IP Library › Granted Patent US 12,616,737
Granted Patent B2
US 12,616,737 · App. 18/707,536 · Granted May 5, 2026

Liquid formulations of amylin analogues

Inventor: Joakim Lundqvist (Søborg, DK)
Assignee: Zealand Pharma A/S
A61K38/22A61K47/18
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,616,737
App. No.
18/707,536
Granted
May 5, 2026
Kind
B2
Abstract

The present invention relates to formulations of amylin analogues, and their use, for example, in the treatment of obesity and metabolic disorders such as diabetes. In particular, the present invention relates to stable aqueous liquid formulations of amylin analogues.

Claims (28)

1 . A stable aqueous liquid pharmaceutical formulation comprising an amylin analogue, which is:

(SEQ ID NO: 3)

[19CD]-isoGlu-RD( )GTATK( )ATERLA-Aad-FLQRSSF-

Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2

wherein “[19CD]” represents 19-carboxy-nonadecanoyl-; and “( )” shown after the amino acid residues indicate residues whose side chains participate in an intramolecular lactam bridge;

or a pharmaceutically acceptable salt thereof;

wherein the formulation comprises:

(a) the amylin analogue at a concentration of from about 0.4 mg/ml to about 25 mg/ml; and

(b) a buffer at a concentration of about 0.5 mM to about 25 mM;

wherein the formulation has a pH of about 6.2 to about 6.8, and wherein the formulation is formulated for administration to a subject by injection.

2 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of at least about 1.2 mg/ml.

3 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at up to about 20 mg/ml.

4 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of about 3 mg/ml to about 12 mg/ml.

5 . The stable aqueous liquid formulation of claim 1 , wherein the buffer is present at a concentration of about 0.5 mM to about 20 mM.

6 . The stable aqueous liquid formulation of claim 5 , wherein the buffer is present at a concentration of about 3 mM to about 7 mM.

7 . The stable aqueous liquid formulation of claim 1 , wherein the buffer is phosphate, histidine or citrate.

8 . The stable aqueous liquid formulation of claim 1 , wherein the buffer is TRIS buffer, and wherein the buffer is present at about 15 mM to about 25 mM.

9 . The stable aqueous liquid formulation of claim 1 , wherein the pH is about 6.5.

10 . The stable aqueous liquid formulation of claim 1 , further comprising a tonicity modifier.

11 . The stable aqueous liquid formulation of claim 1 , wherein the formulation is stable at 2-8° C. for at least 6 months.

12 . The stable aqueous liquid formulation of claim 1 , wherein the formulation displays substantially no turbidity, or aggregation, fibrillation or gelling of the amylin analogue, after storage at 2-8° C. for at least 6 months.

13 . The stable aqueous liquid formulation of claim 1 , wherein at least 80% of the amylin analogue remains in intact monomeric form in the formulation after it has been stored at 2-8° C. for at least 6 months.

14 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is provided as a chloride salt.

15 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of about 1.2 mg/ml to about 18 mg/ml.

16 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of about 1.2 mg/ml to about 10 mg/ml.

17 . The stable aqueous liquid formulation of claim 15 , wherein the amylin analogue is present at a concentration of about 2 mg/ml.

18 . The stable aqueous liquid formulation of claim 4 , wherein the amylin analogue is present at a concentration of about 12 mg/ml.

19 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of about 18 mg/ml.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 3, 2024
From: LUNDQVIST, JOAKIM
To: ZEALAND PHARMA A/S
Reel/Frame 068824/0085 →
Priority Claims (1)
EP 22176247 · May 30, 2022 · regional
Continuity (1)
Related Publication 20240335513A1 · Oct 10, 2024
References Cited (131)
US 5424394A · Lehman de Gaeta et al. · 1995 [cited by applicant]
US 5686411A · Gaeta et al. · 1997 [cited by applicant]
US 5998367A · Gaeta et al. · 1999 [cited by applicant]
US 7407934B2 · Kolterman et al. · 2008 [cited by applicant]
US 7910548B2 · Duft et al. · 2011 [cited by applicant]
US 8575090B2 · Schaeffer et al. · 2013 [cited by applicant]
US 8575091B1 · Dahl et al. · 2013 [cited by applicant]
US 8722849B2 · Schaeffer et al. · 2014 [cited by applicant]
US 8741836B2 · Schaeffer et al. · 2014 [cited by applicant]
US 8895504B2 · Schaffer et al. · 2014 [cited by applicant]
US 9023789B2 · Dahl et al. · 2015 [cited by applicant]
US 10071140B2 · Mathiesen et al. · 2018 [cited by applicant]
US 10766939B2 · Just et al. · 2020 [cited by applicant]
US 11129877B2 · Chan et al. · 2021 [cited by applicant]
US 11382956B2 · Mathiesen et al. · 2022 [cited by applicant]
US 12083164B2 · Mathiesen et al. · 2024 [cited by applicant]
US 20020187923A1 · Gaeta et al. · 2002 [cited by applicant]
US 20080274952A1 · Soares et al. · 2008 [cited by applicant]
US 20100221240A1 · Kapurniotu et al. · 2010 [cited by applicant]
US 20130005646A1 · Schaeffer et al. · 2013 [cited by applicant]
US 20130059770A1 · Schaeffer et al. · 2013 [cited by applicant]
US 20140018286A1 · Schaeffer et al. · 2014 [cited by applicant]
US 20140087995A1 · Dahl et al. · 2014 [cited by applicant]
US 20160184401A1 · Trambaioli Da Rocha E Lima et al. · 2016 [cited by applicant]
US 20160272693A1 · Just et al. · 2016 [cited by applicant]
US 20180071366A1 · Mathiesen et al. · 2018 [cited by applicant]
CL 47901B1 · 2005 [cited by applicant]
CL 2017002256A1 · 2018 [cited by applicant]
KR 1020170126504A · 2017 [cited by applicant]
TW 201542588A · 2015 [cited by applicant]
TW 201811818A · 2018 [cited by applicant]
WO WO9107978A1 · 1991 [cited by applicant]
WO WO9211862A1 · 1992 [cited by applicant]
WO WO9310146A1 · 1993 [cited by applicant]
WO WO9805351A1 · 1998 [cited by applicant]
WO WO9808871A1 · 1998 [cited by applicant]
WO WO9811125A1 · 1998 [cited by applicant]
WO WO9826796A1 · 1998 [cited by applicant]
WO WO9850059A1 · 1998 [cited by applicant]
WO WO9855144A1 · 1998 [cited by applicant]
WO WO9934764A2 · 1999 [cited by applicant]
WO WO9934822A1 · 1999 [cited by applicant]
WO WO200055119A1 · 2000 [cited by applicant]
WO WO200055184A1 · 2000 [cited by applicant]
WO WO2003101395A2 · 2003 [cited by applicant]
WO WO2005000222A2 · 2005 [cited by applicant]
WO WO2005077072A2 · 2005 [cited by applicant]
WO WO2006042745A2 · 2006 [cited by applicant]
WO WO2006068910A1 · 2006 [cited by applicant]
WO WO2006083254A1 · 2006 [cited by applicant]
WO WO2007022123A2 · 2007 [cited by applicant]
WO WO2007104789A2 · 2007 [cited by applicant]
WO WO2008101017A2 · 2008 [cited by applicant]
WO WO2008152403A1 · 2008 [cited by applicant]
WO WO2009034118A1 · 2009 [cited by applicant]
WO WO2009034119A1 · 2009 [cited by applicant]
WO WO2010046357A1 · 2010 [cited by applicant]
WO WO2010070251A1 · 2010 [cited by applicant]
WO WO2010070252A1 · 2010 [cited by applicant]
WO WO2010070253A1 · 2010 [cited by applicant]
WO WO2010070255A1 · 2010 [cited by applicant]
WO WO2010107874A2 · 2010 [cited by applicant]
WO WO2011006497A1 · 2011 [cited by applicant]
WO WO2011064282A1 · 2011 [cited by applicant]
WO WO2011160630A2 · 2011 [cited by applicant]
WO WO2011160633A1 · 2011 [cited by applicant]
WO WO2012168430A2 · 2012 [cited by applicant]
WO WO2012168431A2 · 2012 [cited by applicant]
WO WO2012168432A1 · 2012 [cited by applicant]
WO WO2013092703A2 · 2013 [cited by applicant]
WO WO2013156594A1 · 2013 [cited by applicant]
WO WO2014041195A1 · 2014 [cited by applicant]
WO WO2014197961A1 · 2014 [cited by applicant]
WO WO2015040182A2 · 2015 [cited by applicant]
WO WO2015050182A1 · 2015 [cited by applicant]
WO WO2015055801A1 · 2015 [cited by applicant]
WO WO2015055802A2 · 2015 [cited by applicant]
WO WO2015150564A1 · 2015 [cited by applicant]
WO WO2015168488A2 · 2015 [cited by applicant]
WO WO2016034604A1 · 2016 [cited by applicant]
WO WO2016100456A2 · 2016 [cited by applicant]
WO WO2016146739A1 · 2016 [cited by applicant]
WO WO2018046719A1 · 2018 [cited by examiner]
WO WO2018144671A1 · 2018 [cited by applicant]
WO WO2019122935A1 · 2019 [cited by applicant]
WO WO2020051307A1 · 2020 [cited by applicant]
WO WO2021185821A1 · 2021 [cited by applicant]
Gennaro A R (ed), Remington's Pharmaceutical Sciences, 1985, 17th edition, Mack Publishing Company, Easton, PA, U.S.A. (9 pages). [cited by applicant]
Groenning M et al., Study on the binding of ThioXavin T to -sheet-rich and non-sheet cavities, J. Struct. Biol., 2007, vol. 158, pp. 358-369 (12 pages). [cited by applicant]
Groenning, M., “Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils-current status,” J. Chem. Biol., 2010, vol. 3(1), pp. 1-18. [cited by applicant]
Jones, A J S, “Analysis of polypeptides and proteins,” Adv. Drug Delivery Rev., (1993) vol. 10(1): 29-90 (62 pages). [cited by applicant]
LeVine, H., III. “Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution,” Protein Sci. vol 2(3):404-410 (1993) (7 pages). [cited by applicant]
Pearlman et al. Analysis of Protein Drugs,* [cited by applicant]
Swarbrick J (ed) Encyclopaedia of Pharmaceutical Technology, 2007, Informa Healthcare (14 pages). [cited by applicant]
Yan L-M et al. “Design of a mimic of nonamyloidogenic and bioactive human islet amyload polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis,” Proc Natl Acad Sci. vol 103(7):2046-2051 (20… [cited by applicant]
Yan L-M et al. “Selectively N-Methylated Soluble IAPP Mimics as Potent IAPP Receptor Agonists and Nanomolar Inhibitors of Cytotoxic Self-Assembly of Both IAPP and A-Beta-40,” Angew. Chem. Int. Ed. 52(39):10378-10383 (20… [cited by applicant]
Amino Acids Reference Chart, Sigma-Aldrich, 2014, downloaded from the internet Aug. 2014 (3 pages). [cited by applicant]
Baisley et al., “Amylin receptor signaling in the nucleus accumbens negatively modulates μ-opioid-driven feeding,” Neuropsychopharmacology 39(13):3009-17 (2014) (9 pages). [cited by applicant]
Bogdanowich-Knipp et al., “Solution stability of linear vs. cyclic RGD peptides,” J Pept Res. 53(5):530-41 (1999). [cited by applicant]
Chai et al., “Characterization of binding sites for amylin, calcitonin, and CGRP in primate kidney,” Am J Physiol. 274(1 Pt 2):F51-62 (1998). [cited by applicant]
Database Geneseq [Online] Jun. 14, 2007, “Hybrid polypeptide amylin analog parent molecule Seq ID No 78.”, XP002739549, retrieved from EBI accession No. GSP:AFC32081 Database accession No. AFC32081 (1 page). [cited by applicant]
Fortin et al., “Wildlife sequences of islet amyloid polypeptide (IAPP) identify critical species variants for fibrillization,” Amyloid. 22(3):194-202 (2015) (9 pages). doi: 10.3109/13506129.2015.1070824. [cited by applicant]
Haffner et al., “Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance,” Diabetes. 54(5):1566-72 (2005) (14 pages). [cited by applicant]
He et al., “Synthesis and chemical stability of a disulfide bond in a model cyclic pentapeptide: Cyclo(1,4)-Cys-Gly-Phe-Cys-Gly-OH,” J Pharm Sci. 95(10):2222-34 (2006). [cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/EP2016/055793, mailed Jun. 9, 2017 (37 pages). [cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/EP2016/055793, mailed Jun. 24, 2016 (16 pages). [cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/EP2017/072718, mailed Jan. 3, 2018 (13 pages). [cited by applicant]
Kajava et al., “A model for Ure2p prion filaments and other amyloids: the parallel superpleated beta-structure,” Proc Natl Acad Sci U.S.A. 101(21):7885-90 (2004) (8 pages). [cited by applicant]
Knudsen et al., “Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration,” J Med Chem. 43(9):1664-9 (2000). [cited by applicant]
Koo et al., “Amide inequivalence in the fibrillar assembly of islet amyloid polypeptide,” Protein Eng Des Sel. 21(3):147-54 (2008). [cited by applicant]
Li et al., “Suppression of polyglutamine toxicity by the yeast Sup35 prion domain in [cited by applicant]
Madsen et al., “Structure-activity and protraction relationship of long-acting glucagon-like peptide- 1 derivatives: importance of fatty acid length, polarity, and bulkiness,” J Med Chem. 50(24):6126-32 (2007). [cited by applicant]
Moriarty et al., “Effects of sequential proline substitutions on amyloid formation by human amylin20-29,” Biochemistry 38(6):1811-8 (1999). [cited by applicant]
Muthusamy et al., “Design and study of peptide-based inhibitors of amylin cytotoxicity,” Bioorg Med Chem Lett. 20(4):1360-2 (2010). [cited by applicant]
Redalieu et al., “Pharmacokinetic Effects of Syringe Mixing Pramlintide, Isophane Insulin, and Soluble Insulin,” Diabetology. 1399:A 356 (1997) (1 page). [cited by applicant]
Reidelberger et al., “Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats,” Am J Physiol Regul Integr Comp Physiol. 282(5):R1395-404 (2002) (10 pages). [cited by applicant]
Rijkers et al., “Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides,” Chemistry 8(18):4285-91 (2002). [cited by applicant]
Tenidis et al., “Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties,” J Mol Biol. 295(4):1055-71 (2000). [cited by applicant]
Trivedi et al., “The role of thiols and disulfides on protein stability,” Curr Protein Pept Sci. 10(6):614-25 (2009). [cited by applicant]
Tsai et al., “Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder,” Proc Natl Acad Sci U.S.A. 102(23):8174-9 (2005) (9 pages). [cited by applicant]
Westermark et al., “Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation,” Proc Natl Acad Sci U.S.A. 87(13):5036-40 (1990). [cited by applicant]
Wineman-Fisher et al., “The removal of disulfide bonds in amylin oligomers leads to the conformational change of the 'native' amylin oligomers,” Phys Chem Chem Phys. 18(18):12438-42 (2016). [cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/EP2023/064395, mailed on Aug. 31, 2023 (14 pages). [cited by applicant]
Maikawa C L, Ultra-Fast Insulin-Pramlintide Co-Formulation for Improved Glucose Management in Diabetic Rats, Advanced Science, Sep. 9, 2021, vol. 8, No. 21 Article ID 2101575 (9 pages). [cited by applicant]
Mashkovsky M.D., “Medicines”, Moscow, “Medicine”, 1993, Part I, p. 8. [cited by applicant]
Kim, et al., “Effects of pH and buffer concentration on the thermal stability of etanercept using DSC and DLS,” Biol Pharm Bull, 37(5): 808-816, (May 2014). [cited by applicant]
Frokjaer et al., Pharmaceutical Formulation Development of Peptides and Proteins, 3 pages, (2000). [cited by applicant]
Florence et al., Physicochemical principles of pharmacy, Third Edition, 3 pages (1998). [cited by applicant]
Chang et al. “Lyophilized Biologics in Lyophilized Biologics and Vaccines,” Springer Science, 93-119 (2015). [cited by applicant]
Wang et al. “Technical Report No. 10 Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers,” Journal of Parenteral Science and Technology, Supplement , 42(S2): S22 (1998). [cited by applicant]
Zapadka et al. “Factors affecting the physical stability (aggregation) of peptide therapeutics,” Interface Focus. (Oct. 20, 2017). [cited by applicant]