Claims for Patent: 10,335,489

Summary for Patent: 10,335,489

Title:	Injectable solution at pH 7 comprising at least one basal insulin the pi of which is between 5.8 and 8.5 and a substituted co-polyamino acid
Abstract:	A composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, including at least (a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; and (b) a co-polyamino acid bearing carboxylate charges and substituted with hydrophobic radicals. In one embodiment, the compositions also include a prandial insulin and/or a gut hormone.
Inventor(s):	Soula; Olivier (Meyzieu, FR)
Assignee:	ADOCIA (Lyons, FR)
Application Number:	14/922,663
Patent Claims:	1. A composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a basal insulin, the isoelectric point pI of which is between 5.8 and 8.5; b) a prandial insulin, c) a co-polyamino acid bearing carboxylate charges and substituted with hydrophobic groups, chosen from the co-polyamino acids of formula I: ##STR00026## in which: A independently represents either a --CH.sub.2-- group (aspartic unit) or a --CH.sub.2--CH.sub.2-- group (glutamic unit), R.sub.1 is a radical chosen from the group consisting of an H, a linear C.sub.2 to C.sub.10 acyl group, a branched C.sub.3 to C.sub.10 acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate, R.sub.2 is an --NR'R'' radical, R' and R'', which may be identical or different, being chosen from the group consisting of H, linear or branched or cyclic C.sub.2 to C.sub.30 alkyls and benzyl, and said R' and R'' alkyls being alkyls which can together form one or more saturated, unsaturated and/or aromatic rings which are carbon-based and/or which can comprise heteroatoms, chosen from the group consisting of O, N and S, R'.sub.3 is a radical chosen from the group consisting of the radicals of formulae --OR.sub.3, II or II': ##STR00027## in which * indicates the site of attachment to the co-polyamino acid R.sub.3 and R''.sub.3, which may be identical or different, represent an H or a cationic entity chosen from the group comprising metal cations, --R is a hydrophobic radical chosen from the group consisting of a saturated or unsaturated, linear or branched C.sub.8 to C.sub.30 radical which can comprise heteroatoms or a C.sub.8 to C.sub.30 radical which can form rings which are carbon-based or which can comprise heteroatoms, which are saturated, unsaturated and/or aromatic, said rings possibly being ortho-condensed or peri-condensed, or a radical of formula III or III' as defined below: ##STR00028## in which * indicates the site of attachment to the co-polyamino acid, and R.sub.4 and R'.sub.4, which may be identical or different, represent an H, a cationic entity chosen from the group comprising metal cations, an R''.sub.4 radical or an R'''.sub.4 radical, and at least one of R.sub.4 and R'.sub.4 is equal to R''.sub.4, R''.sub.4 represents a saturated or unsaturated, linear or branched C.sub.8 to C.sub.30 radical which can comprise heteroatoms or a C.sub.8 to C.sub.30 radical which can form rings which are carbon-based or which can comprise heteroatoms, which are saturated, unsaturated and/or aromatic, said rings possibly being ortho-condensed or peri-condensed, R'''.sub.4 represents a saturated or unsaturated, linear or branched C.sub.1 to C.sub.7 radical which can comprise heteroatoms or a C.sub.1 to C.sub.7 radical which can form rings which are carbon-based or which can comprise heteroatoms, which are saturated, unsaturated and/or aromatic, said rings possibly being ortho-condensed or peri-condensed, and B independently represents either a --CH.sub.2-- group (aspartic unit) or a --CH.sub.2--CH.sub.2-- group (glutamic unit), R.sub.5 is a radical chosen from the group consisting of an H, a linear or branched C.sub.1 to C.sub.4 alkyl or a benzyl group, n/(n+m) is defined as the molar degree of grafting with hydrophobic radical of the monomeric units and is between 1 and 50 mol %, n+m represents the degree of polymerization of the co-polyamino acid, i.e. the average number of monomeric units per chain of co-polyamino acid, and 5 .ltoreq.n+m.ltoreq.1000. 2. The composition as claimed in claim 1, wherein the co-polyamino acid is chosen from the co-polyamino acids of formula IV: ##STR00029## in which: A independently represents a --CH.sub.2-- group (aspartic unit) or a --CH.sub.2--CH.sub.2--group (glutamic unit), R.sub.1 is chosen from the group consisting of an H, a linear C.sub.2 to C.sub.10 acyl group, a branched C.sub.3 to C.sub.10 acyl group, a benzyl, a terminal "amino acid" unit and a pyroglutamate, R.sub.2 is an --NR'R'' radical, R' and R'', which may be identical or different, being chosen from the group consisting of H, linear or branched or cyclic C.sub.2 to C.sub.10 alkyls and benzyl, and said R' and R'' alkyls being alkyls which can together form saturated, unsaturated and/or aromatic rings which are carbon-based and/or which can comprise heteroatoms, chosen from the group consisting of O, N and S, the R.sub.3 groups, which may be identical or different, are chosen from the group consisting of an H or a cationic entity chosen from the group comprising metal cations, the R groups each represent, independently from one another, a radical chosen from the radicals of general formula V or V': ##STR00030## in which * indicates the site of attachment to the co-polyamino acid, and R.sub.4 represents a saturated or unsaturated, linear or branched C.sub.8 to C.sub.30 radical which can comprise heteroatoms or a C.sub.8 to C.sub.30 radical which can form rings which are carbon-based or which can comprise heteroatoms, which are saturated, unsaturated and/or aromatic, said rings possibly being ortho-condensed or peri-condensed, B independently represents a --CH.sub.2-- group (aspartic unit) or a --CH.sub.2--CH.sub.2--group (glutamic unit), R.sub.5 independently represents an H, a linear or branched C.sub.1 to C.sub.4 alkyl or a benzyl group, or R is a saturated or unsaturated, linear or branched C.sub.8 to C.sub.30 radical which can comprise heteroatoms or a C.sub.8 to C.sub.30 radical which can form rings which are carbon-based or which can comprise heteroatoms, which are saturated, unsaturated and/or aromatic, said rings possibly being ortho-condensed or peri-condensed, n/(n+m) is defined as the molar degree of grafting with hydrophobic radical of the monomeric units, and is between 1 and 50 mol %, n+m represents the degree of polymerization of the co-polyamino acid, i.e. the average number of monomeric units per chain of co-polyamino acid, and 5.ltoreq.n+m.ltoreq.1000. 3. The composition as claimed in claim 1, wherein the co-polyamino acid is chosen from the co-polyamino acids of formula I or IV, in which the group A is a --CH.sub.2-- group (aspartic unit). 4. The composition as claimed in claim 3, wherein the co-polyamino acids of formula IV can also comprise monomeric units of formula VI'' and/or VI': ##STR00031## 5. The composition as claimed in claim 1, wherein the co-polyamino acid is chosen from the co-polyamino acids of formula I or IV, in which the group A is a --CH.sub.2--CH.sub.2-- group (glutamic unit). 6. The composition as claimed in claim 1, wherein the co-polyamino acid is chosen from the co-polyamino acids of formula I or IV, in which R is chosen from the group of radicals derived from hydrophobic alcohols. 7. The composition as claimed in claim 1, wherein the R group is a tocopheryloxy-radical. 8. The composition as claimed in claim 1, wherein R.sub.2 is --N-morpholyl. 9. The composition as claimed in claim 1, wherein the R.sub.2 group is a radical derived from an amino acid and is chosen from the radicals of formula VII: ##STR00032## in which: R.sub.6 is --OH, --OR.sub.9 or --NHR.sub.10, and R.sub.7, R'.sub.7, R''.sub.7, R.sub.8, R'.sub.8, R''.sub.8, R.sub.9 and R.sub.10, which may be identical or different, independently represent an H, a linear C.sub.2 to C.sub.10 alkyl, a branched C.sub.3 to C.sub.10 alkyl or a benzyl, with 0.ltoreq.p.ltoreq.3, 0.ltoreq.q.ltoreq.3, 0.ltoreq.r.ltoreq.3 and 1.ltoreq.p+q+r.ltoreq.10. 10. The composition as claimed in claim 1, wherein the co-polyamino acid is chosen from the co-polyamino acids of formula I or IV, in which R.sub.4, R'.sub.4 and/or R''.sub.4, which may be identical or different, are chosen from the group of the radicals derived from hydrophobic alcohols. 11. The composition as claimed in claim 1, wherein the R.sub.4, R'.sub.4 and/or R''.sub.4 groups are radicals derived from cholesterol. 12. The composition as claimed in claim 1, wherein the R.sub.5 group is an isobutyl radical. 13. The composition as claimed in claim 1, wherein n+m is between 10 and 500. 14. The composition as claimed in claim 1, wherein n+m is between 15 and 250. 15. The composition as claimed in claim 1, wherein n/(n+m) is between 1 and 30 mol %. 16. The composition as claimed in claim 1, wherein n/(n+m) is between 1 and 20 mol %. 17. The composition as claimed in claim 1, wherein the basal insulin, the isoelectric point of which is between 5.8 and 8.5, is insulin glargine. 18. The composition as claimed in claim 1, which comprises between 40 and 500 IU/ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5. 19. The composition as claimed in claim 1, wherein the concentration of substituted co-polyamino acid is at most 60 mg/ml. 20. The composition as claimed in claim 1, wherein the concentration of substituted co-polyamino acid is at most 40 mg/ml. 21. The composition as claimed in claim 1, wherein the concentration of substituted co-polyamino acid is at most 20 mg/ml. 22. The composition as claimed in claim 1, wherein the concentration of substituted co-polyamino acid is at most 10 mg/ml. 23. The composition as claimed in claim 1, wherein the prandial insulin is human insulin selected from the group consisting of insulin lispro (Humalog.RTM.), insulin glulisine (Apidra.RTM.) and insulin aspart (NovoLog.RTM.). 24. The composition as claimed in claim 23, which comprises in total between 40 and 500 IU/ml of insulin with a combination of prandial insulin and basal insulin, the isoelectric point of which is between 5.8 and 8.5. 25. The composition as claimed in claim 23, wherein the proportions between the basal insulin, the isoelectric point of which is between 5.8 and 8.5, and the prandial insulin are, as a percentage, 25/75, 30/70, 40/60, 50/50, 60/40, 70/30, 80/20 or 90/10. 26. The composition as claimed in claim 1, which also comprises a gut hormone. 27. The composition as claimed in claim 26, wherein the gut hormone is chosen from the group consisting of exenatide, liraglutide and lixisenatide, their analogs or derivatives and their pharmaceutically acceptable salts. 28. The composition as claimed in claim 26, wherein the gut hormone is exenatide, its analogs or derivatives and their pharmaceutically acceptable salts. 29. The composition as claimed in claim 26, wherein the gut hormone is liraglutide, its analogs or derivatives and their pharmaceutically acceptable salts. 30. The composition as claimed in claim 26, wherein the gut hormone is lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts. 31. The composition as claimed in claim 26, wherein the concentration of gut hormone is included in a range of from 0.01 to 10 mg/ml. 32. The composition as claimed in claim 28, which comprises between 500 IU/ml and 40 IU/ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5, and from 0.05 to 0.5 mg/ml of exenatide. 33. The composition as claimed in claim 29, which comprises between 500 IU/ml and 40 IU/ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5, and from 1 to 10 mg/ml of liraglutide. 34. The composition as claimed in claim 30, which comprises between 500 IU/ml and 40 IU/ml of basal insulin, the isoelectric point of which is between 5.8 and 8.5, and from 0.01 to 1 mg/ml of lixisenatide. 35. A single-dose formulation at a pH of between 7 and 7.8, comprising a composition as claimed in claim 1. 36. A single-dose formulation at a pH of between 7 and 7.8, comprising a composition as claimed in claim 26. 37. The composition as claimed in claim 23, wherein the prandial insulin is insulin lispro. 38. The composition as claimed in claim 23, wherein the prandial insulin is insulin glulisine. 39. The composition as claimed in claim 23, wherein the prandial insulin is insulin aspart.

Details for Patent 10,335,489

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982		2032-01-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015		2032-01-09
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998		2032-01-09
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994		2032-01-09
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	May 25, 2018		2032-01-09
Novo Nordisk Inc.	NOVOLIN R	insulin human	Injection	019938	June 25, 1991		2032-01-09