CN115137697A - D-chlorprostenol sodium injection and preparation method and application thereof - Google Patents

D-chlorprostenol sodium injection and preparation method and application thereof Download PDF

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Publication number
CN115137697A
CN115137697A CN202110940561.XA CN202110940561A CN115137697A CN 115137697 A CN115137697 A CN 115137697A CN 202110940561 A CN202110940561 A CN 202110940561A CN 115137697 A CN115137697 A CN 115137697A
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injection
sodium
animal
parts
stabilizer
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CN115137697B (en
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陈君德
王云斌
方斌奇
岳春梅
杜雄伟
郭羽
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Ningbo Creator Animal Pharmacy Co ltd
Zhejiang Keruite Biotechnology Co ltd
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Ningbo Creator Animal Pharmacy Co ltd
Zhejiang Keruite Biotechnology Co ltd
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract

The D-chlorophrostone sodium injection is prepared with progestogen in 5-15 weight portions, animal injection organic solvent 25-40 weight portions, animal injection organic carrier 10-20 weight portions, cosolvent 5-10 weight portions, animal injection stabilizer 1-3 weight portions, and water 50-200 weight portions, and the progestogen includes at least D-chlorophrostone sodium. According to the technical scheme, the ovulation effect of the injection on the female animals and the secretion of the female hormone are effectively improved by adding the composition of multiple progestagens into the injection. By adding a certain amount of organic solvent and cosolvent for compounding, the stability and usability of the injection are improved. And a certain amount of organic carrier is added, so that a part of the progestational hormone is coated in the organic carrier to form a slow release effect, and the effect of promoting ovulation for a long time is achieved after injection of the female animals, so that the conception rate of the female animals is improved.

Description

D-chlorprostinol sodium injection and preparation method and application thereof
Technical Field
The invention belongs to the technical field of veterinary medicaments, and particularly relates to a D-chlorophrostone sodium injection as well as a preparation method and application thereof.
Background
Clonoprost (sodium) is a synthetic racemic prostaglandin F2 alpha analogue. The loprostenol is generally synthesized as a racemic mixture consisting of a pair of isomers, D-and L-loprostenol, in a ratio of about 1: l. D-chlorophrostenol and L-chlorophrostenol are separated from each other through a specific synthesis way and a chromatography method, and then the D-chlorophrostenol is obtained after separation and purification, wherein the D-chlorophrostenol exists in a sodium salt form, namely D-chlorophrostenol sodium. Like other prostaglandin analogues, in the luteal phase of an estrus cycle, D-chlorophrostone can induce the rapid regression of the corpus luteum, increase the release of follicle stimulating hormone, promote follicle maturation, increase estrogen secretion, enable female animals to estrus and effectively ovulate, and simultaneously, D-chlorophrostone can cause uterine smooth muscle contraction and has a contractile effect on the uterus. However, the existing D-chlorophrostone medicines have limited effects on accelerating the follicular maturation of the female animals and the estrogen secretion.
Disclosure of Invention
In order to solve the technical problems, the first aspect of the invention provides a D-chlorophrostone sodium injection, the preparation raw materials of which comprise, by weight, at least 5-15 parts of progestogen, 25-40 parts of organic solvent for animal injection, 10-20 parts of organic carrier for animal injection, 5-10 parts of cosolvent, 1-3 parts of stabilizer for animal injection and 50-200 parts of water, wherein the progestogen at least comprises D-chlorophrostone sodium.
Preferably, the progestogen further comprises at least one or more of progesterone, progesterone analogs, estradiol benzoate, estradiol cypionate, sodium L-chloroprostate, buserelin acetate.
Preferably, the organic solvent for animal injection is at least one selected from alcohols, esters and ketones.
Preferably, the alcohol is at least one selected from the group consisting of ethanol, glycerol, propylene glycol and polyethylene glycol.
Preferably, the organic vehicle for animal injection comprises fatty acid.
Preferably, the cosolvent is selected from polysorbate 80, polyoxyethylated castor oil and its derivatives, poloxamer, lecithin, polyethylene glycol 15-hydroxystearate, cyclodextrin and its derivatives.
Preferably, the stabilizer for animal injection is an inorganic salt stabilizer and/or an organic stabilizer.
Preferably, the organic stabilizer is at least one selected from the group consisting of aminocarboxylic acids, hydroxycarboxylic acids, and hydroxyaminocarboxylic acids.
The second aspect of the invention provides a preparation method of the D-chlorophrostone sodium injection, which at least comprises the following steps:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding animal injection stabilizer and water into the mixture A, and mixing.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Has the beneficial effects that: according to the technical scheme, the composition of multiple progestagens is added into the injection, so that the ovulation effect of the injection on female animals and the secretion of the progestagens are effectively improved. By adding a certain amount of organic solvent and cosolvent for compounding, the stability and usability of the injection are improved. And a certain amount of organic carrier is added, so that a part of the progestogen is coated in the organic carrier to form a slow release effect, and the effect of promoting ovulation for a long time is achieved after the injection is performed on the female animals, so that the conception rate of the female animals is improved. Compared with the common D-chlorophrostone sodium injection, the D-chlorophrostone sodium in the technical scheme has the advantages that the effect is improved by more than 2 times, the using amount is less, and the effect is better.
Detailed Description
For purposes of the following detailed description, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range from "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10. Exemplary subranges of the range 1 to 10 include, but are not limited to, 1 to 6.1, 3.5 to 7.8, 5.5 to 10, and the like.
In order to solve the technical problems, the first aspect of the invention provides a D-treprostinil sodium injection, which comprises, by weight, at least 5-15 parts of progestogen, 25-40 parts of an organic solvent for animal injection, 10-20 parts of an organic carrier for animal injection, 5-10 parts of a cosolvent, 1-3 parts of a stabilizer for animal injection and 50-200 parts of water, wherein the progestogen at least comprises D-treprostinil sodium.
As a preferable technical scheme, the progestogen also comprises at least one or more of progesterone, progesterone analogue, estradiol benzoate, estradiol cypionate, L-treprostinil sodium and buserelin acetate.
As a preferable technical scheme, the progestogen also comprises estradiol benzoate, and the mass ratio of the D-chlorophrostone sodium and the estradiol benzoate is (7-10): 1.
the inventor finds that the progestogen is compounded by using the D-chlorophrostone sodium and the estradiol benzoate according to a certain proportion, can better induce the corpus luteum to quickly subside, quickly dissolve the corpus luteum and induce the female animals to estrus. The pharmaceutical composition can reduce the level of progesterone in circulating blood, promote the release of follistatin to be increased, promote follicular maturation, increase estrogen secretion, and also can promote endometrial hyperplasia and enhance uterine smooth muscle contraction, but when the dosage of the estradiol benzoate is too high, the secretion of estrogen can be inhibited, and when the dosage is too low, a better ovulation promoting effect cannot be achieved.
In a preferred embodiment, the organic solvent for animal injection is at least one selected from alcohols, esters and ketones.
In a preferred embodiment, the alcohol is at least one selected from ethanol, glycerol, propylene glycol and polyethylene glycol.
As a preferred technical solution, the ester is selected from ethyl acetate.
As a preferred technical solution, the ketone is acetone.
As a preferable technical scheme, the organic solvent for animal injection is a mixture of alcohols, esters and ketones, and the mass ratio of the alcohols, the esters and the ketones is (3-5): 1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone.
The inventors found that the use of a certain mixture of propylene glycol, ethyl acetate and acetone for dissolving D-chlorophrostone sodium and estradiol benzoate has not only a good dissolving effect but also a good lubricating effect, and can relieve pain feeling of animals when injected to the animals.
As a preferable technical scheme, the organic carrier for animal injection comprises fatty acid.
As a preferable technical scheme, the organic vehicle for animal injection is at least one of rapeseed oil, soybean oil, sesame oil and palm oil.
As a preferable technical scheme, the organic carrier for palm oil animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is (5-6): 1, the palm oil is 24-degree palm oil.
The inventor finds that the slow release property of the injection can be improved by adding a certain amount of rapeseed oil and palm oil as organic carriers for animal injection, so that the medicine can be slowly released in an animal body, female hormone in the animal body can be kept at a high level for a period of time, and the stability of the injection is improved.
As a preferable technical scheme, the cosolvent is selected from polysorbate 80, polyoxyethylene castor oil and derivatives thereof, poloxamer, lecithin, polyethylene glycol 15-hydroxystearate, cyclodextrin and derivatives thereof.
As a preferable technical scheme, the cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is (1-3): 1, the cyclodextrin is beta-cyclodextrin.
The inventor finds that when a certain amount of polysorbate 80 is mixed with cyclodextrin, the solubility of the drug in water can be improved, the overall compatibility of the injection is improved, the stability of the drug components can be improved, and particularly when the polysorbate 80 and the beta-cyclodextrin are mixed, the beta-cyclodextrin can protect the drug in a hydrophobic cavity, so that the drug is prevented from being invaded by other components, the slow release performance of the drug can be improved, and the effective period can be prolonged.
In a preferred embodiment, the stabilizer for animal injection is an inorganic salt stabilizer and/or an organic stabilizer.
In a preferred embodiment, the organic stabilizer is at least one selected from the group consisting of aminocarboxylic acids, hydroxycarboxylic acids, and hydroxyaminocarboxylic acids.
As a preferable technical scheme, the hydroxycarboxylic acid is sodium alginate.
The inventor uses the sodium alginate as a stabilizer in the injection, which not only can prevent the foreign substances in the injection from settling or aggregating, but also can easily biodegrade the sodium alginate after use, and cannot influence the health of animals.
The second aspect of the invention provides a preparation method of the D-chlorophrostone sodium injection, which at least comprises the following steps:
(1) Adding the progestogen, the organic solvent for animal injection, the organic carrier for animal injection and the cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding animal injection stabilizer and water into the mixture A, and mixing.
The D-chlorophrostone sodium injection is applied to the livestock and poultry.
The application of the D-chlorprostinol sodium injection on the dairy cattle: the D-chlorophrostone sodium injection in the technical scheme has the advantages that the effect is superior to that of common chlorophrostone sodium, 0.15mg per head of D-chlorophrostone sodium in the technical scheme is injected into a cow, the D-chlorophrostone sodium injection in the technical scheme can be manufactured into 20 ML/bottle, 10 cows can be continuously injected into each bottle, the use is more convenient, the cost is saved, the D-chlorophrostone sodium injection is also suitable for the cow timing insemination technology and the postpartum health care, and the D-chlorophrostone sodium injection in the technical scheme has no medicine fallout device and is safer to use.
The application of the D-chlorprostinol sodium injection on pigs comprises the following steps: the corpus luteum is well known to those skilled in the art as a substance that secretes progesterone, a tocolytic hormone. The sow is not in heat due to the excessive corpus luteum. The D-chlorophrostone sodium is dextroisomer of chlorophrostone sodium, and the activity is 180 times higher than that of raceme; uterine receptors are 10 times higher. The D-treprostinil sodium has the strongest function of dissolving corpus luteum, and the D-treprostinil sodium injection in the technical scheme can directly act on corpus luteum cells to reduce the secretion of progesterone on one hand, and can selectively reduce the blood flow of the corpus luteum due to the stronger function of contracting vascular smooth muscle to cause the ischemia of the corpus luteum and the degeneration of the corpus luteum on the other hand, so the D-treprostinil sodium can be used for treating the persistent corpus luteum infertility.
In addition, the starting materials used are all commercially available, unless otherwise specified.
Example 1
The first aspect of the embodiment provides a D-treprostinil sodium injection, which is prepared from, by weight, 5 parts of a progestogen, 25 parts of an organic solvent for animal injection, 10 parts of an organic carrier for animal injection, 5 parts of a cosolvent, 1 part of a stabilizer for animal injection, and 50 parts of water, wherein the progestogen comprises D-treprostinil sodium and estradiol benzoate, and a mass ratio of the D-treprostinil sodium to the estradiol benzoate is 7:1, the D-cloprostol sodium is purchased from korie biotechnology limited, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from Tianjin Xiencsi Biotechnology, inc., CAS number: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols, esters and ketones, wherein the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24 degree palm oil, the rapeseed oil is available from ewingeiville chemicals (shanghai) ltd, and the 24 degree palm oil is available from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is 1:1, the cyclodextrin is beta-cyclodextrin, the polysorbate 80 is purchased from Shaanxi Yangyuan Shen Biotechnology Limited, the beta-cyclodextrin is purchased from Kyowa Macro Biotechnology Limited, and the product number is as follows: 4523699. the stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding stabilizer for animal injection and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Example 2
The first aspect of the embodiment provides a D-treprostinil sodium injection, which is prepared from, by weight, 10 parts of a progestogen, 35 parts of an organic solvent for animal injection, 15 parts of an organic carrier for animal injection, 7 parts of a cosolvent, 2 parts of a stabilizer for animal injection, and 130 parts of water, wherein the progestogen includes D-treprostinil sodium and estradiol benzoate, and a mass ratio of the D-treprostinil sodium to the estradiol benzoate is 7:1, the D-treprostinil sodium was purchased from kory biotechnology, inc, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from Tianjin Xiencsi Biotechnology, inc., CAS number: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols, esters and ketones, and the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24-degree palm oil, the rapeseed oil is purchased from ewingwerer chemical (shanghai) ltd, and the 24-degree palm oil is purchased from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is 1:1, the cyclodextrin is beta-cyclodextrin, the polysorbate 80 is purchased from Shanxi Yangyuan biological technology, inc., the beta-cyclodextrin is purchased from Kyowa Macro-Run biological technology, inc., the Cat number: 4523699. the stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding the animal injection stabilizer and water into the mixture A, mixing, inspecting, and canning.
The D-chlorophrostone sodium injection is applied to the livestock and poultry.
Example 3
The first aspect of the embodiment provides a D-treprostinil sodium injection, which is prepared from, by weight, 15 parts of a progestogen, 40 parts of an organic solvent for animal injection, 20 parts of an organic carrier for animal injection, 10 parts of a cosolvent, 3 parts of a stabilizer for animal injection, and 200 parts of water, wherein the progestogen comprises D-treprostinil sodium and estradiol benzoate, and the mass ratio of the D-treprostinil sodium to the estradiol benzoate is 7:1, the D-cloprostol sodium is purchased from korie biotechnology limited, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from tianjin xienci bio-technology limited, CAS No.: 50-50-0. The organic solvent for animal injection is a mixture of alcohols, esters and ketones, and the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24-degree palm oil, the rapeseed oil is purchased from ewingwerer chemical (shanghai) ltd, and the 24-degree palm oil is purchased from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is 1:1, the cyclodextrin is beta-cyclodextrin, the polysorbate 80 is purchased from Shanxi Yangyuan biological technology, inc., the beta-cyclodextrin is purchased from Kyowa Macro-Run biological technology, inc., the Cat number: 4523699. the stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotechnology Co.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding stabilizer for animal injection and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Example 4
The first aspect of the embodiment provides a D-treprostinil sodium injection, which is prepared from, by weight, 5 parts of a progestogen, 25 parts of an organic solvent for animal injection, 10 parts of an organic carrier for animal injection, 5 parts of a cosolvent, 1 part of a stabilizer for animal injection, and 50 parts of water, wherein the progestogen comprises D-treprostinil sodium and estradiol benzoate, and a mass ratio of the D-treprostinil sodium to the estradiol benzoate is 7:1, the D-treprostinil sodium was purchased from kory biotechnology, inc, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from Tianjin Xiencsi Biotechnology, inc., CAS number: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols, esters and ketones, and the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24-degree palm oil, the rapeseed oil is purchased from ewingwerer chemical (shanghai) ltd, and the 24-degree palm oil is purchased from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of polysorbate 80 to cyclodextrin is 1:1, the cyclodextrin is alpha-cyclodextrin, the polysorbate 80 is purchased from Shaanxi Yangyuan Shen Biotech limited, and the alpha-cyclodextrin is purchased from Shandong Nuphar Polybioscience limited. The stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding the progestogen, the organic solvent for animal injection, the organic carrier for animal injection and the cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding the animal injection stabilizer and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Example 5
The first aspect of the embodiment provides a D-treprostinil sodium injection, which is prepared from, by weight, 5 parts of a progestogen, 25 parts of an organic solvent for animal injection, 10 parts of an organic carrier for animal injection, 5 parts of a cosolvent, 1 part of a stabilizer for animal injection, and 50 parts of water, wherein the progestogen comprises D-treprostinil sodium and estradiol benzoate, and a mass ratio of the D-treprostinil sodium to the estradiol benzoate is 7:1, the D-cloprostol sodium is purchased from korie biotechnology limited, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from Tianjin Xiencsi Biotechnology, inc., CAS number: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols, esters and ketones, and the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24-degree palm oil, the rapeseed oil is purchased from ewingwerer chemical (shanghai) ltd, and the 24-degree palm oil is purchased from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of polysorbate 80 to cyclodextrin is 1:1, the cyclodextrin is gamma-cyclodextrin, the polysorbate 80 is purchased from Shaanxi Yangyuan Shen Biotech limited, and the gamma-cyclodextrin is purchased from Shandong Nuphar Polybioscience limited. The stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
The second aspect of this embodiment provides a method for preparing D-chlorophrostone sodium injection, which comprises the following steps:
(1) Adding the progestogen, the organic solvent for animal injection, the organic carrier for animal injection and the cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding the animal injection stabilizer and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Example 6
The first aspect of the present embodiment provides a D-chlorophrostone sodium injection, whose preparation raw materials include, by weight, 5 parts of a progestogen, 25 parts of an organic solvent for animal injection, 10 parts of an organic carrier for animal injection, 5 parts of a cosolvent, 1 part of a stabilizer for animal injection, and 50 parts of water, where the progestogen includes D-chlorophrostone sodium and estradiol benzoate, and a mass ratio between the D-chlorophrostone sodium and the estradiol benzoate is 7:1, the D-treprostinil sodium was purchased from kory biotechnology, inc, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from Tianjin Xiencsi Biotechnology, inc., CAS number: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols, esters and ketones, wherein the mass ratio of the alcohols, the esters and the ketones is 3:1:1, the alcohol is propylene glycol, the ester is ethyl acetate, and the ketone is acetone. The organic vehicle for animal injection was rapeseed oil, which was purchased from ewingle chemicals (shanghai) ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is 1:1, the cyclodextrin is beta-cyclodextrin, the polysorbate 80 is purchased from Shaanxi Yangyuan Shen Biotechnology Limited, the beta-cyclodextrin is purchased from Kyowa Macro Biotechnology Limited, and the product number is as follows: 4523699. the stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding stabilizer for animal injection and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Example 7
The first aspect of the present embodiment provides a D-chlorophrostone sodium injection, whose preparation raw materials include, by weight, 5 parts of a progestogen, 25 parts of an organic solvent for animal injection, 10 parts of an organic carrier for animal injection, 5 parts of a cosolvent, 1 part of a stabilizer for animal injection, and 50 parts of water, where the progestogen includes D-chlorophrostone sodium and estradiol benzoate, and a mass ratio between the D-chlorophrostone sodium and the estradiol benzoate is 7:1, the D-treprostinil sodium was purchased from kory biotechnology, inc, taizhou, CAS No.: 62561-03-9, said estradiol benzoate is available from tianjin xienci bio-technology limited, CAS No.: 50-50-0.
The organic solvent for animal injection is a mixture of alcohols and esters, and the mass ratio of the alcohols to the esters is 3:1, the alcohol is propylene glycol, and the ester is ethyl acetate. The organic carrier for animal injection is a mixture of rapeseed oil and palm oil, and the mass ratio of the rapeseed oil to the palm oil is 5:1, the palm oil is 24 degree palm oil, the rapeseed oil is available from ewingeiville chemicals (shanghai) ltd, and the 24 degree palm oil is available from guangzhou flourishing cosmetics materials ltd. The cosolvent is a mixture of polysorbate 80 and cyclodextrin, and the mass ratio of the polysorbate 80 to the cyclodextrin is 1:1, the cyclodextrin is beta-cyclodextrin, the polysorbate 80 is purchased from Shanxi Yangyuan biological technology, inc., the beta-cyclodextrin is purchased from Kyowa Macro-Run biological technology, inc., the Cat number: 4523699. the stabilizer is sodium alginate, and the sodium alginate is purchased from Shandong Jianchuan Biotech limited.
In a second aspect of this embodiment, there is provided a method for preparing the D-treprostinil sodium injection, comprising the steps of:
(1) Adding the progestogen, the organic solvent for animal injection, the organic carrier for animal injection and the cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding the animal injection stabilizer and water into the mixture A, mixing, inspecting, and canning.
The D-chlorprostenol sodium injection is applied to the livestock and poultry.
Performance testing
Performance test one
D-Chloroprostol sodium injection was prepared according to the methods of examples 1 to 7, and the stability of the prepared injection was observed, and was recorded as passed if the injection was a uniform transparent solution, and as failed if there were non-uniform substances such as flocculation, sedimentation, etc. in the injection.
Performance test 2
D-Chloroprostol sodium injection was prepared as in examples 1 to 7, and left at 2. + -. 2 ℃ for 60 days, and the long-term stability of the prepared injection was observed, and was recorded as passed if the injection was a uniform transparent solution, and as failed if there were non-uniform substances such as flocculation, sedimentation, etc. in the injection.
Stability of Long term stability
Example 1 Qualified Qualified
Example 2 Qualified Qualified
Example 3 Qualified Qualified
Example 4 Qualified Fail to be qualified
Example 5 Qualified Fail to be qualified
Example 6 Fail to be qualified Fail to be qualified
Example 7 Fail to be qualified Fail to be qualified
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in other forms, and any person skilled in the art may modify or change the technical content of the above disclosure into equivalent embodiments with equivalent changes, but all those simple modifications, equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the present invention.

Claims (10)

1. The D-chlorophrostone sodium injection is characterized by comprising, by weight, at least 5-15 parts of progestogen, 25-40 parts of an organic solvent for animal injection, 10-20 parts of an organic carrier for animal injection, 5-10 parts of a cosolvent, 1-3 parts of a stabilizer for animal injection and 50-200 parts of water, wherein the progestogen at least comprises D-chlorophrostone sodium.
2. The D-treprostinil sodium injection of claim 1, wherein the progestogen further comprises at least one or more of progesterone, progesterone analogs, estradiol benzoate, estradiol cypionate, sodium L-treprostinil, buserelin acetate.
3. The sodium D-chlorophrostate injection according to claim 1, wherein the organic solvent for animal injection is at least one selected from the group consisting of alcohols, esters and ketones.
4. The sodium D-chlorophrostate injection according to claim 1, characterized in that the alcohol is selected from at least one of ethanol, glycerol, propylene glycol and polyethylene glycol.
5. The sodium D-chloroprostate injection according to claim 1, wherein the organic vehicle for animal injection comprises fatty acid.
6. The sodium D-chloroprostate injection according to claim 1, characterized in that the cosolvent is selected from the group consisting of polysorbate 80, polyoxyethylated castor oil and its derivatives, poloxamer, lecithin, polyethylene glycol 15-hydroxystearate and cyclodextrin and its derivatives.
7. The D-chlorophrostone sodium injection according to claim 1, characterized in that the animal injection stabilizer is inorganic salt stabilizer and/or organic stabilizer.
8. The sodium D-chlorophrostate injection according to claim 1, characterized in that the organic stabilizer is at least one selected from the group consisting of aminocarboxylic acids, hydroxycarboxylic acids, and hydroxyaminocarboxylic acids.
9. A method for preparing D-treprostinil sodium injection according to any of claims 1-8, characterised in that it comprises at least the steps of:
(1) Adding progestogen, an organic solvent for animal injection, an organic carrier for animal injection and a cosolvent into a reaction kettle for mixing to obtain a mixture A;
(2) Adding stabilizer for animal injection and water into the mixture A, and mixing.
10. The D-chlorophrostone sodium injection according to any one of claims 1 to 8 is applied to the livestock and poultry.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106618A1 (en) * 2015-12-18 2017-06-22 Proinvet Innovations S.A. Formulations and methods for controlling the reproductive cycle and ovulation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106618A1 (en) * 2015-12-18 2017-06-22 Proinvet Innovations S.A. Formulations and methods for controlling the reproductive cycle and ovulation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HYUN SUK WHANG 等: "NMR Studies of the Inclusion Complex of Cloprostenol Sodium Salt with β-cyclodextrin in Aqueous Solution", 《PHARMACEUTICAL RESEARCH》, vol. 25, no. 5, pages 1142 - 1149, XP019613069 *

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