Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2020109365 - PROCÉDÉS DE FABRICATION D'UN ADJUVANT

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS

1. A method of manufacturing a liposomal adjuvant comprising an aminoalkyl glucosaminide phosphate compound (AGP) or a glucopyranosyl lipid adjuvant (GLA) using a microfluidic device, said method comprising the following steps:

(a) mixing in the device a first solution comprising a solvent, an AGP or GLA and a phosphatidylcholine lipid, and a second solution comprising water; and

(b) removing the solvent.

2. The method according to claim 1 comprising the following steps:

(a) mixing in the device a first solution comprising a solvent, an AGP or GLA and a phosphatidylcholine lipid, and a second solution comprising water;

(b) adding a saponin; and

removing the solvent.

3. The method according to claim 1 comprising the following steps:

(a) mixing in the device a first solution comprising a solvent, an AGP or GLA and a phosphatidylcholine lipid, and a second solution comprising water;

(b) removing the solvent; and

(c) adding a saponin.

4. A method of manufacturing a liposomal concentrate of use in the preparation of a liposomal adjuvant comprising an AGP or GLA using a microfluidic device, comprising the step of mixing in the device a first solution comprising a solvent, an AGP or GLA and a phosphatidylcholine lipid, and a second solution comprising water.

5. The method according to claim 1 or 4 wherein the second solution additionally comprises a saponin.

6. The method according to any one of claims 1 to 5 wherein the phosphatidylcholine lipid is DOPC.

7. The method of any one of claims 1 to 6, wherein the average liposome size is 95-120 nm.

8. The method of any one of claims 1 to 7, wherein the liposome polydispersity is 0.3 or lower. 9. A method for the preparation of an adjuvanted immunogenic composition comprising an immunogen or antigen, or a polynucleotide encoding the immunogen or antigen, said method comprising the steps of:

(i) manufacturing a liposomal adjuvant according to the method of any one of claims 1 to

8;

(ii) mixing the liposomal adjuvant with an immunogen or antigen, or a polynucleotide encoding the immunogen or antigen.

10. A method for the manufacture of an adjuvanted immunogenic composition, said method comprising the step of combining an immunogen or antigen, or a polynucleotide encoding the immunogen or antigen, with a liposomal adjuvant manufactured according to the method of any one of claims 1 to 8.

1 1. A liposomal adjuvant comprising an AGP and phosphatidylcholine lipid produced according to the method of any one of claims 1 to 8.

12. The liposomal adjuvant according to claim 1 1 additionally comprising a sterol.

13. The liposomal adjuvant according to either claim 1 1 or 12 additionally comprising a saponin.

14. An adjuvanted immunogenic composition produced according to the method of claim 9 or 10.

15. The adjuvant or immunogenic composition according to any one of claims 1 1 to 14 comprising saponin, such as QS-21 , at an amount of 1-100 ug per human dose.

16. The adjuvant or immunogenic composition according any one of claims 1 1 to 15 comprising an AGP or GLA, at an amount of 1-100 ug per human dose.

17 A solution comprising a solvent, an AGP or GLA and 100-170 mg/ml lipid, wherein the solvent comprises 70-90% v/v ethanol, such as 75-85% v/v ethanol, and 10-30% v/v isopropyl alcohol such as 15-25% v/v isopropanol.

18. The solution of claim 17 which consists essentially of a solvent and 100-160 mg/ml DOPC and 30-40 mg/ml cholesterol, 4-10 mg/ml AGP or GLA, and wherein the solvent comprises 70-90% v/v ethanol and 10-30% v/v isopropyl alcohol.

19. A method for the preparation of a solution comprising a solvent, lipid, cholesterol and AGP, said method comprising the steps:

(i) preparing a suspension of the AGP or GLA in at least a portion of the solvent;

(ii) combining the suspended AGP or GLA with the phosphatidylcholine lipid and cholesterol;

(iii) adding further solvent;

(iv) mixing.

20. A method for the preparation of a solution comprising a solvent, lipid, cholesterol and an AGP or GLA, said method comprising the steps:

(i) preparing a suspension of an AGP or GLA in at least a portion of the solvent;

(ii) combining the suspended AGP or GLA with the phosphatidylcholine lipid and cholesterol;

(iii) adding further solvent;

(iv) mixing;

(v) adding additional solvent.

21. The method for the preparation of a solution comprising a solvent, lipid, cholesterol and an AGP according to claim 19, said method comprising the steps:

(i) preparing a suspension of an AGP or GLA in at least a portion of the solvent;

(ii) combining the suspended AGP or GLA with the DOPC and cholesterol;

(iii) adding further solvent;

(iv) mixing.

22. A method for the preparation of a solution comprising a solvent, lipid, cholesterol and an AGP or GLA according to claim 20, said method comprising the steps:

(i) preparing a suspension of an AGP or GLA in at least a portion of the solvent;

(ii) combining the suspended AGP or GLA with the DOPC and cholesterol;

(iii) adding further solvent;

(iv) mixing;

(v) adding additional solvent.

23. A liposome containing solution obtainable by mixing the first solution and second solution according to the methods of any one of claims 1 to 8 prior to the removal of solvent.

24. The method, adjuvant, composition or solution according to any one of claims 1 to 23, wherein the phosphatidylcholine lipid is selected from dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC) and diarachidoyl phosphatidylcholine (DAPC, dipalmitoleoyl phosphatidylcholine and dioleoyl phosphatidylcholine (DOPC); and mixtures thereof.

25. The method, adjuvant, composition or solution according to any one of claims 1 to 24, wherein the AGP or GLA is an AGP.

26. The method, adjuvant, composition or solution according to any one of claims 1 to 25, wherein the AGP has the following structure:


(Formula 1 )

wherein

m is 0 to 6;

n is 0 to 4;

X is O or S, in particular O;

Y is O or NH;

Z is O or H;

each Ri, R2, R3 is selected independently from the group consisting of a C1-20 acyl and a Ci- 20 alkyl;

R4 is H or methyl;

R5 is selected independently from the group consisting of -H, -OH, -(Ci-C4)alkoxy, -PO3R8R9, -OPO3R8R9, -SO3R8, -OSO3R8, -NRsRg, -SRe, -CN, -NO2, -CHO, -CO2R8, and -CONRsRg, wherein Re and Rg are each independently selected from H and (C1-C4) alkyl; and each R6 and R7 is independently H or PO3H2;

or a pharmaceutically acceptable salt thereof.

27. The method, adjuvant, composition or solution according to any one of claims 1 to 26, wherein the AGP has the following structure:

(Formula 1 a)

wherein X is O or S, in particular O;

n is 0;

Y is O or NH;

Z is O or H;

each Ri, F¾, F¾ is selected independently from the group consisting of a C1-20 acyl and a Ci- 20 alkyl;

Rs is CO2H;

R6 is PO3H2;

R7 is H;

and R4 is H or methyl;

or a pharmaceutically acceptable salt thereof.

28. The method, adjuvant composition or solution according to claims 1 to 27, wherein the AGP is CRX524, CRX527, CRX529, CRX547, CRX526, CRX601 and/or CRX602, or a salt, such as a pharmaceutically acceptable salt thereof.

29. The method, adjuvant composition or solution according to claim 28, wherein the AGP is CRX601 or a salt, such as a pharmaceutically acceptable salt thereof.

30. The method, adjuvant, composition or solution according to any one of claims 1 to 24, wherein the AGP or GLA is a GLA.

31. The method, adjuvant, composition or solution according to any one of claims 1 to 24, wherein the GLA is:

wherein:

R1, R3, R5 and R6 are each independently Cn-2oalkyl; and

R2 and R4 are each independently C-i2-2oalkyl;

and salts, such as pharmaceutically acceptable salts, thereof.

32. The method, adjuvant, composition or solution according to any one of claims 1 to24, wherein the GLA is:


wherein:

R1, R3, R5 and R6 are each independently Cn-2oalkyl; and

R2 and R4 are each independently C-i2-2oalkyl;

and salts, such as pharmaceutically acceptable salts, thereof.

33. The method, adjuvant, composition or solution according to any one of claims 1 to24, wherein the GLA is:

wherein:

R1, R3 and R6 are each independently Cn-2oalkyl; and

R2 and R4 are each independently C-i2-2oalkyl;

and salts, such as pharmaceutically acceptable salts, thereof.

34. The method, adjuvant, composition or solution according to any one of claims 1 to24, wherein the GLA is:


wherein:

R1, R3 and R6 are each independently Cn-2oalkyl; and

R2 and R4 are each independently C-i2-2oalkyl;

and salts, such as pharmaceutically acceptable salts, thereof.

35. The method, adjuvant, composition or solution according to any one of claims 30 to 34, wherein all of R1 to R6 are linear alkyl groups.

36. The method, adjuvant, composition or solution according to any one of claims 30 to 35, wherein each of R1, R3, R5 and R6 is independently selected from CiMsalkyl.

37. The method, adjuvant, composition or solution according to any one of claims 30 to 36, wherein each of R1, R3, R5 and R6 is identical.

38. The method, adjuvant, composition or solution according to any one of claims 30 to 37, wherein each of R1, R3, R5 and R6 is Cualkyl.

39. The method, adjuvant, composition or solution according to any one of claims 30 to 38, wherein each of R2 and R4 is independently selected from Ci2-i6alkyl.

40. The method, adjuvant, composition or solution according to any one of claims 30 to 39, wherein each of R2 and R4 is identical.

41. The method, adjuvant, composition or solution according to any one of claims 30 to 40, wherein each of R2 and R4 is Cualkyl.

42. The method, adjuvant, composition or solution according to any one of claims 30 to 41 , wherein the GLA is:


or a salt, such as a pharmaceutically acceptable salt, thereof.

43. The method, adjuvant, composition or solution according to any one of claims 30 to 42, wherein the GLA is:

or the acid or other salt forms thereof, such as pharmaceutically acceptable salts.