Crystalline teriparatide

A crystallization and cube technology, applied in the field of teriparatide, can solve problems such as instability

Inactive Publication Date: 2001-01-24
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because it is a protein, it is very unstable compared to traditional small molecular weight drugs, however, parathyroid hormone formulations face challenges not often encountered by the pharmaceutical industry

Method used

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  • Crystalline teriparatide
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Recombinant human rhPTH(1-34) (SEQ ID NO: 2) was prepared from previously purified and lyophilized material. The lyophilized protein was dissolved in water at a concentration of 5 mg / ml to 20 mg / ml. Protein was mixed with storage solution (20% isopropanol, 0.2M sodium citrate, 0.1M tris(hydroxymethyl)aminomethane in HCl buffer, pH=8.0) at a ratio of 1:1 on a silicon-coated glass coverslip. ratio mix. Slides were inverted and sealed over wells containing 1 mL of storage solution. Tetragonal flaky crystals appeared within 48-96 hours, with a size of 0.1mm×0.1mm×0.05mm. Mass spectroscopy confirmed the product. figure 1 Photographs of crystal growth are given.

[0058] X-ray crystallography of the tetrahedral platelets showed a P422 spacer and the following unit cell constants: a=b=91.071 Å, c=37.665 Å, α=β=γ=90°.

Embodiment 2

[0060] The same experiment was repeated as in Example 1 and mixed with a stock solution of 10% isopropanol, 10% polyethylene glycol, 0.1 M glycine buffer, pH=8.5.

Embodiment 3

[0062] Batch crystallization: rhPTH (SEQ ID NO: 1) with a concentration of 10 mg / ml and 50% isopropanol, 100 mM tris (hydroxymethyl) aminomethane, pH = 7.5, 0.2 M sodium citrate stock solution at a ratio of 1:1 ratios were mixed in test tubes. Crystals appeared within 48-96 hours, with a size of 0.1 mm x 0.1 mm x 0.05 mm.

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PUM

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Abstract

Pure, stable crystalline forms of parathyroid hormone, particularly teriparatide, are described as well as methods of preparation and purification.

Description

technical field [0001] The present invention relates to pure crystalline forms of parathyroid hormone. More specifically, the present invention relates to teriparatide, a crystalline form of PTH(1-34), and methods for the preparation and purification of fragments of this hormone. Background of the invention [0002] Parathyroid hormone (PTH) is an 84 amino acid product secreted by the mammalian parathyroid gland that controls serum calcium levels through actions on various tissues including bone. Studies in humans of certain forms of PTH have demonstrated anabolic effects on bone, raising considerable concerns about their use in the treatment of osteoporosis and related bone diseases. [0003] Using the N-terminal 34 amino acids of the bovine and human hormones, which all published reports consider biologically equivalent to the full-length hormone, it has been demonstrated that when parathyroid hormone is administered subcutaneously in a pulsatile manner , parathyroid hor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/14C07K1/30C07K14/635
CPCC07K14/635A61P19/00
Inventor 张发明
Owner ELI LILLY & CO
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