Claims for Patent: 12,377,133

Summary for Patent: 12,377,133

Title:	Dry pharmaceutical formulations of CNP conjugates
Abstract:	A dry pharmaceutical formulation, wherein the pharmaceutical formulation comprises a CNP conjugate, a buffering agent and a bulking agent and wherein the CNP conjugate comprises a CNP moiety that is covalently and reversibly conjugated to a polymeric moiety.
Inventor(s):	Anja R. H. Skands, Ulrich Hersel, Charlotte PINHOLT, Stefan HEINIG
Assignee:	Ascendis Pharma Endocrinology Division AS
Application Number:	US17/428,604
Patent Claims:	1. A dry pharmaceutical formulation, wherein the pharmaceutical formulation comprises based on the total weight of the dry pharmaceutical formulation: a CNP conjugate at 1.3-45.4% (w/w), succinic acid at 0.2-3.2% (w/w), trehalose dihydrate at 52.6-98.4% (w/w), and Tris at 0.1-5.6% (w/w); wherein the formulation is reconstitutable with water to pH 4-6; wherein the CNP conjugate comprises CNP-38 (SEQ ID NO:24) reversibly conjugated to a branched PEG polymer of 12-60 kDa. 2. The dry pharmaceutical formulation of claim 1, wherein the formulation comprises based on the total weight of the dry pharmaceutical formulation: the CNP conjugate at 1.3-38.7% (w/w). 3. The dry pharmaceutical formulation of claim 1, wherein the CNP conjugate is of formula (Ia) or (Ib): ZL2-L1-D)x (Ia) DL1-L2-Z)y (Ib), wherein D is the CNP-38; -L1- is a reversible linker moiety; -L2- is a single chemical bond or a spacer moiety; Z is the branched PEG polymer; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; and y is an integer selected from the group consisting of 1, 2, 3, 4 and 5. 4. The dry pharmaceutical formulation of claim 3, wherein x of formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6 and 8. 5. The dry pharmaceutical formulation of claim 3, wherein y of formula (Ib) is an integer selected from the group consisting of 2, 3, 4 and 5. 6. The dry pharmaceutical formulation of claim 3, wherein the CNP conjugate is of formula (Ia) and x is 1. 7. The dry pharmaceutical formulation of claim 3, wherein -L1- is connected to -D through an amide linkage. 8. The dry pharmaceutical formulation of claim 3, wherein -L2- is a spacer moiety. 9. The dry pharmaceutical formulation of claim 3, wherein -L2- has a molecular weight ranging from 14 g/mol to 750 g/mol. 10. The dry pharmaceutical formulation of claim 3, wherein -L2- has a chain length of 1 to 20 atoms. 11. The dry pharmaceutical formulation of claim 3, wherein -L2- is of formula (i): wherein the dashed line marked with the asterisk indicates attachment to -L1-; the unmarked dashed line indicates attachment to -Z; -R1 is selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18; and wherein the moiety of formula (i) is optionally further substituted. 12. The dry pharmaceutical formulation of claim 11, wherein n of formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8 and 9. 13. A method of manufacturing the dry pharmaceutical formulation of claim 1, wherein the method comprises the steps of (i) admixing the CNP conjugate with at least a buffering agent and a bulking agent; ii adjusting the pH of the admixture of step (i); iii) optionally, filtering the admixture from step (ii); (iv) transferring amounts of the admixture from step (ii) or (iii) equivalent to the desired number of dosages into a container; (v) drying the admixture; (vi) sealing the container; and wherein the order of steps (ii) and (iii) may optionally be reversed. 14. A method of reconstituting the dry pharmaceutical formulation of claim 1, wherein the method comprises the step of (a) contacting the dry pharmaceutical formulation of claim 1, with a reconstitution solution. 15. A reconstituted pharmaceutical formulation obtainable from the method of reconstituting of claim 14. 16. A method of treating, controlling, delaying or preventing in a patient one or more diseases which can be treated by CNP, the method comprising administering to the patient a therapeutically effective amount of the reconstitution pharmaceutical formulation of claim 15 wherein the disease is achondroplasia. 17. The dry pharmaceutical formulation of claim 1, wherein the dry pharmaceutical formulation comprises a mixture of one or more acid and base pH-adjusting agents. 18. The dry pharmaceutical formulation of claim 1 that is free of antioxidants. 19. The dry pharmaceutical formulation of claim 18 that is free of surfactants. 20. The dry pharmaceutical formulation of claim 1, wherein the CNP conjugate is of formula (IIf): or a pharmaceutically acceptable salt thereof; wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of a CNP moiety of SEQ ID NO:24 by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z having the structure wherein each Za is wherein each c1 is an integer independently ranging from 200 to 250. 21. The dry pharmaceutical formulation of claim 20, wherein each cl is about 225. 22. The dry pharmaceutical formulation of claim of claim 2 of formula (IIf′) wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of a CNP moiety of SEQ ID NO:24 by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z having the structure wherein each -Za is wherein each c1 is an integer independently ranging from 200 to 250. 23. The dry pharmaceutical formulation of claim 22, wherein each c1 is about 225. 24. The dry pharmaceutical formulation of claim 22, wherein -Z has the structure of formula (h-i): wherein each Za is: 25. The dry pharmaceutical formulation of claim 24, wherein each c1 is about 225. 26. The dry pharmaceutical formulation of claim 25, wherein the CNP conjugate is at 5.8-12.4% (w/w), the succinic acid is at 0.3-3.2% (w/w), the trehalose dihydrate is at 78.8-93.8% (w/w) and the Tris is at 0.1-5.6% (w/w).