Claims for Patent: 9,962,452

Summary for Patent: 9,962,452

Title:	Soluble complexes of drug analogs and albumin
Abstract:	The present invention provides novel, non-covalently bound complexes of serum albumin and analogs of poorly soluble drugs, such as camptothecin. The novel complexes are significantly more water-soluble than the camptothecin analogs and are useful as prodrug forms of the camptothecin analogs for the treatment of mammalian cell proliferative diseases, such as cancer.
Inventor(s):	Sun; Qun (Princeton, NJ)
Assignee:	Zhuhai Beihai Biotech Co., Ltd. (Zhuhai, CN)
Application Number:	14/765,773
Patent Claims:	1. A non-covalently bound complex, comprising: serum albumin, and a camptothecin analog of Formula I: ##STR00083## wherein R.sub.1 is OH or a linker-serum-albumin-binding-moiety wherein R.sub.11 is O; R.sub.2-6 are each, independently, H, halo, OH, NO.sub.2, NH.sub.2, lower alkyl, O-lower alkyl, NH-lower alkyl, N(lower alkyl).sub.2, lower alkyl-N(lower alkyl).sub.2, lower alkyl-Si(lower alkyl).sub.3, ##STR00084## or a linker-serum-albumin-binding-moiety; wherein: R.sub.4 and R.sub.5 optionally, together form --OCH.sub.2CH.sub.2O--, R.sub.2 and R.sub.3 optionally, together form --C(NH.sub.2)H--CH.sub.2--CH.sub.2--, and at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 comprises a linker-serum-albumin-binding-moiety, wherein the linker-serum-albumin-binding-moiety comprises: ##STR00085## wherein R.sub.11 is: O, if the linker-serum-albumin-binding-moiety substitutes for an alcohol group on the camptothecin analog of Formula I, S, if the linker-serum-albumin-binding-moiety substitutes for a thiol group on the camptothecin analog of Formula I, NH, if the linker-serum-albumin-binding-moiety substitutes for a primary amine group on the camptothecin analog of Formula I, or --N-lower alkyl, if the linker-serum-albumin-binding-moiety substitutes for a secondary amine group on the camptothecin analog of Formula I; R.sub.7 is a covalent bond, if R.sub.11 is S; otherwise, R.sub.7 is selected from the group consisting of O, NH and a covalent bond; A is ##STR00086## R.sub.9 is an unbranched or branched alkyl, alkylene or alkyne of 2 to 30 carbon atoms optionally including one or more ring structures of 3 to 6 atoms when R.sub.9 has at least 7 carbon atoms, including heteroatoms of oxygen in an integer number from 0 to one fifth the total number of carbon atoms in R.sub.9, and optionally substituted with up to three groups selected from the groups consisting of halo, nitro, amine, amide, hydroxyl, O-lower alkyl and carboxy; with the proviso that there be no covalent bonds between oxygen atoms in R.sub.9; R.sub.10 is, independently in each instance, H or lower alkyl; R.sub.13 is, independently in each instance, H, OH, NO.sub.2, NH.sub.2, NH.sub.3.sup.+, SH or a branched or unbranched alkyl, alkylene or alkyne of 1 to 8 carbon atoms, wherein the alkyl, alkylene or alkyne is optionally substituted with one or two substituents selected from the group consisting of halo, OH, NO.sub.2, NH.sub.2, NH.sub.3.sup.+, SH and .dbd.O, and optionally includes up to two heteroatoms independently selected from O, S and N, with the proviso that no O, S or N atom in the alkyl, alkylene or alkyne is covalently bonded to any other O, S or N atom; R.sub.14 is, independently in each instance, H, OH, NO.sub.2, NH.sub.2, NH.sub.3.sup.+, SH or a branched or unbranched alkyl, alkylene or alkyne of 1 to 10 carbon atoms, wherein the alkyl, alkylene or alkyne optionally includes one or more ring structures of 3 to 9 atoms, is optionally substituted with one or two substituents selected from the group consisting of halo, OH, NO.sub.2, NH.sub.2, NH.sub.3.sup.+, SH and .dbd.O, and optionally includes up to two heteroatoms independently selected from O, S and N, with the proviso that no O, S or N atom in the alkyl, alkylene or alkyne is covalently bonded to any other O, S or N atom; R.sub.20 is, independently in each instance, H or lower alkyl, and two R.sub.20 may optionally together form a ring structure of up to 8 carbon atoms; k is 0, 1 or 2; m, independently in each instance, is 0, 1, 2 or 3; n is an integer from 1 to 8; v is 0 or 1; w is 0 or 1; x is 0 or 1, with the proviso that x is 0 when a di-sulfide bond is present in A; y is 0, 1, 2 or 3; and z is 0 or 1, wherein the non-covalently bound complex has a molar ratio of the camptothecin analog of Formula I to serum albumin from about 1:1 to about 16:1 and has a solubility in aqueous solution of at least 5 mg/ml. 2. The non-covalently bound complex of claim 1, wherein the serum albumin is human serum albumin. 3. The non-covalently bound complex of claim 1, in a solid formulation. 4. The non-covalently bound complex of claim 2, in an aqueous formulation. 5. The non-covalently bound complex of claim 2, wherein the aqueous formulation is substantially free of solvents other than water. 6. The non-covalently bound complex of claim 1, wherein the camptothecin analog of Formula I is selected from the group consisting of camptothecin, topotecan, irinotecan, 7-ethyl-10-hydroxy-camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, (S)-ethyl-8-hydroxy-15-(4-methylpiperazin-1-ylmethyl)-2,3,8,9,11,12-hexah- ydro-14H-1,4-dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,1- 2-dione, (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydrox- y-4-methyl-10H,13H-benzo(de)pyrano(3',4':6,7) indolizino(1,2-b)quinoline-10,13-dione, and (4S)-4-ethyl-4-hydroxy-11-(2-trimethylsilyl)ethyl)-1H-pyrano[3',4': 6,7]indolizino[1,2-b]quinoline-3,14(4H, 12H)-dione, wherein at least one alcohol or a primary amine group in the camptothecin analog is substituted with the linker-serum-albumin-binding-moiety. 7. The non-covalently bound complex of claim 6, wherein the serum albumin is human serum albumin. 8. The non-covalently bound complex of claim 7, in an aqueous formulation. 9. The non-covalently bound complex of claim 8, wherein the aqueous formulation is substantially free of solvents other than water. 10. The non-covalently bound complex of claim 1, wherein R.sub.2 is --CH.sub.2CH.sub.3; R.sub.3 is --H: R.sub.4 is ##STR00087## R.sub.5 is H; R.sub.6 is H; and R.sub.1 is linker-HSA binding moiety, wherein R.sub.11 is O. 11. The non-covalently bound complex of claim 1, wherein R.sub.2 is H; R.sub.3 is ##STR00088## R.sub.4 is --OH or linker-HSA binding moiety; R.sub.5 is H; R.sub.6 is H; R.sub.1 is --OH or linker-HSA binding moiety; wherein at least one of R.sub.1 and R.sub.4 is linker-HSA binding moiety, wherein R.sub.11 is O. 12. The non-covalently bound complex of claim 1, wherein R.sub.2 is --CH.sub.2CH.sub.3; R.sub.3 is H; R.sub.4 is --OH or linker-HSA binding moiety; R.sub.5 is H; R.sub.6 is H; R.sub.1 is --OH or linker-HSA binding moiety; wherein at least one of R.sub.1 and R.sub.4 is linker-HSA binding moiety, wherein R.sub.11 is O. 13. The non-covalently bound complex of claim 10, wherein linker-HSA binding moiety is: ##STR00089## 14. The non-covalently bound complex of claim 7, wherein the camptothecin analog of Formula I is: ##STR00090## 15. The non-covalently bound complex of claim 7, wherein the camptothecin analog of Formula I is: ##STR00091## 16. A method to treat cancer in a patient comprising administering a composition comprising a non-covalently bound complex of claim 7 to said patient in an effective amount to treat said cancer.

Details for Patent 9,962,452

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		2033-02-04
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		2033-02-04
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		2033-02-04
Grifols Biologicals Llc	ALBUTEIN	albumin (human)	Injection	102478	08/15/1978		2033-02-04