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Prostaglandin E1 methyl ester injection freeze-dry preparation, and preparation and application of prostaglandin E1 methyl ester injection freeze-dry preparation

A technology of prostaglandins and freeze-dried preparations, which is applied in the field of medicine, can solve problems such as not meeting the requirements of emulsion droplet size, harsh product storage conditions, and low safety risks, achieve optimal drug activity and therapeutic effect, and improve pharmacokinetics Learning behavior, avoiding the effect of vascular injection stimulation

Active Publication Date: 2019-03-01
XIAN LIBANG ZHAOXIN BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the current commercially available prostaglandin E1 fat emulsion injection itself also has several obvious disadvantages: poor chemical stability, high temperature sterilization causes the content of prostaglandin E1 to decrease, and the content of the degradation product PGA1 obviously increases, and the product storage The conditions are harsh (0-5°C), and the validity period is only 1 year; because prostaglandin E1 itself is an inflammatory substance, it has a strong sense of pain when it is clinically applied to the human body, causing phlebitis, which limits the promotion of this product
The fat emulsion preparation of alprostadil methyl ester is disclosed in U.S. Patent No. 4,849,451, but we prepare the fat emulsion of the alprostadil methyl ester that obtains according to its embodiment in the research process, in using the new method of U.S. Pharmacopoeia about emulsion particle size measurement Method - photoresist method (the original commonly used dynamic light scattering method cannot accurately measure the number of particles with a particle size above 5um). After the measurement, it was found that there were obviously more emulsion droplets with a large particle size (>5um), which did not meet the requirements for the particle size of the emulsion droplets. , Large emulsion droplets (>5um) can block capillaries and cause embolism, which has a greater potential safety hazard. There have been medical accidents in the United States where injection of large particles of fat emulsion resulted in the death of a patient. Investigations and studies have proved that the presence of emulsion particles larger than 5um caused it. Therefore, in 2004, the United States Pharmacopoeia formulated the detection method and standard for measuring the large particle size of emulsion. In view of the shortcomings and deficiencies of existing products, the present invention aims to provide a new type of Better prostaglandin E1 methyl ester products

Method used

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  • Prostaglandin E1 methyl ester injection freeze-dry preparation, and preparation and application of prostaglandin E1 methyl ester injection freeze-dry preparation
  • Prostaglandin E1 methyl ester injection freeze-dry preparation, and preparation and application of prostaglandin E1 methyl ester injection freeze-dry preparation
  • Prostaglandin E1 methyl ester injection freeze-dry preparation, and preparation and application of prostaglandin E1 methyl ester injection freeze-dry preparation

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Experimental program
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Embodiment 1

[0053] Compound 1 of the present invention ([(1R,2R,3R)-3-hydroxyl-2-(S,E)-3-hydroxyl-1-enyl)-5-oxocyclopentyl]heptanoic acid methyl ester) Synthesis (Prostaglandin E1 methyl ester)

[0054]

[0055] The raw material PGE1 (63mg, 0.18mmol) was added to a three-necked flask, and then the prepared 1M dry THF / Et2O solution was added and stirred to dissolve. Under ice bath conditions, the MeI (26mg, 1M) solution was slowly added dropwise to the reaction solution, After the dropwise addition, KOH (10mg, 0.18mmol) and Bu 4 NBr (6 mg, 0.018 mmol). After the reaction was stirred for 1 h, it was heated to room temperature and monitored by TLC until the reaction was completed. Add 20ml of water to quench the reaction, extract with EtOAc (10mL×3), combine the organic phases, wash with anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluent n-hexane / EA=1 / 1) to obtain the product as a white solid (24.8 mg...

Embodiment 2

[0059] Synthesis of compound 2 ([(1R,2R,3R)-3-hydroxyl-2-(S,E)-3-hydroxyl-1-enyl)-5-oxocyclopentyl]heptanoic acid ethyl ester) ( prostaglandin E1 ethyl ester)

[0060]

[0061] The raw material PGE1 (63mg, 0.18mmol) was added to the three-necked flask, and then the prepared 1M dry THF / Et 2 The O solution solution was stirred and dissolved, and under the condition of ice bath, EtBr (20mg, 1M) solution was slowly added dropwise to the reaction solution, and after the dropwise addition, KOH (10mg, 0.18mmol) and Bu 4 NBr (6 mg, 0.018 mmol). After the reaction was stirred for 1 h, it was heated to room temperature and monitored by TLC until the reaction was completed. Add 20ml of water to quench the reaction, extract with EtOAc (10mL×3), combine the organic phases, wash with anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: n-hexane / EA=1 / 1) to obtain a white solid product (20.5 mg, 29.8% y...

Embodiment 3

[0066]

[0067] The preparation process is as follows:

[0068] Oil phase: Weigh 2g of soybean oil, add 0.5g of egg yolk phospholipid, 0.5mg of prostaglandin E1 methyl ester, and shear until dissolved at 50°C;

[0069] Water phase: Weigh 90g of water for injection, add 0.75g of glycerin, 12.5g of lactose, 0.01g of sodium oleate, mix well by shearing, adjust the pH to 6.5 with 0.1M sodium citrate, then add 2g of phospholipid, continue to shear for 10min;

[0070] Slowly add the oil phase to the water phase, continue to shear at 50°C for 10 minutes to obtain colostrum, add water to 100mL;

[0071] Put the colostrum through the homogenizer, and homogenize it 8 times under the pressure of 850bar;

[0072] Sterile filter the homogenized emulsion, sub-package, pre-freeze at -40°C for 150 minutes, then vacuumize at -20°C, 80mTorr for 480 minutes, 10°C, 60mTorr for 300 minutes, 40°C, 40mTorr for 360 minutes Minutes, vacuumize and press the cap to obtain the freeze-dried powder in...

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Abstract

The invention provides a prostaglandin E1 methyl ester injection freeze-dry preparation, and preparation and application of the prostaglandin E1 methyl ester injection freeze-dry preparation. The prostaglandin E1 methyl ester injection freeze-dry preparation comprises, by weight, 0.1-10 parts of prostaglandin E1 methyl ester, 500-4000 parts of injection oil, 500-2000 parts of emulsifiers, 0-10 parts of co-emulsifiers, 5000-50000 parts of freeze-dry protective agents and 200-1500 parts of glycerin. The prostaglandin E1 methyl ester injection freeze-dry preparation, the preparation and the application have the advantages that the prostaglandin E1 methyl ester injection freeze-dry preparation is little in vascular stimulation and good in medicine stability and is superior in medicine activityas compared with like prostaglandin E1 products, and treatment effects of the prostaglandin E1 methyl ester injection freeze-dry preparation are superior to treatment effects of the like prostaglandin E1 products.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a freeze-dried preparation for injection of prostaglandin E1 methyl ester and its preparation and application. Background technique [0002] Prostaglandin E1 (PGE1) is a natural endogenous vasodilator that can be synthesized by human cells. It is an important substance that regulates cell function. It does not accumulate in the body, does not produce tolerance, and is non-toxic and has no damaging side effects. The effect is exact, better than exogenous drugs. PGE1 has extremely strong physiological activity and has a wide range of pharmacological activities. It can be applied clinically to cardiovascular and cerebrovascular diseases, diabetic complications, respiratory diseases, pulmonary hypertension, hepatorenal syndrome (HRS), liver failure, and kidney disease. Studies have found that prostate Element E1 not only has the effect of dilating blood vessels and reducing the load on the h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19A61K9/107A61K31/5575A61K47/44A61P7/02A61P9/08A61P9/10A61P9/14
CPCA61K47/44A61P7/02A61P9/08A61P9/10A61P9/14A61K9/0019A61K9/107A61K9/19A61K31/5575A61K9/1075A61K47/24A61K47/26A61K47/14A61K47/10A61K47/12
Inventor 王汝涛安龙赵熠庞菁华陈涛
Owner XIAN LIBANG ZHAOXIN BIOTECH CO LTD
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