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A kind of paliperidone polyethylene glycol conjugated prodrug and its preparation

A technology of paliperidone and polyethylene glycol, which is applied in the fields of medicine and chemical synthesis, can solve the problems of high requirements for quality control, high requirements for preparation equipment, and difficult to control the particle size and distribution of nanocrystals.

Active Publication Date: 2019-02-19
石家庄蒎格医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, Paliperidone Palmitic Acid Injection (Shanstar@) is a white to off-white suspension, which has the following defects: (1) It is difficult to develop and require high preparation equipment, and the particle size and distribution of nanocrystals Difficult to control, production requires special nano crystallization technology and corresponding special equipment, current domestic production equipment is difficult to achieve and has no responsive testing equipment; Special items such as resuspension and needle withdrawal test, particle size distribution, release degree, storage stability, and content uniformity need to be controlled; (3) The price is expensive, and each tube (1ml: 100mg) is imported at 2,000 yuan; (4) The dosage needs to be strictly controlled. It is recommended that patients inject 150 mg of Sanstar on the first day of initial treatment, and then inject 100 mg again one week later.
[0008] In addition to the physical and chemical properties of the drug itself, the reason why paliperidone palmitic acid injection (Shanstar@) is made into such a complex long-acting preparation also has pharmacoeconomic considerations: (1) The half-life of the paliperidone molecule itself It is very short and cannot be made into common oral preparations; (2) the oral absolute bioavailability of paliperidone sustained-release tablets is low (about 28%); (3) although the half-life of paliperidone palmitate is effectively extended, the water-soluble (4) Nanocrystalline technology, especially the purpose of sustained release by combining different particle size distributions of nanocrystals combined with poor solubility, is a proprietary technology with high technical content, which is difficult to imitate; (5) Although brown Paliperidone Acid Injection (Shanstar@) has the potential risk of blood clot formation when the drug enters the blood vessel, but due to the particularity of medication for mental patients, the benefits of this product far outweigh the risks

Method used

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  • A kind of paliperidone polyethylene glycol conjugated prodrug and its preparation
  • A kind of paliperidone polyethylene glycol conjugated prodrug and its preparation
  • A kind of paliperidone polyethylene glycol conjugated prodrug and its preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 (preparation of double-arm PEG-paliperidone):

[0035] Dissolve 20.0 g (10.0 mmol) of double-arm polyethylene glycol acetic acid (average molecular weight 2000, distribution coefficient <1.05), 4.9 g (24.0 mmol) of dicyclohexylcarbodiimide (DCC) in 200 mL of anhydrous In dichloromethane, stir, add paliperidone 9.4g (22.0mmol) and 0.12g (1.0mmol) DMAP, react at room temperature for 16h, filter out insoluble matter, remove the solvent by rotary evaporation, add 100mL isopropanol (IPA) Recrystallize, filter, and vacuum-dry the product to obtain 16.7 g of double-arm polyethylene glycol-paliperidone ester.

[0036] 1 H-NMR (400MHz, CDCl 3)δ: 7.75-7.68 (m, 2H), 7.25-7.21 (m, 2H), 7.07-7.01 (m, 2H), 5.80 (t, J=5.4Hz, 2H), 4.22 (s, 4H), 4.06 -3.72(m, 4H), 3.77-3.72(m, 4H), 3.65-3.58(m, 188H), 3.33-3.23(m, 4H), 3.18-3.10(m, 2H), 2.86-2.78(m, 4H) ), 2.72-2.63 (m, 4H), 2.55-2.36 (m, 4H), 2.30-1.92 (m, 22H).

Embodiment 2

[0037] Embodiment 2 (preparation of four-arm PEG-paliperidone):

[0038] Four-arm polyethylene glycol acetic acid (average molecular weight 20000, distribution coefficient<1.05) 20.0g (1.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI) 0.92g (4.8mmol), dissolved in 200mL anhydrous dichloromethane at room temperature, stirred, added paliperidone 1.88g (4.4mmol) and 0.01g (0.1mmol) DMAP, reacted at room temperature for 16h, filtered off The insoluble matter was removed by rotary evaporation of the solvent, recrystallized by adding 100 mL of isopropanol (IPA), filtered, and the product was vacuum-dried to obtain 15.8 g of four-armed polyethylene glycol-paliperidone ester.

[0039] 1 H-NMR (400MHz, CDCl 3 )δ: 7.63-7.59 (m, 4H), 7.25-7.21 (m, 4H), 7.20-7.11 (m, 4H), 4.58-4.50 (m, 8H), 4.25 (s, 8H), 4.16-4.08 ( m, 8H), 3.93-3.02 (m, 1830H), 3.01-2.87 (m, 8H), 2.50-2.48 (m, 8H), 2.38-2.05 (m, 44H), 1.90-1.73 (m, 8H).

Embodiment 3

[0040] Embodiment 3 (preparation of four-arm PEG-glycine paliperidone):

[0041] Four-arm polyethylene glycol-acetic acid (average molecular weight 20000, distribution coefficient <1.04) 20.0g (1.0mmol), paliperidone-glycinate 3.88g (8.0mmol), 4-dimethylaminopyridine (DMAP) 0.98g (8.0mmol), 1.08g (8.0mmol) of 1-hydroxybenzotriazole (HOBT), be dissolved in 200ml of dichloromethane, drop dicyclohexylcarbodiimide (DCC) 1.65g (8.0 mmol) in dichloromethane (16mL), dropwise, and react overnight under nitrogen protection. The solid matter was removed by filtration, and the excess solvent was removed by rotary evaporation. The residue was recrystallized by adding 200 ml of isopropanol (IPA), filtered, and the product was dried in vacuum to obtain 17.2 g of four-arm polyethylene glycol-glycine-paliperidone.

[0042] 1 H-NMR (400MHz, CDCl 3 )δ: 7.74-7.65(m, 4H), 7.21-7.15(m, 4H), 7.12-7.05(m, 4H), 4.58-4.52(m, 8H), 4.40-4.35(m, 8H), 4.16( s, 8H), 3.93-3.05 (m, 1852H), 3.12-2.78 (m, ...

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Abstract

The invention discloses a novel paliperidone polyethylene glycol conjugated prodrug (PEG-paliperidone) and relates to preparation and an application of the paliperidone polyethylene glycol conjugated prodrug. The general formula of the PEG-paliperidone is shown in the description; the PEG-paliperidone comprises a carrier (polyethylene glycol, PEG), a connecting arm (AA) and paliperidone, wherein the carrier is single-arm polyethylene glycol, double-arm polyethylene glycol and four-arm polyethylene glycol, and the polymerization is 10-500 degrees; the connecting arm is an amino acid or oligopeptides comprising the amino acid. The paliperidone is subjected to PEGylation transformation, the half-life period of the medicine is prolonged and reaches 1 time per week or even 1 time per month, the use compliance is improved; the water solubility of the medicine is improved, the novel paliperidone polyethylene glycol conjugated prodrug can be prepared into a common injection, the ultra-hard process using a nanocrystalline prolonged action preparation is avoided, and the production difficulty and the use risk are reduced. The preparation process is simple in operation, is green and environmentally friendly, is low in cost, and is easy to realize industrial production. The general formulas of the single-arm polyethylene glycol, the double-arm polyethylene glycol and the four-arm polyethylene glycol are as shown in the description.

Description

technical field [0001] The invention belongs to the field of medicine and chemical synthesis, and specifically relates to the invention of a new drug paliperidone polyethylene glycol conjugated prodrug. The application also provides a preparation method and application of the paliperidone polyethylene glycol conjugated prodrug . Background technique [0002] Paliperidone (Paliperidone) is an atypical antipsychotic drug developed and listed by Johnson Company of the United States, and belongs to the 5-HT antagonist of benzisoxazole derivatives. Paliperidone (Paliperidone), also called 9-hydroxy-risperidone (9-hydroxy-risperidone), is the main active metabolite of Risperidone (Risperidone), and its pharmacological characteristics are similar to Risperidone, mainly by antagonizing 5 -HT receptors and dopamine DZ receptors exert antipsychotic effects, and compared with other atypical antipsychotics, they exhibit higher receptor affinity and better therapeutic effect. [0003] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K31/519A61P25/18C08G65/333
CPCA61K31/519C08G65/33396
Inventor 解兵亮曹敏慧齐艳国宋艳杰董文弟
Owner 石家庄蒎格医药科技有限公司
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