Search

US-12616737-B2 - Liquid formulations of amylin analogues

US12616737B2US 12616737 B2US12616737 B2US 12616737B2US-12616737-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.

Inventors

  • Joakim Lundqvist

Assignees

  • ZEALAND PHARMA A/S

Dates

Publication Date
20260505
Application Date
20230530
Priority Date
20220530

Claims (19)

  1. 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. 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. 3 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at up to about 20 mg/ml.
  4. 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. 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. 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. 7 . The stable aqueous liquid formulation of claim 1 , wherein the buffer is phosphate, histidine or citrate.
  8. 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. 9 . The stable aqueous liquid formulation of claim 1 , wherein the pH is about 6.5.
  10. 10 . The stable aqueous liquid formulation of claim 1 , further comprising a tonicity modifier.
  11. 11 . The stable aqueous liquid formulation of claim 1 , wherein the formulation is stable at 2-8° C. for at least 6 months.
  12. 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. 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. 14 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is provided as a chloride salt.
  15. 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. 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. 17 . The stable aqueous liquid formulation of claim 15 , wherein the amylin analogue is present at a concentration of about 2 mg/ml.
  18. 18 . The stable aqueous liquid formulation of claim 4 , wherein the amylin analogue is present at a concentration of about 12 mg/ml.
  19. 19 . The stable aqueous liquid formulation of claim 1 , wherein the amylin analogue is present at a concentration of about 18 mg/ml.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 3, 2024, is named “50412-151001_Sequence_Listing_5_3_24” and is 7,745 bytes in size. FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION Amylin is one of a family of peptide hormones that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin and intermedin (intermedin also being known as AFP-6), and has been implicated in various metabolic diseases and disorders. Human amylin was first isolated, purified and characterized as the major component of amyloid deposits in the islets of pancreases from type 2 diabetes patients. Native human amylin is a 37-amino acid peptide having the formula (SEQ ID NO: 1)H-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2 wherein H- at the N-terminus designates a hydrogen atom, corresponding to the presence of a free amino group on the N-terminal amino acid residue [i.e. the lysine (K) residue at sequence position number 1 in the sequence shown above]; wherein —NH2 at the C-terminus indicates that the C-terminal carboxyl group is in the amide form; and wherein the parentheses “( )” associated with the two cysteine (C, Cys) residues at sequence positions 2 and 7 indicate the presence of an intramolecular disulfide bridge between the two Cys residues in question. Amylin may be beneficial in treating metabolic disorders such as diabetes and/or obesity. Amylin is believed to regulate gastric emptying, and to suppress glucagon secretion and food intake, thereby regulating the rate of glucose release to the circulation. Amylin appears to complement the actions of insulin. Compared to healthy adults, type 1 diabetes patients have no circulating amylin, and type 2 diabetes patients exhibit reduced postprandial amylin concentrations. In human trials an amylin analogue known as pramlintide, described in WO 93/10146 and having the sequence Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 2), which also possesses a disulphide bridge between the Cys residues at positions 2 and 7, has been shown to reduce body weight or reduce weight gain. An alternative amylin analogue incorporating N-methylated residues and having a reduced tendency to fibrillation, designated IAPP-GI, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; WO2006/042745). IAPP-GI appears to have lower activity than native amylin, however. WO 2018/046719 describes amylin analogues having, inter alia, a lactam bridge instead of a disulfide bridge, N-methylated residues, and a deletion corresponding to the residues Asn21 and Asn22 of native human amylin. Such analogues have considerably lower tendency towards fibrillation than native amylin, while also having higher potency than the analogues described by Yan et al. (supra). They are typically amenable to formulation at, or near to, physiological pH. However, there is a need to develop improved formulations for these analogues, especially to provide stable formulations capable of long-term storage without undue fibrillation or degradation of the active monomeric form of the peptide. SUMMARY OF THE INVENTION Broadly, the invention is based on studies described in the examples that led to surprising findings regarding aqueous formulations of the amylin analogue, that are particularly suitable for long term storage. In particular, it was found that a low buffer concentration and a particular pH range are unexpectedly significant for optimal stability. The invention provides 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-NH2or a pharmaceutically acceptable salt and/or derivative 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 5.8 to about 6.9. The amylin analogue is present at a concentration of from about 0.4 mg/ml to about 25 mg/ml. In some embodiments, the amylin analogue is present at a concentration of at least about 0.4 mg/ml, at least about 0.5 mg/ml, at least about 0.6 mg/ml, at least about 1.2 mg/ml, or at least about 2.5 mg/ml. The amylin analogue may be present at up to about 25 mg/ml, up to about 20 mg/ml, up to about 15 mg/ml, or up to about 10 mg/ml. The amylin analogue may be present at a conce