CN112516086B - Breynolone fat emulsion for injection and preparation method thereof - Google Patents
Breynolone fat emulsion for injection and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention provides a brigregate fat emulsion for injection and a preparation method thereof. The brianolone fat emulsion for injection contains brianolone, oil for injection, phospholipid, poloxamer, oleic acid and water for injection, wherein the weight percentage of each component is 0.1-1% w/v of brianolone, 10-30% w/v of oil for injection, 0.5-7% w/v of phospholipid, 0.05-0.7% w/v of poloxamer and 0.01-0.2% w/v of oleic acid. The brimonilong fat emulsion provided by the invention has uniform appearance, narrow distribution and stable quality, the average particle size is between 150-250nm, the production process is simple and feasible, the controllability is strong, and the industrial production is easy.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to a pharmaceutical preparation for resisting postpartum depression, and particularly relates to a brigrel fat emulsion for injection and a preparation method thereof.
Background
The active ingredients of the invention are brexanolone (brexanolone), also known as allopregnanolone, isopregnanolone, allopregnanolone and tetrahydroprogesterone, are natural endogenous pregnane neurosteroids, and are positive allosteric modulators of synapses and external-synaptic gamma-aminobutyric acid A type receptors. The structure is as follows:
the breynolone was originally developed by university of california, usa and later licensed to the Sage biopharmaceutical company, usa, and its injection was injected in 20193-month 19-day-of-the-year FDA approval (RLD \ RS) on the market in the United states with a specification of 20mL:100mg and a trade name of 100mg
It is suitable for treating adult puerperal depression (PPD).
Is the first drug to obtain FDA approval for treatment of postpartum depression, and contains 5mg of breynolone, 250mg of sulfobutyl-beta-cyclodextrin, 0.265mg of citric acid monohydrate, 2.57mg of sodium citrate dihydrate and water for injection per ml of intravenous solution, and hydrochloric acid/sodium hydroxide is used for pH adjustment. Wherein, the sulfobutyl-beta-cyclodextrin is a key auxiliary material of the injection and acts as a solubilizer.
Cyclodextrin-based bulking materials cause liver and kidney damage, cyclodextrin is concentrated and reabsorbed in the renal tubules, interacts with cellular structures and extracts cholesterol and other lipid membrane components therefrom, and cyclodextrin-based materials are strongly irritating to blood vessels. Although many of the marketed drugs containing sulfobutyl- β -cyclodextrin in their prescription have been shown in clinical studies to reduce the risk of renal injury in normal persons, they are still at great risk for renal insufficiency or reduction, and do not completely solve the problem of vascular irritation, and erythema, extravasation, pain and cellulitis may locally occur at the site of delivery. In addition, the sulfobutyl-beta-cyclodextrin is expensive, and the components of the marketed breynolone injection are high in proportion, so that the product cost is greatly increased.
The breynolone is insoluble in water, but the currently marketed injection only focuses on improving the drug solubility, the ratio of the breynolone to the sulfobutyl-beta-cyclodextrin is 1:50, namely the weight of the sulfobutyl-beta-cyclodextrin reaches 250mg surprisingly per ml, which inevitably greatly increases the risk of renal injury and vascular irritation.
In view of the above, it is necessary to provide a novel formulation which is highly safe, less irritating and stable in quality to solve the above problems.
Disclosure of Invention
The invention aims to solve the problem of poor solubility of the breynolone; meanwhile, aiming at the risk of toxic and side effects caused by adding a large amount of bulking agent into the existing injection on the market, the breynolone fat emulsion for injection is provided, and the safety of the preparation is greatly improved on the premise of solving the solubility.
In order to achieve the purpose, the invention provides a breynolone fat emulsion for injection, which comprises breynolone, oil for injection, phospholipid, poloxamer, oleic acid and water for injection, wherein the weight percentage of each component is as follows:
preferably, the weight percentage of the breynolone is 0.5-1% w/v, the weight percentage of the phospholipid is 1-7% w/v, the weight percentage of the poloxamer is 0.1-0.7% w/v, and the weight percentage of the oleic acid is 0.05-0.15% w/v.
The phospholipid is selected from natural phospholipid and its salt, synthetic phospholipid and its salt, or their combination.
Preferably, the content of phosphatidylcholine contained in the phospholipid is more than 75%.
Preferably, the weight ratio of the phospholipid to the poloxamer is 10: 1.
The oil for injection is selected from soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium chain monoglyceride, medium chain diglyceride, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol diester, linoleic acid glyceride, polyethylene glycol lauric acid glyceride or the combination thereof; preferably soy oil and medium chain triglycerides in a 3:1 weight ratio.
In some embodiments, the breynolone fat emulsion for injection further comprises a pH adjusting agent selected from sodium hydroxide, hydrochloric acid, citric acid, phosphoric acid, acetic acid, or any combination thereof.
Preferably, the pH of the brimonilong fat emulsion for injection is 4.0-8.0.
In some embodiments, the injectable breynolone fat emulsion further comprises an isotonic agent selected from the group consisting of glycerol, glucose, propylene glycol, polyethylene glycol, sucrose, inorganic salts, lactose, sorbitol, dextrose, or any combination thereof.
In order to achieve the above object, the present invention further provides a method for preparing an injectable breynolone fat emulsion, which is used for preparing the injectable breynolone fat emulsion according to any one of the above technical solutions, and comprises the following steps:
(1) preparation of oil phase: adding the breynolone, phospholipid, poloxamer and oleic acid into the oil for injection, heating, stirring and dissolving;
(2) preparation of the aqueous phase: adding glycerol into water for injection, heating, stirring, and dissolving;
(3) preparing colostrum: slowly adding the water phase obtained in the step (2) into the oil phase obtained in the step (1), and carrying out high-speed shearing and dispersion to form primary emulsion;
(4) preparation of refined milk: homogenizing and homogenizing the primary emulsion obtained in the step (3) under high pressure to obtain refined emulsion;
(5) and (4) filtering, filling and sterilizing the refined milk obtained in the step (4) to obtain the finished product of the breynolone fat milk for injection.
The invention has the beneficial effects that:
(1) the breynolone fat emulsion for injection provided by the invention greatly improves the safety of the preparation on the premise of solving the problem of solubility;
(2) the preparation method of the briulone fat emulsion for injection provided by the invention is convenient to operate, strong in controllability, suitable for industrial mass production and high in stability.
Drawings
FIG. 1 is a milk particle size distribution diagram of an injectable Brennolone fat milk of example 3 of the present invention after being left for 60 days at 40 ℃. + -. 75% RH.
Detailed Description
The technical solutions of the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
Comparative examples 1 to 3
The preparation methods of the fat milks of comparative examples 1 to 3 were as follows:
(1) preparation of oil phase: heating soybean oil and medium-chain triglyceride to 70 deg.C, adding lecithin, breynolone and oleic acid, stirring and dissolving to obtain oil phase;
(2) preparation of the aqueous phase: heating water for injection to 70 deg.C, adding glycerol to dissolve to obtain water phase;
(3) preparing colostrum: slowly adding the water phase into the oil phase at a high shear speed of 12000rpm, and shearing for 10min to obtain primary emulsion;
(4) preparation of refined milk: adjusting pH to 6.5-7.0(0.1M NaOH), and supplementing water for full injection; homogenizing the primary emulsion under high pressure, and performing 4 cycles under the homogenization condition of 800bar pressure to obtain refined emulsion;
(5) and (4) filtering, filling and sterilizing the refined milk obtained in the step (4) (F0 is more than 8) to obtain the fat milk.
The preparation steps of comparative example 1, comparative example 2 and comparative example 3 are the same, and the main difference is that the formulas are different, and the preparation method comprises the following steps:
formulation of comparative example 1:
| prescription | Dosage of | ％(w/v) | Function(s) | |
| Breynolone | 5g | 0.5 | Active ingredient | |
| Soybean | 100g | 10 | Oil phase | |
| Medium chain | 100g | 10 | Oil phase | |
| Lecithin E80 | 25g | 2.5 | Emulsifier | |
| Glycerol | 22.5g | 2.25 | Isotonic regulator | |
| Oleic acid | 0.6g | 0.06 | Stabilizer | |
| Water for injection | To 1000mL | Aqueous phase |
Formulation of comparative example 2:
| prescription | Dosage of | ％(w/v) | Function(s) |
| Breynolone | 5g | 0.5 | Active ingredient |
| Soybean oil | 140g | 14 | Oil phase |
| Medium chain oil triesters | 140g | 14 | Oil phase |
| Lecithin E80 | 25g | 2.5 | Emulsifier |
| Glycerol | 22.5g | 2.25 | Isotonic regulator |
| Oleic acid | 0.6g | 0.06 | Stabilizer |
| Water for injection | To 1000mL | Aqueous phase |
Formulation of comparative example 3:
because the water solubility of the breynolone is poor and the fat solubility is relatively common, the investigation on the proportion and the dosage of the oil for injection is very important, and the investigation needs to be carried out by a method for investigating the centrifugal stability of the fat emulsion for injection.
The specific operation steps and the investigation indexes are as follows:
the self-made refined emulsions prepared in comparative examples 1 to 3 are placed in a 10mL clean centrifuge tube, and after centrifugation is carried out at 5000rpm for 10min, the emulsion is uniform, no drug precipitation, oil-water stratification or oil drop floating is caused, the particle size, Zeta potential and pH value of the emulsion are not obviously changed, and specific results are shown in Table 1.
TABLE 1 values of various investigation indexes before and after centrifugation
As can be seen from Table 1, comparative example 3 has good centrifugal stability, the particle size increases from 221.6nm before centrifugation to 247.2nm, which is slightly larger, and the proportion and the type of the emulsifier adjusted subsequently are improved. From table 1, it can be seen that: 1) the solubility of the breynolone in medium-chain triglyceride is relatively good; 2) the preparation of the fat emulsion for injection needs to control the medicine in the oil in a certain supersaturated state, and the medicine is relatively stable.
Example 1
(1) preparation of oil phase: heating soybean oil and medium chain triglyceride to 70 deg.C, adding Breynolone, lecithin and oleic acid, heating, stirring, and dissolving to obtain oil phase;
(2) preparation of the aqueous phase: heating water for injection to 70 deg.C, adding glycerol, stirring, and dissolving to obtain water phase;
(3) preparing colostrum: slowly adding the water phase obtained in the step (2) into the oil phase obtained in the step (1) at a high shear speed of 12000rpm, and carrying out high-speed shear dispersion for 10min to form primary emulsion;
(4) preparation of refined milk: adjusting pH to 6.5-7.0(0.1M NaOH), and supplementing water for full injection; homogenizing and homogenizing the primary emulsion obtained in the step (3) at high pressure, and performing 4 cycles under the homogenizing condition of 800bar pressure to obtain refined emulsion;
(5) and (4) filtering, filling and sterilizing the refined milk obtained in the step (4) (F0 is more than 8), so as to obtain the finished product of the breynolone fat milk for injection.
Recipe for example 1:
| prescription | Dosage of | ％(w/v) | Function(s) |
| Breynolone | 5g | 0.5 | Active ingredient |
| Soybean oil | 70g | 7 | Oil phase |
| Medium chain oil triesters | 210g | 21 | Oil phase |
| Lecithin E80 | 35g | 3.5 | Emulsifier |
| Glycerol | 22.5g | 2.25 | Isotonic regulator |
| Oleic acid | 0.6g | 0.06 | Stabilizer |
| Water for injection | To 1000mL | Aqueous phase |
Example 2 and example 3
Embodiments 2 and 3 respectively provide a method for preparing an injectable breynolone fat emulsion, which comprises the following steps:
(1) preparation of oil phase: heating soybean oil and medium chain triglyceride to 70 deg.C, adding lecithin, breynolone, oleic acid and poloxamer, stirring, and dissolving to obtain oil phase;
(2) preparation of the aqueous phase: heating water for injection to 70 deg.C, adding glycerol to dissolve to obtain water phase;
(3) preparing colostrum: slowly adding the water phase into the oil phase at a high shear speed of 12000rpm, and shearing for 10min to obtain primary emulsion;
(4) adjusting pH to 6.5-7.0(0.1M NaOH), and supplementing water for full injection;
(5) preparation of refined milk: homogenizing the primary emulsion under high pressure, and performing 4 cycles under the homogenization condition of 800bar pressure to obtain refined emulsion;
(6) filtering, filling and sterilizing the refined milk (F0 is more than 8) to obtain the finished product of the breynolone fat milk for injection.
The preparation steps of the example 2 and the example 3 are basically the same, and the main difference is the difference of the prescription, which is as follows:
formulation of example 2:
| prescription | Dosage of | ％(w/v) | Function(s) |
| Breynolone | 5g | 0.5 | Active ingredient |
| Soybean oil | 70g | 7 | Oil phase |
| Medium chain oil triesters | 210g | 21 | Oil phase |
| Lecithin E80 | 35g | 3.5 | Emulsifier |
| Poloxamer 188 | 3.5g | 0.35 | Auxiliary emulsifier |
| Glycerol | 22.5g | 2.25 | Isotonic regulator |
| Oleic acid | 0.6g | 0.06 | Stabilizer |
| Water for injection | To 1000mL | Aqueous phase |
Formulation of example 3:
example 4 stability study
In this example, the samples prepared in comparative example 3 and examples 1 to 3 were placed at 40 ℃. + -. 75% RH, and the average particle size, pH and content of fat milk were measured for 0 day, 30 days and 60 days, respectively. The specific results are shown in Table 2.
Table 2 examination of each item of test index
From the above table of emulsion particle results, it can be seen that the stability results of example 2 and example 3, which have a phospholipid and poloxamer complex emulsifier, are relatively good after being left for 60 days at 40 ℃, compared to example 1, which has only lecithin E80 as the emulsifier; the emulsifying effect is good under the action of the phospholipid and poloxamer composite emulsifier, and the emulsion particles are relatively stable in the placing process. In particular, in example 3, when lecithin S75 was used as an emulsifier, the particle size of the milk particles was relatively small compared to examples 1 and 2, which used lecithin E80 as an emulsifier.
From the pH and content results, it can also be seen that the pH and content measures of example 2 and example 3 are relatively stable during standing compared to example 1.
In conclusion, when the weight ratio of the medium-chain triglyceride to the soybean oil in the formula is controlled to be 3:1 (the weight percentage in the formula is 25-30% w/v), lecithin (the content of phosphatidylcholine is more than 75%) and poloxamer are used as a composite emulsifier, and the weight ratio of the lecithin to the poloxamer is 10:1, the prepared brinolone fat emulsion for injection has good stability.
Example 5 vascular irritation test
This example is a blood vessel stimulation test of the briulon fat emulsions for injection prepared in example 1 and example 3.
6 healthy rabbits were randomly divided into 2 groups, each group had 3 animals, and the breynolone injection solution for injection (containing 250mg/mL of sulfobutyl- β -cyclodextrin), the breynolone fat emulsion for injection prepared in example 1, the breynolone fat emulsion for injection prepared in example 3 were injected into the vein of the left ear, and the equal volume of 0.9% sodium chloride injection was administered into the right ear. Slowly injecting the test substance at a position 1cm away from the top end of the ear marginal vein, and dripping once a day for 3 days continuously, wherein the administration dosage of the injection breynolone injection and the breynolone fat emulsion is the same. The irritation response at the injection site and in the ear epidermis and surrounding subcutaneous tissues was observed after each administration and before the next administration and recorded. The results of the specific vascular irritation test are shown in table 3.
TABLE 3 results of the vascular irritation test
| Group of | Results of the vascular irritation test |
| 0.9% sodium chloride solution | The blood vessel has no obvious expansion, and no pathological changes such as thrombosis and the like are found in the wall. |
| Breynolone injection | The blood vessel has no obvious expansion, and the lesion such as thrombosis and the like is slightly seen in the wall. |
| Example 1 | The blood vessel has no obvious expansion, and no pathological changes such as thrombosis and the like are found in the wall. |
| Example 3 | The blood vessel has no obvious expansion, and no pathological changes such as thrombosis and the like are found in the wall. |
The test result shows that the morphology of the brimonilone fat emulsion for injection prepared in the example 1 and the example 3 is obviously superior to that of brimonilone injection (containing 250mg/mL of sulfobutyl-beta-cyclodextrin), and the brimonilone fat emulsion has no obvious irritation.
Example 6 hemolytic experiment
This example is a hemolytic experiment of the breynolone fat emulsion for injection prepared in examples 1-3:
taking a plurality of milliliters of rabbit blood, slightly stirring the rabbit blood with a glass rod to remove fibrin, adding physiological saline for shaking up, centrifuging and then pouring off supernatant, repeating the operation for 3 to 4 times until the supernatant is not red and transparent, and preparing 2 percent erythrocyte suspension with 0.9 percent sodium chloride injection for test.
Adding 2% erythrocyte suspension and normal saline into the test tube, placing in water bath at 37 ℃, continuously observing for 4 hours, and recording whether hemolysis and cell agglutination occur at 0.5h, 1h, 2h, 3h and 4h respectively. The results of the specific hemolytic experiments are shown in Table 4.
Judging standard of hemolysis:
1) the solution was clear red, and no cells remained at the bottom of the tube, indicating total hemolysis (positive).
2) The solution was clear red or brownish red, with a small number of red blood cells at the bottom of the tube, indicating partial hemolysis (positive).
3) The cells all settled down and the supernatant was milky white, indicating no hemolysis (negative).
TABLE 4 in vitro hemolysis test results
| Group/time | 0.5h | 1h | 2h | 3h | 4h |
| Physiological saline group | Negative of | Negative of | Negative of | Negative of | Negative of |
| Example 1 | Negative of | Negative of | Negative of | Negative of | Negative of |
| Example 2 | Negative of | Negative of | Negative of | Negative of | Negative of |
| Example 3 | Negative of | Negative of | Negative of | Negative of | Negative of |
The results of this experiment show that the breynolone fat emulsion (examples 1-3) is free from hemolysis and erythrocyte agglutination.
The experimental results of the comprehensive examples 4-6 show that the breynolone fat emulsion for injection provided by the invention has stable quality, can hopefully replace the water injection on the market to meet the clinical application, can be used as a medicine for treating postpartum depression, and can ensure the curative effect and safety and reduce the vascular irritation.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the spirit and scope of the present invention.
Claims (10)
1. The brinolone fat emulsion for injection is characterized in that: comprises breynolone, oil for injection, phospholipid, poloxamer, oleic acid and water for injection, wherein the weight percentage of each component is as follows:
0.1-1.0% w/v of breynolone
10.0-30.0% w/v oil for injection
Phospholipid 0.5-7.0% w/v
Poloxamer 0.05-0.7% w/v
Oleic acid 0.01-0.2% w/v;
and the content of phosphatidylcholine contained in the phospholipid is more than 75%.
2. The briulone fat emulsion for injection according to claim 1, characterized in that: the weight percentage of the breynolone is 0.5-1% w/v, the weight percentage of the phospholipid is 1-7% w/v, the weight percentage of the poloxamer is 0.1-0.7% w/v, and the weight percentage of the oleic acid is 0.05-0.15% w/v.
3. The briulone fat emulsion for injection according to claim 1, characterized in that: the phospholipid is selected from natural phospholipid and its salt, synthetic phospholipid and its salt, or their combination.
4. The briulone fat emulsion for injection according to claim 1, characterized in that: the weight ratio of the phospholipid to the poloxamer is 10: 1.
5. The briulone fat emulsion for injection according to claim 1, characterized in that: the oil for injection is selected from soybean oil, safflower oil, cotton seed oil, olive oil, coconut oil, castor oil, fish oil, medium chain monoglyceride, medium chain diglyceride, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol diester, linoleic acid glyceride, polyethylene glycol lauric acid glyceride or their combination.
6. The briulone fat emulsion for injection according to claim 5, characterized in that: the oil for injection is a combination of soybean oil and medium chain triglyceride, and the weight ratio of the soybean oil to the medium chain triglyceride is 3: 1.
7. The briulone fat emulsion for injection according to claim 1, characterized in that: further comprising a pH adjusting agent selected from sodium hydroxide, hydrochloric acid, citric acid, phosphoric acid, acetic acid, or any combination thereof.
8. The briulone fat emulsion for injection according to claim 1, characterized in that: the pH value of the breynolone fat emulsion for injection is 4.0-8.0.
9. A briulon fat emulsion for injection according to claim 1, characterized in that: further comprising an isotonic agent selected from the group consisting of glycerol, glucose, propylene glycol, polyethylene glycol, sucrose, inorganic salts, lactose, sorbitol, dextrose, or any combination thereof.
10. A method for preparing the breynolone fat emulsion for injection according to any one of claims 1 to 9, which comprises the following steps:
(1) preparation of oil phase: adding the breynolone, phospholipid, poloxamer and oleic acid into the oil for injection, heating, stirring and dissolving;
(2) preparation of the aqueous phase: adding glycerol into water for injection, heating, stirring, and dissolving;
(3) preparing colostrum: slowly adding the water phase obtained in the step (2) into the oil phase obtained in the step (1), and carrying out high-speed shearing and dispersion to form primary emulsion;
(4) preparation of refined milk: homogenizing and homogenizing the primary emulsion obtained in the step (3) under high pressure to obtain refined emulsion;
(5) and (4) filtering, filling and sterilizing the refined milk obtained in the step (4) to obtain the finished product of the breynolone fat milk for injection.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109414444A (en) * | 2016-03-08 | 2019-03-01 | 萨奇治疗股份有限公司 | Neuroactive steroids, its composition and purposes |
| WO2020083839A1 (en) * | 2018-10-22 | 2020-04-30 | Industriale Chimica S.R.L. | Process for the preparation of 3alpha-hydroxy-5αlpha-pregnan-20-one (brexanolone) |
| WO2020231837A1 (en) * | 2019-05-10 | 2020-11-19 | Brii Biosciences, Inc. | Pharmaceutical composition containing brexanolone, ganaxolone, or zuranolone, and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109414444A (en) * | 2016-03-08 | 2019-03-01 | 萨奇治疗股份有限公司 | Neuroactive steroids, its composition and purposes |
| WO2020083839A1 (en) * | 2018-10-22 | 2020-04-30 | Industriale Chimica S.R.L. | Process for the preparation of 3alpha-hydroxy-5αlpha-pregnan-20-one (brexanolone) |
| WO2020231837A1 (en) * | 2019-05-10 | 2020-11-19 | Brii Biosciences, Inc. | Pharmaceutical composition containing brexanolone, ganaxolone, or zuranolone, and use thereof |
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