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A preparation method for preparing sustained-release leuprolide acetate microspheres

A technology of leuprolide acetate and leuprolide, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve the problem of long release time and increased particle size of microspheres , increase the difficulty of industrialization and other issues

Active Publication Date: 2018-10-16
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] 680-683) adding 5% sodium chloride to the water phase makes the w / o / w emulsion more stable, and the average particle size of the prepared 3-month slow-release microspheres is 117 μm. Compared with the prescription of the marketed product, an auxiliary material is added The addition of sodium chloride, and the particle size of the microspheres increased significantly; the newly added excipients in this literature will greatly increase the difficulty of industrialization, and the increase in the particle size of the microspheres will increase the pain level during clinical injection
[0006] Hiroaki Okada dissolved 500mg of leuprolide acetate in distilled water and 4g of PLA in 7.5ml of dichloromethane in 1994 to prepare the water phase and oil phase respectively, and then prepared leuprolide acetate microspheres, disclosed in the study The effect of drug loading and molecular weight of PLA on the release performance of leuprolide acetate PLA sustained-release microspheres for 3 months. It was found that PLGA had a longer sustained-release time than PLA, indicating that for 3-month sustained-release microspheres It is more suitable to use PLA; the increase of drug loading will increase the burst release, and the optimized microspheres prepared by this document can be continuously released for 3 months through prescription and process, but a severe burst will be produced in the eighth week (H.Okada, Y.Doken, Y.Ogawa, H.Toguchi, Preparation of three-month depotinjectable microspheres of leuprorelin acetate using biodegradable polymers, Pharm.Res.11(1994)1143-1147)

Method used

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  • A preparation method for preparing sustained-release leuprolide acetate microspheres
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  • A preparation method for preparing sustained-release leuprolide acetate microspheres

Examples

Experimental program
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Effect test

Embodiment 1

[0053] (1) 225mg of leuprolide acetate is dissolved in 150ul of water for injection to form a leuprolide aqueous solution with a leuprolide concentration of 1.5g / ml;

[0054] (2) 2g PLA was dissolved in 6.26ml methylene chloride to form a PLA methylene chloride solution with a PLA concentration of 320mg / ml;

[0055] (3) Mix the above two solutions and ultrasonically form colostrum (o / w);

[0056] (4) Add colostrum (o / w) to 2L 0.5% PVA (Polyvinyl alcohol) solution, stir to form double milk (w / o / w);

[0057] (5) Double emulsion (w / o / w) is stirred to remove methylene chloride and form microspheres;

[0058] (6) filter, remove PVA solution, form microsphere wet product;

[0059] (7) adding an appropriate amount of mannitol solution and freeze-drying to obtain leuprolide acetate microspheres.

Embodiment 2

[0061] (1) 225mg leuprolide acetate is dissolved in water for injection to form leuprolide aqueous solution for injection;

[0062] (2) 2g PLA was dissolved in 6.26ml methylene chloride to form a PLA methylene chloride solution with a PLA concentration of 320mg / ml;

[0063] (3) Mix the above two solutions and ultrasonically form colostrum (o / w);

[0064] (4) Add colostrum (o / w) to 2L 0.5% PVA (Polyvinyl alcohol) solution, stir to form double milk (w / o / w);

[0065] (5) Double emulsion (w / o / w) is stirred to remove methylene chloride and form microspheres;

[0066] (6) filter, remove PVA solution, form microsphere wet product;

[0067] (7) adding an appropriate amount of mannitol solution and freeze-drying to obtain leuprolide acetate microspheres.

[0068] The leuprolide concentration in the leuprolide aqueous solution for injection in the step (1) is adjusted to 0.9g / ml, 1.0g / ml, 1.3g / ml, 1.5g / ml, 2.0g / ml, 2.5 g / ml, 2.7g / ml and according to the method test blood drug concen...

Embodiment 3

[0074] Two groups of male Beagle dogs: G1 and G2, 4 dogs in each group were subcutaneously injected with 0.35 mg / kg leuprolide; serum samples were collected at different time points, treated with solid-phase extraction and organic solvent respectively, and treated with liquid The concentration of leuprolide in the serum of groups G1 and G2 was determined by phase chromatography tandem mass spectrometry. The quantitative range of leuprolide is 0.100-50.0ng / mL and 0.0200-10.0ng / mL.

[0075] The leuprolide acetate injected by the male Beagle dogs of the G1 group was prepared according to the method described in Example 1 of the present invention;

[0076] The leuprolide acetate injected into the male beagle dogs in the G2 group was leuprolide acetate PLA sustained-release microspheres (trade name "LUPRON DEPOT-PED") for 3 months.

[0077] The 4 male Beagle dogs in the G1 group are numbered G1M01, G1M02, G1M03, and G1M04;

[0078] The 4 male Beagle dogs in the G2 group are numbe...

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Abstract

The invention aims at providing a preparation method of sustained-release leuprolide acetate microspheres. The preparation method comprises the following steps: (1) dissolving leuprolide acetate in water for injection, thus forming leuprolide acetate aqueous solution for injection, wherein the concentration of leuprolide acetate is 1g / ml-2.5g / ml; (2) dissolving PLA in methylene dichloride, thus forming PLA methylene dichloride solution, wherein the concentration of PLA in the PLA methylene dichloride solution is 280mg / ml-350mg / ml; (3) mixing the leuprolide acetate aqueous solution for injection obtained in the step (1) and the PLA methylene dichloride solution obtained in the step (2), and carrying out ultrasonic treatment to obtain primary emulsion; (4) adding the primary emulsion obtained in the step (3) into PVA solution, and carrying out stirring to obtain compound emulsion; and (5) stirring the compound emulsion, filtering the stirred compound emulsion, adding mannitol solution into microsphere wet products, and carrying out freeze-drying to obtain the sustained-release leuprolide acetate microspheres.

Description

technical field [0001] The invention relates to a preparation method of a freeze-dried preparation of sustained-release leuprolide acetate microspheres. Background technique [0002] Leuprolide acetate is a highly active LH-RH derivative. Its resistance to proteolytic enzymes and affinity to LH-RH receptors is stronger than that of LH-RH. It can effectively inhibit the function of the pituitary-gonadal system. Clinically, it is mainly For the treatment of prostate cancer, endometriosis and premenopausal breast cancer. Since the treatment of prostate cancer, endometriosis and premenopausal breast cancer usually takes several months to 1 year or even more than a year, ordinary leuprolide acetate injection and 1-month sustained-release microsphere preparation will give patients The drug brought about a great change, and the research and marketing of longer-term sustained-release preparations has become the research and development trend of leuprolide acetate injection. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/19A61K38/09A61K47/34A61K47/32A61K47/26A61P15/00A61P35/00
CPCA61K9/0002A61K9/0019A61K9/19A61K38/09A61K47/26A61K47/32A61K47/34
Inventor 陆文岐王燕清孔祥生徐鹏刘智慧蔡诗敏高田宇陈斌
Owner LIVZON PHARM GRP INC