Alprostadil freeze-dried emulsion for injection and preparation method thereof

Abstract

The invention relates to an alprostadil freeze-dried emulsion for injection and a preparation method thereof. Cyclodextrin substances and polysaccharide substances are taken as freeze-drying protective agents, the high-stability alprostadil freeze-dried emulsion for injection is prepared, the chemical stability and physiological activity of the alprostadil are improved, the requirements on production, transport, and storage conditions are reduced, the period of validity is prolonged, untoward effects of local swelling and pain in the injection process are avoided simultaneously, and the patient compliance is improved in the process of clinical use.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular to a freeze-dried alprostadil emulsion for injection and a preparation method thereof. Background technique

[0002] Alprostadil (also known as prostaglandin E) 1 (prostaglandin E 1 , PGE 1 ), chemical name: (1R, 2R, 3R)-3-hydroxy 2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentane heptanoic acid, molecular formula :C 20 h 34 o 5 , molecular weight 354.48.

[0003] Alprostadil is a compound with definite curative effect. After intravenous injection, it stimulates the endothelial cells of the blood vessel wall, activates platelet adenylase, promotes the increase of platelet endothelial CAMP content, and inhibits platelet thromboxane TAX. 2 generation. It is widely used clinically to treat limb ulcers caused by chronic arterial occlusive disease (thromboangiitis obliterans, arteriosclerosis obliterans, etc.) Antithrombotic therapy after organ transplantation, to inhibit throm...

Examples

Embodiment 1

[0025] 1. Dissolve 6.7mg of the main drug alprostadil in 5g of olive oil as the oil phase;

[0026]2. Disperse 1.0g of soybean lecithin in water, and add 5g of glycerin as the water phase;

[0027] 3. Add the oil phase to the water phase under stirring, stir at 20°C at high speed to make it colostrum, and adjust the pH to 8.0 with 0.1mol / L NaOH solution to obtain colostrum;

[0028] 4. The colostrum is homogenized by a homogenizer to obtain a uniform emulsion, which is dissolved with 67 mg of α-cyclodextrin and stirred to obtain solution I;

[0029] 5. Dissolve 400g of sucrose with an appropriate amount of water to obtain solution II;

[0030] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen filling completed under the conditions.

Embodiment 2

[0032] 1. Dissolve 100mg of the main drug alprostadil in 100g of soybean oil as the oil phase;

[0033] 2. Disperse 20g of egg yolk phospholipids in water, and add 2g of glycerin as the water phase;

[0034] 3. Add the oil phase to the water phase under stirring, stir at 40°C at high speed to make it colostrum, and adjust the pH to 7.5 with 0.1mol / L sodium citrate buffer to obtain colostrum;

[0035] 4. The colostrum is homogenized by a homogenizer to obtain a uniform emulsion, which is dissolved with 1g of β-cyclodextrin and stirred to solution I;

[0036] 5. Dissolve 100g of glucose with an appropriate amount of water to obtain solution II;

[0037] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen filling completed under the conditions.

Embodiment 3

[0039] 1. Dissolve 1 mg of the main drug alprostadil and 25 g of egg yolk phospholipids in 300 g of soybean oil for injection as the oil phase;

[0040] 2. Disperse 25g of soybean lecithin in water, then add 2.0g of sodium chloride and 1g of sodium oleate as the water phase;

[0041] 3. Add the water phase to the oil phase under stirring, stir at 90°C at high speed to make it colostrum, and adjust the pH to 4.0 with 0.5mol / L citric acid buffer to obtain colostrum;

[0042] 4. Homogenize the colostrum through a homogenizer to obtain a uniform emulsion, dissolve the emulsion with 1 mg γ-cyclodextrin and stir to obtain solution I;

[0043] 5. Dissolve 200g of maltose in an appropriate amount of water to obtain solution II;

[0044] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen fi...

technical field

[0001] The invention relates to the technical field of medicine, in particular to a freeze-dried alprostadil emulsion for injection and a preparation method thereof. Background technique

[0002] Alprostadil (also known as prostaglandin E) 1 (prostaglandin E 1 , PGE 1 ), chemical name: (1R, 2R, 3R)-3-hydroxy 2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentane heptanoic acid, molecular formula :C 20 h 34 o 5 , molecular weight 354.48.

[0003] Alprostadil is a compound with definite curative effect. After intravenous injection, it stimulates the endothelial cells of the blood vessel wall, activates platelet adenylase, promotes the increase of platelet endothelial CAMP content, and inhibits platelet thromboxane TAX. 2 generation. It is widely used clinically to treat limb ulcers caused by chronic arterial occlusive disease (thromboangiitis obliterans, arteriosclerosis obliterans, etc.) Antithrombotic therapy after organ transplantation, to inhibit throm...

Examples

Embodiment 1

[0025] 1. Dissolve 6.7mg of the main drug alprostadil in 5g of olive oil as the oil phase;

[0026]2. Disperse 1.0g of soybean lecithin in water, and add 5g of glycerin as the water phase;

[0027] 3. Add the oil phase to the water phase under stirring, stir at 20°C at high speed to make it colostrum, and adjust the pH to 8.0 with 0.1mol / L NaOH solution to obtain colostrum;

[0028] 4. The colostrum is homogenized by a homogenizer to obtain a uniform emulsion, which is dissolved with 67 mg of α-cyclodextrin and stirred to obtain solution I;

[0029] 5. Dissolve 400g of sucrose with an appropriate amount of water to obtain solution II;

[0030] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen filling completed under the conditions.

Embodiment 2

[0032] 1. Dissolve 100mg of the main drug alprostadil in 100g of soybean oil as the oil phase;

[0033] 2. Disperse 20g of egg yolk phospholipids in water, and add 2g of glycerin as the water phase;

[0034] 3. Add the oil phase to the water phase under stirring, stir at 40°C at high speed to make it colostrum, and adjust the pH to 7.5 with 0.1mol / L sodium citrate buffer to obtain colostrum;

[0035] 4. The colostrum is homogenized by a homogenizer to obtain a uniform emulsion, which is dissolved with 1g of β-cyclodextrin and stirred to solution I;

[0036] 5. Dissolve 100g of glucose with an appropriate amount of water to obtain solution II;

[0037] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen filling completed under the conditions.

Embodiment 3

[0039] 1. Dissolve 1 mg of the main drug alprostadil and 25 g of egg yolk phospholipids in 300 g of soybean oil for injection as the oil phase;

[0040] 2. Disperse 25g of soybean lecithin in water, then add 2.0g of sodium chloride and 1g of sodium oleate as the water phase;

[0041] 3. Add the water phase to the oil phase under stirring, stir at 90°C at high speed to make it colostrum, and adjust the pH to 4.0 with 0.5mol / L citric acid buffer to obtain colostrum;

[0042] 4. Homogenize the colostrum through a homogenizer to obtain a uniform emulsion, dissolve the emulsion with 1 mg γ-cyclodextrin and stir to obtain solution I;

[0043] 5. Dissolve 200g of maltose in an appropriate amount of water to obtain solution II;

[0044] 6. Stir and mix solution I and solution II, dilute the solution to 1000ml, filter aseptically through a 0.22 μm filter, and remove moisture by lyophilization to obtain dry alprostadil lyophilized emulsion. The above processes are all under nitrogen fi...

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