more solvents to form the solid composition.

10. A process for preparing a solid composition as claimed in claim 8 or claim 9 wherein step (ii) comprises a freeze-drying step.

11. A pharmaceutical or veterinary composition in injectable form comprising a solid composition according to any one of claims 1 to 7, and optionally one or more additional (pharmaceutically acceptable) excipients.

12. A pharmaceutical or veterinary composition as claimed in claim 11 in intramuscularly-injectable and/or subcutaneously-injectable form.

16. A pharmaceutical or veterinary composition as claimed in claim 12, an intramuscularly-injectable formulation as claimed in claim 13 or 15, or a subcutaneously-injectable formulation as claimed in claim 14 or claim 15, in depot form.

17. A pharmaceutical or veterinary composition, an intramuscularly-injectable formulation, or a subcutaneously-injectable formulation, as claimed in claim 16 wherein, when administered to a patient releases atovaquone into the bloodstream of the patient over a period of at least about two weeks from the date of administration.

20. An intramuscularly-injectable formulation or a subcutaneously-injectable formulation as claimed in claim 16 or 17, an aqueous dispersion as claimed in claim 18, or an oily dispersion as claimed in claim 19, wherein the one or more carrier materials provide hydrophilic polymeric and surfactant activity, and are selected from the group consisting of:

polyvinyl alcohol-polyethylene glycol graft copolymer;

polyvinyl alcohol;

polyvinylpyrrolidone k30;

polyoxyethylene (20) sorbitan monolaurate;

polyoxyethylene (20) sorbitan monooleate;

sodium deoxycholate;

D-α

-tocopherol polyethylene glycol 1000 succinate; and

polyethylene glycol (15)-hydroxystearate.

21. An intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, or an oily dispersion, as claimed in claim 20, wherein the one or more carrier materials are provided in any one or more of the following combinations:

polyvinyl alcohol-polyethylene glycol graft copolymer AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monolaurate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyethylene glycol (15)-hydroxystearate;

polyvinylpyrrolidone k30 AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate;

polyvinylpyrrolidone k30 AND polyethylene glycol (15)-hydroxystearate;

polyvinyl alcohol AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol AND sodium deoxycholate;

polyvinyl alcohol AND polyethylene glycol (15)-hydroxystearate.

22. An intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, or an oily dispersion, as claimed in claim 20, wherein the one or more carrier materials are selected from the group consisting of:

polyvinyl alcohol-polyethylene glycol graft copolymer;

polyvinyl alcohol;

polyvinylpyrrolidone k30;

polyoxyethylene (20) sorbitan monolaurate;

polyoxyethylene (20) sorbitan monooleate;

sodium deoxycholate; and

D-α

-tocopherol polyethylene glycol 1000 succinate.

23. An intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, or an oily dispersion, as claimed in claim 22, wherein the one or more carrier materials are provided in any one or more of the following combinations:

polyvinyl alcohol-polyethylene glycol graft copolymer AND polyoxyethylene (20) sorbitan monooleate;

polyvinylpyrrolidone k30 AND D-α

-tocopherol polyethylene glycol 1000 succinate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monolaurate;

polyvinylpyrrolidone k30 AND polyoxyethylene (20) sorbitan monooleate;

polyvinyl alcohol AND sodium deoxycholate.

24. An intramuscularly-injectable formulation or a subcutaneously-injectable formulation as claimed in any one of claims 16 to 23, an aqueous dispersion as claimed in any one of claims 18 or 20 to 23, or an oily dispersion as claimed in any one of claims 19 to 23, wherein each core consists essentially of atovaquone.

25. An intramuscularly-injectable formulation or a subcutaneously-injectable formulation as claimed in any one of claims 16 to 24, an aqueous dispersion as claimed in any one of claims 18 or 20 to 24, or an oily dispersion as claimed in any one of claims 19 to 24, wherein the nanoparticles of atovaquone have an average particle size between 100 and 800 nm.

26. An intramuscularly-injectable formulation or a subcutaneously-injectable formulation as claimed in any one of claims 16 to 25, an aqueous dispersion as claimed in any one of claims 18 or 20 to 25, or an oily dispersion as claimed in any one of claims 19 to 25, wherein the average zeta potential of the nanoparticles of atovaquone when dispersed in an aqueous medium is between −

100 and +100 mV.

27. An intramuscularly-injectable formulation or a subcutaneously-injectable formulation as claimed in any one of claims 16 to 26, an aqueous dispersion as claimed in any one of claims 18 or 20 to 26, or an oily dispersion as claimed in any one of claims 19 to 26, comprising the atovaquone in a concentration of at least 10 mg/mL.

28. A process for preparing an aqueous dispersion according to any one of claims 18 or 20 to 27, comprising dispersing a solid composition according to any one of claims 1 to 7 in an aqueous medium.

29. A process for preparing an oily dispersion according to any one of claims 19 to 27, comprising dispersing a solid composition according to any one of claims 1 to 7 in an oily medium.

33. A solid composition according to any one of claims 1 to 7, a pharmaceutical or veterinary injectable composition according to any one of claims 11, 12, 16, 17, 30, 31 or 32, an intramuscularly-injectable formulation according to any one of claims 13, 15, 16, 17 or 20 to 27, a subcutaneously-injectable formulation according to any one of claims 14 to 17 or 20 to 27, an aqueous dispersion according to any one of claims 18 or 20 to 27, or an oily dispersion according to any one of claims 19 to 27, for use as a medicament.

34. A solid composition, a pharmaceutical or veterinary injectable composition, an intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, and an oily dispersion for use as a medicament as claimed in claim 33, wherein said use is as a monotherapy or, as a combination therapy by combination with any one or more of the following other drugs:

proguanil, mefloquine, chloroquine, hydroxychloroquine, quinine, quinidine, artemether, lumefantrine, primaquine, doxycycline, tetracycline, clindamycin, dihydroartemisinin, piperaquine, and pyrimethamine with or without sulfadoxine.

35. A solid composition according to any one of claims 1 to 7, a pharmaceutical or veterinary injectable composition according to any one of claim 11, 12, 16, 17, 30, 31 or 32, an intramuscularly-injectable formulation according to any one of claims 13, 15, 16, 17 or 20 to 27, a subcutaneously-injectable formulation according to any one of claims 14 to 17 or 20 to 27, an aqueous dispersion according to any one of claims 18 or 20 to 27, or an oily dispersion according to any one of claims 19 to 27, for use in the treatment and/or prevention of parasitic and/or fungal infections.

36. A solid composition, a pharmaceutical or veterinary injectable composition, an intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, and an oily dispersion for use in the treatment and/or prevention of parasitic and/or fungal infections as claimed in claim 35, wherein said use is as a monotherapy or, as a combination therapy by combination with any one or more of the following other drugs:

proguanil, mefloquine, chloroquine, hydroxychloroquine, quinine, quinidine, artemether, lumefantrine, primaquine, doxycycline, tetracycline, clindamycin, dihydroartemisinin, piperaquine, and pyrimethamine with or without sulfadoxine.

37. A solid composition, a pharmaceutical or veterinary injectable composition, an intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, or an oily dispersion, as claimed in claim 35 or claim 36, wherein the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.

38. A solid composition, a pharmaceutical or veterinary injectable composition, an intramuscularly-injectable formulation, a subcutaneously-injectable formulation, an aqueous dispersion, or an oily dispersion, as claimed in claim 37, wherein the parasitic infection is malaria, toxoplasmosis, or babesiosis, or wherein the fungal infection is Pneumocystis pneumonia.

39. A method of treating and/or preventing a parasitic or fungal infection, the method comprising administering a therapeutically effective amount of a solid composition according to any one of claims 1 to 7, a pharmaceutical or veterinary injectable composition according to any one of claim 11, 12, 16, 17, 30, 31 or 32, an intramuscularly-injectable formulation according to any one of claims 13, 15, 16, 17 or 20 to 27, a subcutaneously-injectable formulation according to any one of claims 14 to 17 or 20 to 27, an aqueous dispersion according to any one of claims 18 or 20 to 27, or an oily dispersion according to any one of claims 19 to 27, to a patient suffering from or at risk of suffering from a parasitic or fungal infection.

40. A method as claimed in claim 39, wherein the solid composition, the pharmaceutical or veterinary injectable composition, the intramuscularly-injectable formulation, the subcutaneously-injectable formulation, the aqueous dispersion, and.or the oily dispersion is administered as a monotherapy, or as a combination therapy by combination with any one or more of the following other drugs:

proguanil, mefloquine, chloroquine, hydroxychloroquine, quinine, quinidine, artemether, lumefantrine, primaquine, doxycycline, tetracycline, clindamycin, dihydroartemisinin, piperaquine, and pyrimethamine with or without sulfadoxine.

41. A method as claimed in claim 39 or claim 40 wherein the parasitic infection is caused by parasites of the genus Plasmodium, or by parasites of the genus Toxoplasma, or by parasites of the genus Babesiidae, or wherein the fungal infection is caused by fungus of the genus Pneumocystis.

42. A method as claimed in claim 41, wherein the parasitic infection is malaria, toxoplasmosis, or babesiosis, or wherein the fungal infection is Pneumocystis pneumonia.

43. A method of preventing malaria as claimed in claim 42, wherein the atovaquone is administered by intramuscular injection at a dose of about 200 mg/kg.

44. A method of preventing malaria as claimed in claim 42 or claim 43, wherein the prophylactic effect persists for at least 28 days after administration.

45. A kit for the preparation of a sterile liquid formulation of nanoparticles of atovaquone for injection, the kit comprising:

a first container comprising a solid composition according to any one of claims 1 to 7, a pharmaceutical or veterinary injectable composition according to any one of claim 11, 12, 16, 17, 30, 31 or 32, an intramuscularly-injectable formulation according to any one of claims 13, 15, 16, 17 or 20 to 27, or a subcutaneously-injectable formulation according to any one of claims 14 to 17 or 20 to 27, and

a second container comprising a sterile aqueous or oily diluent in an amount sufficient to dilute the atovaquone to a concentration of at least 10 mg/mL.

46. A kit as claimed in claim 45 wherein the formulation is a depot formulation.

47. A kit as claimed in claim 45 or claim 46 wherein the injection is an intramuscular injection.

48. A kit as claimed in claim 45 or claim 46 wherein the injection is a subcutaneous injection.

13. An intramuscularly-injectable formulation of nanoparticles of atovaquone.

15. An intramuscularly-injectable formulation as claimed in claim 13, or a subcutaneously-injectable formulation as claimed in claim 14, wherein each nanoparticle of atovaquone is a core around which an outer layer composed of one or more carrier materials is provided.

14. A subcutaneously-injectable formulation of nanoparticles of atovaquone.

18. An aqueous dispersion, comprising a plurality of nanoparticles of atovaquone dispersed in an aqueous medium, each nanoparticle of atovaquone being a core around at least some of which an outer layer composed of one or more carrier materials is provided, wherein the atovaquone is present in a concentration of at least 10 mg/mL.

30. A pharmaceutical or veterinary composition in injectable form comprising an aqueous dispersion according to any one of claims 18 or 20 to 27, or an oily dispersion according to any one of claims 19 to 27, and optionally one or more additional (pharmaceutically acceptable) excipients.

31. A pharmaceutical or veterinary composition as claimed in claim 30 in intramuscularly-injectable or subcutaneously-injectable form.

32. A pharmaceutical or veterinary composition as claimed in claim 31 in depot form.

19. An oily dispersion, comprising a plurality of nanoparticles of atovaquone and one or more carrier materials dispersed in an oily medium, wherein the atovaquone is present in a concentration of at least 10 mg/mL