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US-20260125422-A1 - POLYMORPHIC FORMS OF CYCLO (-HIS-PRO) AND METHODS OF USE TO TREAT KIDNEY DISEASE

US20260125422A1US 20260125422 A1US20260125422 A1US 20260125422A1US-20260125422-A1

Abstract

The present disclosure relates to synthesis and characterization of novel polymorphic forms of Cyclo(-His-Pro)(“CHP”).

Inventors

  • Kay Olmstead
  • David Pearson
  • Elaine McPherson

Assignees

  • NOVMETAPHARMA CO., LTD.

Dates

Publication Date
20260507
Application Date
20251229

Claims (17)

  1. 1 . A cyclo(-His-Pro) hydrate compound characterized by an X-ray powder diffraction (XRPD) diffractogram comprising three or more peaks at 2θ values selected from the group consisting of 13.5°-13.9°, 16.9°-17.3°, 22.4°-22.6°, 24.1°-24.5°, and 27.2°-27.5°.
  2. 2 . The compound of claim 1 , which is characterized by XRPD diffractogram further comprising peaks at 2θ values at 17.9°-18.4°.
  3. 3 . The compound of claim 1 having a differential scanning calorimetry (DSC) endotherm onset at about 75° C. to about 100° C.
  4. 4 . The compound of claim 1 having a DSC exotherm onset of about 115° C. to about 120° C.
  5. 5 . The compound of claim 1 having a DSC thermogram having two endothermic peaks with peak maxima at about 100° C. and about 170° C.
  6. 6 . The compound of claim 1 , wherein the compound is substantially free of solvent.
  7. 7 . A composition comprising the cyclo(-His-Pro) hydrate compound of claim 1 .
  8. 8 . The composition of claim 7 , wherein the XRPD diffractogram further comprises a peak at 20 value at 17.9°-18.4°.
  9. 9 . The composition of claim 7 , wherein the XRPD diffractogram is substantially similar as shown in FIG. 2 ( b ) .
  10. 10 . The composition of claim 7 , wherein the cyclo(-His-Pro) hydrate compound comprises XRPD peaks at 2θ values at 13.5°-13.9°, 16.9°-17.3°, and 27.2°-27.5°.
  11. 11 . The composition of claim 7 , further comprising a pharmaceutically acceptable carrier.
  12. 12 . The composition of claim 7 , wherein the composition comprises about 1%-about 10% 50% (w/w) of the cyclo(-His-Pro) hydrate compound based on the total weight of the composition.
  13. 13 . The composition of claim 12 , wherein the composition comprises about 1 to about 20 percent (wt %) of cyclo(-His-Pro) hydrate compound.
  14. 14 . The composition of claim 7 , further comprising a metal or a metal compound wherein the metal is selected from the group consisting of copper, zinc, manganese, iron, cobalt, and chromium.
  15. 15 . The composition of claim 14 , wherein the metal is zinc.
  16. 16 . The composition of claim 14 , wherein the metal or metal compound is zinc element, zinc cation, zinc gluconate, zinc acetate, zinc sulfate, zinc picolinate, zinc orotate, or zinc citrate.
  17. 17 . The composition of claim 7 , which is lyophilized.

Description

RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 18/377,656 (allowed) filed Oct. 6, 2023, which is a continuation application of U.S. application Ser. No. 16/901,676 (now U.S. Pat. No. 11,820,834) filed Jun. 15, 2020 which is a continuation-in-part application of U.S. application Ser. No. 16/448,083 filed Jun. 21, 2019 (now U.S. Pat. No. 10,683,300) which claims priority to U.S. Provisional Appl. Ser. No. 62/696,190 filed on Jul. 10, 2018, which are incorporated herein by reference in their entireties to the full extent permitted by law. TECHNICAL FIELD The present disclosure is directed to novel polymorphic forms of Cyclo(-His-Pro) (“CHP”). BACKGROUND Cyclo(-His-Pro), C11H14N4O2, has been known as an anhydrous dipeptide having the CAS Registry Number 53109-32-3. It is an endogenous cyclic dipeptide derived in vivo from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone. Cyclo(-His-Pro) can all be synthesized ex-vivo by conventional chemical methods. It may be important in regulating the nature of the glial cell contribution. Grotelli et al., The Role of Cyclo(His-Pro) in Neurodegeneration, Int J Mol Sci. 2016 August; 17(8): 1332. Cyclo (His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. The crystalline anhydrous form of cyclo(-His-Pro) (“anhydrous CHP” or “Pattern 1”) is the form that has heretofore been reported in literature and has potential therapeutic applications. However, certain anhydrous forms may be unstable. Possible disadvantages of using Pattern 1 include: (1) apparent physical instability at ambient to high humidity conditions; and (2) potential chemical instability due to water activity resulting in the formation of diastereomers of the desired L,L-dipeptides such as D,L-CHP, L,D-CHP, or D,D-CHP. Thus, there is a need in the art for more stable forms of CHP. SUMMARY The present disclosure provides Cyclo(-His-Pro) hydrate crystalline form (“CHP Hydrate” or “Pattern 2” compound) that may be characterized and distinguished from other solid forms of CHP using various analytical techniques including, but not limited to, X-ray powder diffraction (XRPD), solid-state nuclear magnetic resonance (NMR, or 13C SSNMR), Raman spectroscopy, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and thermogravimetric analysis (TGA). Applicant has unexpectedly discovered that CHP hydrate (CAS RN: 2254826-95-2 (Jan. 2019)) has superior stability over amorphous cyclo(-His-Pro) or Pattern 1. Based on this surprising discovery, Pattern 2 can be used alone as a single component drug rather than using Pattern 1 or a mixture of Pattern 1 and Pattern 2. In one embodiment, the present disclosure relates to a process for isolating Pattern 2 by crystallization using solvents rather than column chromatography currently used to isolate the anhydrous CHP. In another embodiment, Pattern 2 is stable at typical room temperature storage conditions for about 6 months, or about 12 months, or about 18 months, or about 24 months, or about 36 months. In yet another embodiment, the present disclosure is directed to substantially pure Pattern 2 material. In some embodiments, the Pattern 2 material is at least about 90% pure, or at least about 95%, 96%, 97%, 98%, 99%, or 100% pure. In one embodiment, the purity of a sample is measured by any analytical method. In one embodiment, the purity is measured by high pressure liquid chromatography (HPLC), X-ray powder diffraction (XRPD), pKa analysis, polarized light microscopy (PLM), thermogravimetric analysis/differential thermal analysis (TG/DTA), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), dynamic vapor sorption (DVS), variable temperature and humidity X-ray powder diffractometry (VT-/VH-XRPD), 1H nuclear magnetic resonance (NMR), and/or heteronuclear single quantum coherence (HSQC) NMR. In another embodiment, the purity of the sample is measured by HPLC. In one embodiment, the Pattern 2 material is at least about 90% pure, or at least about 95%, 96%, 97%, 98%, 99%, or 100% pure as measured by HPLC. In another embodiment, Pattern 2 material may be characterized by at least two of the following: (a) an X-ray powder diffractogram comprising at least two peaks chosen from the following list: 10, 13.7, 17, 18.1, 20.2 and 27.3 degrees (±0.2° in 2θ);(b) pKa of about 6.4;(c) birefringent with a fragmented, rod-like morphology when analyzed by polarized light microscopy;(d) an initial weight loss of about 6.5% (0.9 equivalent of water), followed by sample degradation at about 280° C. when analyzed by thermogravimetric analysis technique;(e)