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Alprostadil submicron emulsion for injection and preparing method thereof

A technology of dierythia microemulsion and alprostadil, which is applied in the direction of medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, which can solve the problems of large fluctuations in the preparation process, large differences in product quality, and expiration dates. To achieve the effect of ensuring clinical equivalence and stable product quality

Inactive Publication Date: 2010-09-15
辽宁中海康生物制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] (2) The validity period is short, only 12 months (0~5℃)
[0012] What this patent document discloses is alprostadil lyophilized emulsion, and it also uses nonionic surfactant, poloxamer, surfactants such as Tween except using phospholipid, and the prepared product is different from this product It is completely consistent, so its disclosed preparation method cannot replace the preparation method of this product:
[0013] (1) From the quality of the obtained product: one of the key quality indicators of the submicron emulsion is particle size, and the common shortcoming of the above-mentioned prior art is that the product particle size range of preparation is wider, and the particle size range in the embodiment From 92nm to 962nm (Table 1 on page 4 of the manual)
The quality of the product is closely related to the preparation process of the product, and the large difference in product quality indicates that the preparation process fluctuates greatly, which may easily lead to large differences between batches
[0014] (2) In the above-mentioned prior art, because of adding multiple emulsifiers, this product is used for intravenous injection administration. In the prior art, multiple emulsifiers have been added, and surfactants such as Tween can produce irritation Such adverse reactions will inevitably bring safety hazards
[0015] (3) The preparation temperature range of the above-mentioned prior art is too wide, and is not suitable for the preparation of alprostadil submicroemulsion for injection, so it is necessary to optimize the preparation temperature parameters, thereby ensuring stable quality of the product

Method used

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  • Alprostadil submicron emulsion for injection and preparing method thereof
  • Alprostadil submicron emulsion for injection and preparing method thereof
  • Alprostadil submicron emulsion for injection and preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: selection of lyoprotectant

[0041] 1. Prescription:

[0042] Alprostadil (PGE 1 ) 5mg

[0043] Refined soybean oil 100g

[0044] Egg yolk lecithin 18g

[0045] Oleic acid 2.4g

[0046] Lyoprotectant 100g

[0047] Appropriate amount of pH adjuster

[0048]

[0049] Add water for injection to 1000ml

[0050] 2. Process:

[0051] (1) Preparation of the water phase: dissolve the lyoprotectant in water, heat to 55-70°C, and set aside;

[0052] (2) Preparation of oil phase: heat refined soybean oil to 55-70°C, add egg yolk lecithin, dissolve oleic acid, add alprostadil, stir to dissolve;

[0053] (3) Preparation of colostrum: Add the oil phase of step (2) into the water phase of step (1), at a temperature of 55-70°C, high-speed shear dispersion, shear speed of 8000rpm, and time of 15 minutes to form colostrum

[0054] (4) High-pressure homogenization: Adjust the pH of the colostrum in step (3) to 6.0-7.5...

Embodiment 2

[0076] Embodiment 2: the influence of pH on emulsion particle size and drug stability

[0077] Using sucrose as the freeze-drying protective agent, the effects of different pH values ​​on the particle size of milk particles before and after freeze-drying were investigated, and the average particle size, prostaglandin E 1 and prostaglandin A 1 content as an indicator. The results are shown in Table 2 below.

[0078] 1. Prescription

[0079] Alprostadil (PGE 1 ) 5mg

[0080] Refined soybean oil 100g

[0081] Egg yolk lecithin 18g

[0082] Oleic acid 2.4g

[0083] Sucrose 120g

[0084] Appropriate amount of pH adjuster

[0085]

[0086] Add water for injection to 1000ml

[0087] 2. Process:

[0088] (1) Preparation of the water phase: dissolve the lyoprotectant in water, heat to 55-70°C, and set aside;

[0089] (2) Preparation of oil phase: heat refined soybean oil to 55-70°C, add egg yolk lecithin, dissolve oleic acid, ad...

Embodiment 3

[0103] Embodiment 3: the comparison of freeze-drying process

[0104] Alprostadil submicroemulsion for injection is a very difficult freeze-drying system. Because it also contains liquid oil, phospholipids, oleic acid, etc., the components are relatively complex and the solution is relatively viscous. The requirements for freeze-drying conditions are extremely strict and the control is not good. , it is difficult to freeze-dry and even lead to demulsification and oil separation, and more often lead to the increase of the particle size of the emulsion after reconstitution, which exceeds the limit. Use the conventional freeze-drying method for freeze-drying: pre-freeze at -40°C to -20°C for 2 hours, dry once under reduced pressure at 0-10°C, and then dry at 15-25°C under reduced pressure Secondary drying. As a result, oil precipitation occurred during a drying process, which indicated that this method was not suitable for the freeze-drying of alprostadil submicroemulsion for in...

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Abstract

The invention discloses an alprostadil submicron emulsion for injection and a preparing method thereof. The alprostadil submicron emulsion is prepared from alprostadil, oil for injection, emulsifying agent, stabilizing agent and freeze-dry protector. The preparing method comprises following steps: (1) preparing oil phase, (2) preparing water phase, (3) preparing primary emulsion, (4) high-pressure homogenizing, (5) primary filtering, (6) sterile filling and (7) freeze drying. Particle diameters of the alprostadil submicron emulsion for injection prepared by the method are stable and uniform. Degradation productions are reduced to 10% and the effective period is prolonged to 24 months.

Description

technical field [0001] The invention relates to an alprostadil submicroemulsion for injection and a preparation method thereof. Background technique [0002] Alprostadil, also known as prostaglandin E 1 (PGE 1 ), is a highly active physiologically active substance that can inhibit platelet aggregation, thromboxane A 2 generation, atherosclerosis lipid plaque formation and the role of immune complexes, and can expand the pharmacological effects of peripheral and coronary vessels, mainly used for the treatment of chronic arterial occlusion (thromboangiitis obliterans, arteriosclerosis obliterans Etc.) limb ulcers and resting pain in limbs caused by microvascular circulation disorders, improving cardiovascular and cerebrovascular microcirculation disorders and adjuvant treatment of chronic hepatitis. The currently marketed varieties are alprostadil powder injection (cyclodextrin inclusion compound) and alprostadil injection. During clinical use, alprostadil powder injection ...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K31/5575A61K47/26A61K47/44A61P7/02A61P9/10A61P1/16
Inventor 黄海马红萍宋华先张占军程宇刘启悦
Owner 辽宁中海康生物制药股份有限公司
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