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Pharmaceutically acceptable salts of sepiapterin

A mopterin, pharmaceutical technology, applied in the salt and/or co-crystal of mopterin, in the field of treating tetrahydrobiopterin-related diseases, and can solve the problems of neuromotor defects, reducing the formation of neurotransmitters, etc.

Pending Publication Date: 2021-03-23
PTC医疗MP公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reduced Tyr synthesis and impaired Tyr and tryptophan hydroxylase activity lead to reduced neurotransmitter formation and subsequent neuromotor deficits

Method used

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  • Pharmaceutically acceptable salts of sepiapterin
  • Pharmaceutically acceptable salts of sepiapterin
  • Pharmaceutically acceptable salts of sepiapterin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Embodiment 1. Preparation of the salt of mepterin

[0220] Production of mepterin and hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid by slurrying the free base and acid of meptterin in acetone / water (9 / 1, v / v) or methanol for 2-17 days Salts and / or co-crystals of nicotinic acid, niacin, sulfuric acid, phosphoric acid, malonic acid, L-tartaric acid, fumaric acid, gentisic acid and glycolic acid.

[0221] Salts were analyzed by DSC, TGA, HPLC, IR and XRPD. The results are summarized in Table 15 below. The IR spectrum is displayed on Figure 1-13 middle.

[0222] Table 15. Summary of Mepterin Salts and / or Cocrystal Analysis

[0223]

Embodiment 2

[0224] Example 2. Stability Analysis of Salts and / or Co-crystals of Mepterin

[0225] The prepared salts and / or co-crystals were analyzed for stability after 1 and 2 weeks at 25°C and 60% relative humidity and at 40°C and 75% relative humidity. The results are summarized in Table 16 below. Surprisingly, of all salts and / or co-crystals tested, phosphate and / or co-crystal, tartrate and / or co-crystal and nicotinate and / or co-crystal were significantly more stable than the others. None of the phosphate, tartrate, or nicotinate salts and / or co-crystals underwent a change in form during stability testing, and each of them remained greater than 97% pure over the two weeks studied. In fact, both tartrate and nicotinate remained greater than 99% pure.

[0226] Table 16. Summary of Stability Study Results

[0227]

[0228]

Embodiment 3

[0229] Example 3. Solubility and disproportionation of various mepterin salts and / or co-crystals

[0230] The kinetic solubility of the nicotinate, phosphate, L-tartrate and fumarate salts and / or co-crystals of metopterin was evaluated in water and Medisca Oral Mix. X-ray powder diffraction (XRPD) was performed on the residual solid to identify form change / disproportionation. Suspend the solid in the medium at a target concentration of approximately 7 mg / mL (calculated as free base). The suspension was stirred for 1, 4 and 24 hours at 25 rpm on a rolling incubator. At each time point, 1 mL of the suspension was removed for centrifugation at 10000 rpm (2 min) and filtered through a 0.45 μm membrane to obtain supernatants for HPLC solubility and pH testing, residual solids were analyzed by XRPD. Solubility results are summarized in Tables 17-20.

[0231] Table 17. Solubility Summary of Niacinates and / or Co-crystals

[0232]

[0233] *: Calculated using free base.

[0234...

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Abstract

The present invention relates to new pharmaceutical salts and / or co-crystals of sepiapterin which exhibit improved properties. In particular, the invention relates to salts of sepiapterin with improved stability. The invention also relates to pharmaceutical compositions including a pharmaceutically effective amount of one or more salts and / or co-crystals of sepiapterin, as well as methods of treating tetrahydrobiopterin-related disorders including administration of a sepiapterin salt and / or co-crystal of the invention to a subject in need thereof.

Description

[0001] Background of the invention [0002] Primary tetrahydrobiopterin deficiency (PBD) results from deficiency of GTP cyclohydrolase I (GTP-CH), 6-pyruvyl-tetrahydropterin synthase (PTPS), or mepterin reductase (SR) (impaired tetrahydrobiopterin (BH4) biosynthesis), or by defects in BH4 recycling (pterin-4a-methanolamine dehydratase (PCD) or dihydropteridine reductase (DHPR) deficiency) . PBD accounts for 1-3% of all cases of hyperphenylalaninemia (HPA), while nearly all remaining cases are due to phenylalanine hydroxylase deficiency. [0003] BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, fatty acid glyceryl ether oxygenase, and nitric oxide (NO) synthase. [0004] In PBD, impaired phenylalanine (Phe) to tyrosine (Tyr) hydroxylation leads to HPA. Reduced Tyr synthesis and impaired Tyr and tryptophan hydroxylase activity lead to reduced neurotransmitter formation and subsequent neuromotor deficits. [0005] Phenoty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/00C07D475/04C07D491/052
CPCC07D475/04C07D213/80A61P25/00C07C55/08C07C57/15C07C65/05C07C59/06C07B2200/13C07C309/04C07C309/30C07C309/29A61K31/519C07C209/04C07C209/30A61K45/06
Inventor D·E·莱维N·史密斯J·雷斯H·约施诺T·科莫达Y·施罗S·穆拉塔T·马楚莫托K·基施莫托
Owner PTC医疗MP公司
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