PHARMACEUTICAL PREPARATION AND PREPARATION METHOD THEREFOR

Abstract

A pharmaceutical preparation containing a GABA.sub.A receptor reinforcing agent and a bacteriostat, a preparation method therefor, and use of the pharmaceutical preparation in preparing a drug for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis in animals or humans, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy. The GABA.sub.A receptor reinforcing agent is as represented by formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein R.sup.1, R.sup.2 and n are defined in the description.

##STR00001##

Claims

1. A pharmaceutical preparation, comprising: (A) 0.01 w/v%-5 w/v% of an active ingredient, wherein the active ingredient is a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, ##STR00032## wherein R.sup.1 and R.sup.2 are each independently selected from H, C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl; and n is selected from 1 or 2, or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form C.sub.3-6 cycloalkyl; and (B) 0.0005 w/v%-0.1 w/v% of a bacteriostat.

2. The pharmaceutical preparation according to claim 1, wherein R.sup.1 is selected from H, methyl, ethyl, or isopropyl; and R.sup.2 is selected from methyl, ethyl, isopropyl or cyclopropyl.

3. The pharmaceutical preparation according to claim 2, wherein the compound of general formula (I) is selected from one of the following structures: ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## .

4. The pharmaceutical preparation according to claim 1, wherein the compound of general formula (I) is selected from one of the following structures: ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## .

5. The pharmaceutical preparation according to claim 1, wherein the prodrug of the compound of formula (I) is selected from a compound of formula (II) below or a stereoisomer and a pharmaceutically acceptable salt: ##STR00060## .

6. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is in the form of a fat emulsion, and the fat emulsion further comprises 5 w/v%-30 w/v% of an oil ingredient and 0.1 w/v%-5 w/v% of an emulsifier.

7. The pharmaceutical preparation according to claim 6, wherein the fat emulsion comprises 0.05 w/v%-2.5 w/v% of the active ingredient, 10 w/v%-25 w/v% of the oil ingredient, 0.2 w/v%-2 w/v% of the emulsifier, and 0.001 w/v%-0.03 w/v% of the bacteriostat.

8. The pharmaceutical preparation according to claim 7, wherein the fat emulsion further comprises 0-4 w/v% of an osmotic pressure regulator.

9. The pharmaceutical preparation according to claim 8, wherein the oil ingredient is selected from any one of or a mixture of some, at any ratio, of soybean oil, olive oil, fish oil, linseed oil, medium chain triglycerides or structured triglycerides; the emulsifier is selected from any one of or a mixture of some, at any ratio, of poloxamer, Tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin or soybean lecithin; the bacteriostat is selected from any one of or a mixture of some, at any ratio, of sodium caprylate, benzoic acid, benzyl alcohol, sodium benzoate, methyl benzoate, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, pyrogallate, ethylenediaminetetraacetic acid, disodium edetate, calcium edetate or sodium calcium edetate; and the osmotic pressure regulator is selected from any one of or a mixture of some, at any ratio, of glycerol, saccharides or sugar alcohols.

10. The pharmaceutical preparation according to claim 8, wherein the fat emulsion further comprises a pH regulator, and the pH regulator is selected from any one or some of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, phosphoric acid, citric acid, acetic acid or malic acid; and the pharmaceutical preparation has a pH in a range of 3.0-10.0, 4.0-9.0 or 6.0-9.0.

11. The pharmaceutical preparation according to claim 10, wherein the fat emulsion further comprises 0 w/v%-2 w/v% of a stabilizer, and the stabilizer is selected from any one or a mixture of two at any ratio of oleic acid or sodium oleate.

12. The pharmaceutical preparation according to claim 11, wherein the pharmaceutical preparation comprises 0.1 w/v%-2 w/v% of the active ingredient, any one or a mixture of two at any ratio of 10 w/v%-20 w/v% of soybean oil or medium chain triglycerides, 0.2 w/v%-2 w/v% of egg yolk lecithin, 0.001 w/v%-0.03 w/v% of any one of a mixture of any two at any ratio of disodium edetate, sodium calcium edetate, sodium pyrosulfite or benzyl alcohol of any proportion, and any one or a mixture of two at any ratio of 1 w/v%-4 w/v% of glycerol and 0.01 w/v%-2 w/v% of oleic acid or sodium oleate.

13. A method for inducing and maintaining anesthesia in animals or humans, promoting sedation and hypnosis, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy in animals or humans, comprising administering said animals or humans the pharmaceutical preparation according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIG. 1 shows growth curves of 5 test microorganisms in a sample prepared in Example 3; and

[0046] FIG. 2 shows growth curves of 5 test microorganisms in a sample prepared in Example 4.

DETAILED DESCRIPTION OF EMBODIMENTS

[0047] The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help a person skilled in the art better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present application.

[0048] The compounds required by the present invention are all prepared according to the method disclosed in patent application CN201580001777.

Example 1

[0049] TABLE-US-00001 A formulation is as follows: Compound 1 1 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Oleic acid 0.4 g Edetate disodium 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0050] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), oleic acid (source: Lipoid GmbH, Germany), and compound 1 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Disodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd) and glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 10.10 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 1 just after same was checked to be accepted.

Example 2

[0051] TABLE-US-00002 A formulation is as follows: Compound 2 5 g Soybean oil (for injection) 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Sodium calcium edetate 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0052] Soybean oil (for injection) (source: SHINSUN PHARMA) was weighed and heated to about 50° C. under nitrogen protection, egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany) and compound 2 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Calcium sodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.82 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 2 just after same was checked to be accepted.

Example 3

[0053] TABLE-US-00003 A formulation is as follows: Compound 3 2.5 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Disodium edetate 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0054] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Disodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.91 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 4

[0055] TABLE-US-00004 A pharmaceutical preparation not containing a bacteriostat was prepared according to the following formulation: Compound 3 2.5 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0056] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.95 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 5

[0057] TABLE-US-00005 A formulation is as follows: Compound 3 10 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.4 g Sodium calcium edetate 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0058] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Calcium sodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.87 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 6

[0059] TABLE-US-00006 A formulation is as follows: Compound 3 10 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Disodium edetate 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0060] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Disodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.69 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 7

[0061] TABLE-US-00007 A formulation is as follows: Compound 5 10 g Soybean oil (for injection) 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.4 g Sodium calcium edetate 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0062] Soybean oil (for injection) (source: SHINSUN PHARMA) was weighed and heated to about 50° C. under nitrogen protection, egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany) and compound 5 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Calcium sodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 10.05 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 5 just after same was checked to be accepted.

Example 8

[0063] TABLE-US-00008 A formulation is as follows: Compound 3 10 g Soybean oil (for injection) 100 g Medium chain triglyceride 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Sodium pyrosulfite 0.25 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0064] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Sodium pyrosulfite (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.99 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 9

[0065] TABLE-US-00009 A formulation is as follows: Compound 3 2.5 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Disodium edetate 0.01 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0066] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Disodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.89 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 10

[0067] TABLE-US-00010 A formulation is as follows: Compound 3 5 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Benzyl alcohol 0.01 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0068] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Benzyl alcohol (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.49 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 11

[0069] TABLE-US-00011 A formulation is as follows: Compound 3 20 g Soybean oil (for injection) 100 g Medium chain triglyceride 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Oleic acid 0.4 g Sodium pyrosulfite 0.025 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0070] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), oleic acid (source: Lipoid GmbH, Germany), and compound 3 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Sodium pyrosulfite (source: Hunan ER-KANG Pharmaceutical Co., Ltd) and glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.75 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 3 just after same was checked to be accepted.

Example 12

[0071] TABLE-US-00012 A formulation is as follows: Compound 4 15 g Soybean oil (for injection) 200 g Egg yolk lecithin 2.4 g Glycerol (for injection) 22.5 g Oleic acid 0.3 g Ethylene diamine tetraacetic acid 0.05 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0072] Soybean oil (for injection) (source: SHINSUN PHARMA) was weighed and heated to about 50° C. under nitrogen protection, egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), oleic acid (source: Lipoid GmbH, Germany), and compound 4 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Ethylene diamine tetraacetic acid (source: Chengdu Kelong Chemical Co., Ltd) and glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.98 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 4 just after same was checked to be accepted.

Example 13

[0073] TABLE-US-00013 A formulation is as follows: Compound 5 20 g Soybean oil (for injection) 100 g Medium chain triglyceride 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Oleic acid 0.4 g Sodium pyrosulfite 0.025 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0074] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), oleic acid (source: Lipoid GmbH, Germany), and compound 5 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Sodium pyrosulfite (source: Hunan ER-KANG Pharmaceutical Co., Ltd) and glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 10.34 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 5 just after same was checked to be accepted.

Example 14

[0075] TABLE-US-00014 A formulation is as follows: Compound 6 10 g Soybean oil (for injection) 100 g Medium chain triglyceride 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.3 g Disodium edetate 0.01 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0076] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 6 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Disodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.79 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 6 just after same was checked to be accepted.

Example 15

[0077] TABLE-US-00015 A formulation is as follows: Compound 7 2.5 g Olive oil 100 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.4 g Sodium pyrosulfite 0.025 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0078] Olive oil (source: Lipoid GmbH) was weighed and heated to about 50° C. under nitrogen protection, egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany) and compound 7 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Sodium pyrosulfite (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 10.55 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 7 just after same was checked to be accepted.

Example 16

[0079] TABLE-US-00016 A formulation is as follows: Compound 8 2.5 g Soybean oil (for injection) 50 g Medium chain triglyceride 50 g Egg yolk lecithin 12 g Glycerol (for injection) 22.5 g Sodium oleate 0.4 g Sodium calcium edetate 0.025 g Sodium hydroxide Q.s. Water for injection, making up the volume to 1,000 ml

[0080] Soybean oil (for injection) (source: SHINSUN PHARMA) and a medium chain triglyceride (source: SHINSUN PHARMA) were weighed and mixed under nitrogen protection, and heated to about 50° C., egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), and compound 8 were added under high-speed stirring, the materials were uniformly stirred, with the temperature controlled to be 55-75° C., to obtain an oil phase. Calcium sodium edetate (source: Hunan ER-KANG Pharmaceutical Co., Ltd), glycerol (for injection) [source: Croda Sipo (Sichuan) Co., Ltd)] and sodium oleate (source: Lipoid GmbH, Germany) were added into an appropriate amount of water for injection, mixed, and adjusted to a pH value of 9.91 with sodium hydroxide (source: Hunan ER-KANG Pharmaceutical Co., Ltd), with the temperature controlled to be 55-75° C., to obtain an aqueous phase. The oil phase was added into the aqueous phase under high-speed stirring (by a high shear mixing emulsifier, produced by IKA) to prepare a primary emulsion, the primary emulsion was repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro), when the emulsion particles were checked to meet the requirements, the emulsion was filtered, filled under introduction of nitrogen, sterilized in a steam sterilizer, and cooled, to obtain an emulsion injection containing compound 8 just after same was checked to be accepted.

Stability Test:

[0081] The samples prepared in examples 3, 4 and 6 are reserved at 30 ± 2° C./65% ± 5% RH, 25 ± 2° C./60% ± 5% RH for a stability test. The data are shown in Table 1-3 below:

TABLE-US-00017 Results of stability test of sample prepared in example 3 Conditions for reserving sample Examination item 30 ± 2° C./65% ± 5% RH 25 ± 2° C./60% ± 5% RH Day 0 3rd month 6th month 3rd month 6th month 12th month 24th month Character Uniformwhite emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion pH value 8.20 7.92 7.65 8.11 7.84 7.46 6.70 Free fatty acids (mmol/L) 1.4 2.5 2.5 2.2 2.4 2.9 4.5 Peroxide value 0.09 0.25 0.23 0.14 0.16 0.19 0.25 Anisidine value 1.71 3.18 2.52 1.98 2.13 2.85 2.19 Average particle size (nm) 225.8 236.5 242.9 233.1 241.7 241.8 229.6 95% particle size (nm) <357.6 <327.5 <348.6 <357.7 <380.3 <381.4 <360.3 Impurity B (%) 0.01 0.01 0.01 0.01 0.01 0.02 Not detected Impurity C (%) Not detected Not detected Not detected Not detected Not Detected Not Detected Not Detected Labeled content (%) 99.3 101.1 99.7 101.0 99.7 99.0 99.7

TABLE-US-00018 Results of stability test of sample prepared in example 6 Conditions for reserving sample Examination item 30 ± 2° C./65% ± 5% RH 25 ± 2° C./60% ± 5% RH Day 0 3rd month 6th month 3rd month 6th month 12th month 24th month Character Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion Uniform white emulsion pH value 8.15 7.85 7.51 8.01 7.76 7.43 6.81 Free fatty acids (mmol/L) 1.67 2.43 2.21 1.91 1.89 3.32 2.88 Peroxide value 0.12 0.16 0.27 0.13 0.27 0.28 0.26 Anisidine value 1.62 1.89 1.47 1.77 1.65 1.83 1.56 Average particle size (nm) 227.0 228.2 223.0 241.5 225.2 235.8 234.6 95% particle size (nm) < 356.2 < 354.3 < 350.4 < 344.1 < 342.5 < 353.3 < 366.2 Impurity B (%) 0.02 0.01 0.004 0.02 0.01 0.01 0.005 Impurity C (%) 0.01 0.005 0.002 0.005 0.002 0.005 0.006 Labeled content (%) 100.6 100.2 101.2 99.7 100.1 100.9 101.0

TABLE-US-00019 Results of stability test of sample prepared in example 4 Conditions for reserving sample 30 ± 2° C./65% ± 5% RH 25 ± 2° C./60% ± 5% RH Day 0 3rd month 6th month 3rd month 6th month 12th month 24th month Examination item Character Uniform white emulsion Uniform white emulsion Unifor m white emulsion Uniform white emulsion Unifor m white emulsion Uniform white emulsion Uniform white emulsion pH value 8.71 8.50 7.70 8.66 7.96 7.37 7.06 Free fatty acids (mmol/L) 2.2 2.7 2.8 2.6 2.8 3.1 5.4 Peroxide value 0.15 0.19 0.20 0.17 0.18 0.20 0.25 Anisidine value 3.31 3.98 4.15 3.67 3.82 4.06 4.95 Average particle size (nm) 223.7 232.0 228.2 232.9 231.1 227.9 230.5 95% particle size (nm) < 348.6 < 389.8 < 326.1 < 389.4 < 347.8 < 333.5 < 358.3 Impurity B (%) 0.01 0.01 0.01 0.01 0.01 0.03 0.01 Impurity C (%) 0.06 0.03 0.03 0.06 0.02 0.06 0.02 Labeled content (%) 100.7 101.8 99.3 101.0 99.1 99.6 99.5

[0082] The test results showed that within the quality standard range, the anisidine value and impurity C of the samples in example 3 and example 6 are better than those of the sample in example 4, indicating that the addition of disodium edetate in the formulation could significantly improve the drug stability.

Biological Test Example

Test Method:

[0083] With reference to Antimicrobial Effectiveness Testing (section 1121) of the fourth edition (2015 edition) of the Chinese Pharmacopoeia, the pharmaceutical preparation of the present invention is taken and separately inoculated with 0.1 ml (10.sup.5-10.sup.6 cfu/ml) of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans suspensions and an Aspergillus niger spore suspension, the materials are evenly mixed. The number of viable Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger is determined separately at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h and 12 h according to the above verified determination method of the number of microorganisms, and the antimicrobial effectiveness is evaluated by the change of the number of microorganisms.

[0084] The samples of example 3 and example 4 are taken as examples. The samples prepared in example 3 and example 4 are separately taken. With reference to Antimicrobial Effectiveness Testing (section 1121) of the fourth edition (2015 edition) of the Chinese Pharmacopoeia, 10 ml of the prepared samples are separately inoculated with 0.1 ml (about 10.sup.5-10.sup.6 cfu/ml) of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans suspensions and an Aspergillus niger spore suspension. The number of viable Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger is determined separately at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h and 12 h according to the verified determination method of the number of microorganisms. Growth curves of the microorganisms are shown in FIG. 1 and FIG. 2.

[0085] It can be seen from FIG. 1 and FIG. 2 that the number of viable Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger in the sample prepared in example 3 at 12 h is less than 0.5 1 g compared with that at 0 h. Only the number of viable Pseudomonas aeruginosa and Aspergillus niger in the sample prepared in example 4 at 12 h is less than 0.5 1 g compared with that at 0 h.

[0086] The concentration of the bacteriostat added in example 3 could not produce a sufficient antimicrobial effect, which is non-conforming to the antimicrobial effectiveness in the fourth edition (2015 edition) of the Chinese Pharmacopoeia. However, the above antimicrobial test results show that 0.005% disodium edetate in the prescription can actually slow down the growth of microorganisms and ensure safety of clinical medication.

[0087] Test results:

TABLE-US-00020 Counting and conversion to logarithmic cfu/ml (1 g) of test samples at different storage time after inoculation with microorganism suspensions Measurement time 0 h 2 h 4 h 6 h 8 h 10 h 12h Compared with 0 h Different value of 1 g Staphyloco cus aureus Example 3 13,000 11,00 0 16,00 0 22,00 0 28,000 26,000 27,000 Number of microorganis ms 1 g 4.11 4.04 4.20 4.34 4.45 4.41 4.43 0.32 Example 4 16,000 18,00 0 32,00 0 36,00 0 58,000 75,000 102,00 0 Number of microorganis ms 1 g 4.20 4.26 4.51 4.56 4.76 4.88 5.01 0.80 Pseudomona s aeruginosa Example 3 25,000 20,00 0 19,00 0 20,00 0 21,000 26,000 32,000 Number of microorganis ms 1 g 4.40 4.30 4.28 4.30 4.32 4.41 4.51 0.11 Example 4 21,000 20,00 0 10,00 0 23,00 0 35,000 49,000 54,000 Escherichia coli Example 3 12,400 5,100 3,000 2,600 2,000 4,300 7,500 Number of microorganis ms 1 g 4.09 3.71 3.48 3.41 3.30 3.63 3.88 -0.22 Example 4 15,000 20,00 0 28,00 0 86,00 0 150,00 0 200,00 0 280,00 0 Number of microorganis ms 1 g 4.18 4.30 4.45 4.93 5.18 5.30 5.45 1.27 Candida albicans Example 3 7,000 9,000 6,500 18,00 0 15,000 16,000 19,000 Number of microorganis ms 1g 3.85 3.95 3.81 4.26 4.18 4.20 4.28 0.43 Example 4 6,000 9,000 11,00 0 16,00 0 25,000 39,000 82,000 Number of microorganis ms 1g 3.78 3.95 4.04 4.20 4.40 4.59 4.91 1.14 Aspergillus niger Example 3 8,300 6,200 6,000 6,200 6,400 7,000 7,100 Number of microorganis ms 1g 3.92 3.79 3.78 3.79 3.81 3.85 3.85 -0.07 Example 4 7,700 6,900 7,600 5,100 6,100 7,900 7,900 Number of microorganis ms 1g 3.89 3.84 3.88 3.71 3.79 3.90 3.90 0.01

[0088] The test results show that the growth of the contaminating microorganisms can be significantly inhibited by adding an appropriate amount of a bacteriostat ingredient such as disodium edetate, sodium calcium edetate, sodium pyrosulfite, benzyl alcohol, ethylenediaminetetraacetic acid, etc. For example, the pharmaceutical preparation of the present invention (Example 3) has an obvious inhibitory effect on the growth of the contaminating microorganisms during a service life on the basis of maintaining a good stability. The sample not containing a bacteriostat (example 4) has no inhibitory effect on the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans. Therefore, the pharmaceutical preparation of the present invention reduces the potential microbial contamination risk caused by uncertain factors during the clinical use and improves safety of clinical use.

[0089] Although specific embodiments of the present invention have been described, those skilled in the art should know that the present invention can be changed and modified in many ways without departing from the range and spirit of the present invention. Therefore, the present invention is intended to cover all these changes and modifications falling within the scope of the attached claims and their equivalents.