WO2016124162A1 - Propanidid pharmaceutical composition and preparation method therefor - Google Patents

Abstract

A propanidid pharmaceutical composition, comprising propanidid, oil for injection, phospholipid, and water for injection, the parts by weight of propanidid being 1 to 10, the parts by weight of oil for injection being 10 to 60, the parts by weight of phospholipid being 1 to 4, and the parts by weight of water for injection being 100 to 200.

Description

Propionil pharmaceutical composition and preparation method thereof

Related application

The present application claims the priority of the Chinese Patent Application No. 201510061033.1, entitled "A Propionil Pharmaceutical Composition and Its Preparation Method", which is hereby incorporated by reference in its entirety herein. reference.

Technical field

The invention relates to a new pharmaceutical preparation for anesthetic drugs, in particular to a pharmaceutical composition of piranil and a preparation method thereof.

Background technique

The active ingredient in the present invention is Propanidid, and its chemical structural formula is as follows:

Propionil is a short-acting anesthetic, which is insoluble in water. In order to increase its water solubility, the marketed product Eponol is made of polyoxyethylene castor oil (Cremophor EL) as a surfactant solubilizing, the specification is 0.5g: 10ml. As a nonionic surfactant, polyoxyethylene castor oil is mainly used in oral preparations, external preparations and injections, and is also widely used in cosmetics and veterinary medicines. For those drugs which have extremely low solubility and cannot reach the desired concentration by adjusting pH, adding latent solvent and inclusion, the use of nonionic surfactants represented by polyoxyethylene castor oil is preferred. A large number of practices have shown that polyoxyethylene castor oil can almost solubilize most poorly soluble drugs, which is particularly advantageous for preclinical research and development of these drugs. By using polyoxyethylene castor oil, a higher concentration of the drug solution can be prepared, thereby facilitating pharmacological and pharmacodynamic evaluation and pharmacokinetic studies. At present, the listed injections containing polyoxyethylene castor oil have antitumor drugs such as paclitaxel, clonaflurane, teniposide; sedatives such as diazepam; immunosuppressive agents such as cyclosporine A; local anesthetics Such as propofol and the like.

Polyoxyethylene castor oil is non-toxic and non-irritating in various acute and long-term toxicity tests, but many adverse reactions occur after intravenous injection of polyoxyethylene castor oil. Adverse reactions caused by injection of polyoxyethylene castor oil are associated with a variety of factors. Polyoxyethylene castor oil can degranulate mast cells, release histamine, or activate complement to cause an allergic reaction. In addition, the polyoxyethylene castor oil in the injection contact with the polyvinyl chloride plastic tube and the infusion bag can be immersed in a large amount of plasticizer diethyl ethyl phthalate to cause toxicity. The amount of polyoxyethylene castor oil in the propanolidine injection is as high as 20%, and is subsequently withdrawn due to an allergic reaction caused by polyoxyethylene castor oil.

There are also reports in the literature (International Journal of Pharmaceutics 159 (1997) 191-196) using hydroxypropyl beta ring Dextrin HP-β-CD increases its water solubility. 2 g of propanolil was added to 40 ml of a 42% (w/v) HP-β-CD aqueous solution.

The above prior art merely improves the solubility of the drug blindly, but at the same time, a large amount of irritating solvents such as polyoxyethylene castor oil and cyclodextrin are used, and it is inevitable that an adverse reaction such as irritation may be caused during the injection. Therefore, it is necessary to provide a high-safety propanol injection.

Summary of the invention

The object of the present invention is to provide a high-safety pharmaceutical composition of piranil, and at the same time solve the problem of stability of the pharmaceutical composition

The pharmaceutical composition of the present invention contains propylidene, an injectable oil, a phospholipid and water for injection, a part by weight of acrylonitrile and a weight fraction of 10 to 60, and a phospholipid. The parts by weight are from 1 to 4, and the parts by weight of water for injection are from 100 to 200. It is preferable to contain 1 to 6 parts by weight of the injection oil, 0.1 to 0.4 parts by weight of the phospholipid, and 10 to 20 parts by weight of the water for injection per 1 part by weight of the propanil.

The phospholipid contains phosphatidylcholine, phosphatidylethanolamine, phosphatidylcholine content of 80% or more (w/w), phosphatidylethanolamine content of 14% (w/w) or less, preferably 11 to 14%. (w/w).

The phospholipid further contains phosphatidylinositol in an amount of 0.5 to 5% (w/w), preferably 0.5 to 3% (w/w).

More preferably, the phospholipid choline content in the phospholipid is 80% (w/w) or more, the phosphatidylethanolamine content is 8% (w/w) or less, and the phosphatidylinositol content is 0.5 to 1% (w/w).

The phospholipid is selected from the group consisting of phospholipids extracted from egg yolk, and the contents of the above phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol are determined by HPLC.

The phospholipids may also be formulated in a ratio of the above-mentioned contents using synthetic phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol.

The synthetic phosphatidylcholine is selected from the group consisting of distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoyl phosphatidyl Choline (DMPC), didecanoylphosphatidylcholine DDPC, dilauroylphosphatidylcholine (DLPC), di-erucylphosphatidylcholine (DEPC), 1-stearoyl-2-oleoylphosphatidylcholine Base (SOPC), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), 1-myristoyl-2-oleoylphosphatidylcholine (MOPC), 1-stearoyl-2-palmitoyl Phosphatidylcholine (SPPC), 1-stearoyl-2-myristoylphosphatidylcholine (SMPC), 1-palmitoyl-2-stearoylphosphatidylcholine (PSPC), 1-palmitoyl- 2-Myristoyl phosphatidylcholine (PMPC), 1-myristoyl-2-stearoylphosphatidylcholine (MSPC), 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC) or Its combination.

The synthetic phosphatidylethanolamine is selected from the group consisting of distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine (DOPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE). , erucylphosphatidylethanolamine (DEPE), dilauroylphosphatidylethanolamine (DLPE) or a combination thereof.

The synthetic phosphatidylinositol is selected from the group consisting of distearoylphosphatidylinositol (DSPI), dioleoylphosphatidylinositol (DOPI), dipalmitoylphosphatidylinositol (DPPI), dimyristoyl phosphatidyl Inositol (DMPI), 1-palmitoyl-2-oleoylphosphatidylinositol (POPI), di-erucylphosphatidylinositol (DEPI), dilauroylphosphatidylinositol (DLPI) or a combination thereof.

The oil for injection is selected from the group consisting of refined soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium chain monoglyceride, medium chain diglyceride, medium chain triglyceride, oleic acid. Ethyl ester, acetylated monoglyceride, propylene glycol diester, linoleic acid glyceride, polyethylene glycol lauric acid glyceride or a combination thereof.

The procarbazine pharmaceutical composition further comprises a pH adjusting agent selected from the group consisting of sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, or a combination thereof.

The procarbazine pharmaceutical composition further comprises an isotonicity adjusting agent selected from the group consisting of glycerin, glucose, mannitol, propylene glycol, or a combination thereof.

The invention provides a preparation method of a pharmaceutical composition of piranil, comprising the following steps:

(1) Preparation of oil phase: adding propofol, a phospholipid to an oil for injection, stirring and dissolving it as an oil phase;

(2) Preparation of colostrum: the oil phase of step (1) is added to water containing isotonicity adjusting agent for injection, and is sheared at high speed to form colostrum;

(3) High-pressure homogenization: step (2) colostrum high-pressure homogenization to obtain fine milk;

(4) Filtration, potting, sterilization (F0>8), that is.

The pharmaceutical composition of the present invention prepared by the present invention has higher safety (Test Example 1), lower irritation (Test Example 2), and has better stability (Test Example 3) ).

detailed description

Example 1

The phospholipid has a phosphatidylcholine content of 80%, a phosphatidylethanolamine content of 17%, and no phosphatidylinositol.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) determine the pH value of colostrum by 7.4, add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

Example 2

The phospholipid has a phosphatidylcholine content of 80% and a phosphatidylethanolamine content of 14%, and does not contain phosphatidylinositol.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Determine the pH value of colostrum by 6.9, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

Example 3

The phospholipid has a phosphatidylcholine content of 80%, a phosphatidylethanolamine content of 11%, and no phosphatidylinositol.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

Example 4

The phospholipid has a phosphatidylcholine content of 80%, a phosphatidylethanolamine content of 8%, and no phosphatidylinositol.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

Example 5

The phospholipid has a phosphatidylcholine content of 80%, a phosphatidylethanolamine content of 8%, and a phosphatidylinositol 1%.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

Test Example 1 Hemolysis Test

Preparation of 2% red blood cell suspension Take a few milliliters of rabbit blood, shake it into a triangular flask filled with glass beads for 10 minutes, or stir the blood with glass beads to remove the fiber protein, and add about 10 times the defibrinated blood. The amount of physiological saline, shake well, centrifuge, remove the supernatant, and the precipitated red blood cells are washed 2-3 times with physiological saline, until the supernatant is not red, and the obtained red blood cells are mixed with physiological saline to 2% suspension. Liquid for testing purposes.

Test method: Take 6 tubes, add 2% red blood cell suspension and physiological saline according to the ratio of the table, mix them, place them in the incubator at 37 °C for half an hour, and then add different test solutions respectively. 6 tube is the control tube), shake it, set the incubator at 37 ° C, start to observe every 15 minutes, after 1 hour, observe once every 1 hour, generally observe 4 hours, if the solution is transparent red, indicating hemolysis. If there is a brownish red or reddish brown flocculent precipitate in the solution, it means that there is red blood cell agglutination.

The result is judged: 1 Generally, the hemolysis effect of the test solution (the third tube) of 0.3 ml is not satisfied within 2 hours. 2 If there is red blood cell agglomeration, it can be further judged by the following method. If the condensate can be evenly dispersed after shaking in the test tube, or the condensate is placed on the glass slide, two drops of physiological saline are added to the edge of the cover glass, and the condensed red blood cells can be pseudo-coagulated by the scatter. It is judged to be in compliance with the regulations; if the aggregate is not shaken or is not smashed on the slide, it is judged as not complying with the regulations.

	Example 1	Example 2	Example 3	Example 4	Example 5
Hemolytic	negative	negative	negative	negative	negative

Test Example 2 Local irritation test

9 rabbits, female, 2.0-2.4 kg, divided into two groups, 3 in each group, each of which was given a solution of propylidene (polyoxyethylene castor oil 20%) and Example 1 and Example 5 The emulsion, the right ear is given an equal volume of 0.9% sodium chloride injection. After each ear was disinfected with medical alcohol before injection, the needle was inserted about 1 cm from the tip of the ear vein, and the test article was slowly injected once a day for 3 consecutive days. The stimulatory response of the vein (vessel) at the injection site and the surrounding subcutaneous tissue and the epidermis was observed after each administration and before the next administration, and detailed records were made. The score was scored according to the "Vascular Stimulation Test Scoring Criteria - Visual Inspection Grading". The animals were sacrificed 24 hours after the last administration, and the ear shell of the injection site was cut to a length of about 5 cm, and fixed in 10% formalin, and then examined for pathology. Finally, the results of the test were evaluated by comprehensive visual and histological scores.

No significant changes were observed in the venous (vascular) and peripheral subcutaneous tissues and the epidermis of the ear at the injection site after each administration and before the next administration. The pathological examination results also showed no significant changes in the blood vessels and surrounding tissues. According to the cumulative score of the vascular stimulation scoring standard, the scores of Example 1 and Example 5 were all less than 0.5, thereby judging that the pharmaceutical composition of the present invention was not Vascular irritation; the propionate (polyoxyethylene castor oil 20%) solution group scored 2, irritating. The results showed that the local irritation was reduced after the fat emulsion was made.

Test Example 3 Stability

The samples of Examples 1 to 5 were placed at 40 ° C for 4 weeks, and the milk particles, related substances and contents were measured.

According to the results of the emulsion, the particle size of Example 4 was significantly larger, and it was significantly increased after 4 weeks of standing. When the phosphatidylethanolamine content is less than 8%, it is difficult to control the particle size of the granule, and it is necessary to control the phosphatidylethanolamine content to 11% (Example 3) to control the particle size of the product, or when the phosphatidylethanolamine content is less than 8 At %, phosphatidylinositol (Example 5) is required to control the particle size of the product.

According to the results of the related substances, from Example 1 to Example 4, as the content of phosphatidylethanolamine decreased, the related substances gradually decreased, and the content of the substance of Example 1 exceeded 0.5% at 4 weeks, which was significantly higher than that of Example 2 4. Therefore, it is necessary to control the content of phosphatidylethanolamine in the phospholipid to 14% or less. Example 5 added phosphatidylinositol to Example 4, which significantly reduced the amount of related substances.

There were no significant differences between the examples based on the results of the content determination.

In combination with the above results, it is necessary to control the milk particles and related substances at the same time. One method is to control the content of phosphatidylethanolamine in the range of 11% to 14%, or to control the content of phosphatidylethanolamine to be less than 8%, and to add phosphatidylinositol. alcohol.

Example 6

The phospholipid has a phosphatidylcholine content of 85%, distearoylphosphatidylethanolamine (DSPE) content of 11%, and phosphatidylinositol 3%.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil and medium chain triglyceride, heating to 65 ° C, adding phospholipids and propylidene, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

After testing, the relevant substance was 0.077% and the average particle diameter was 179 nm.

Example 7

The phospholipid has a phosphatidylcholine content of 87%, distearoylphosphatidylethanolamine (DSPE) content of 11%, and phosphatidylinositol 0.5%.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

The substance was determined to be 0.092% and the average particle diameter was 182 nm.

Example 8

The phospholipid has a phosphatidylcholine content of 94%, does not contain phosphatidylethanolamine, and has a phosphatidylinositol content of 5%.

The general steps for emulsion preparation are described below:

(1) taking water for injection, heating to 65 ° C, adding glycerol to dissolve, as an aqueous phase;

(2) taking soybean oil, heating to 65 ° C, adding phospholipids and propanol, stirring and dissolving, as an oil phase;

(3) Under high-speed shearing, the oil phase is added to the aqueous phase at 65 ° C, and the high-speed shearing speed is 10000 rpm for 10 min to form colostrum;

(4) Adjust the pH value of colostrum to 6.6, and add water for injection to the full amount;

(5) Transfer the colostrum to a high pressure homogenizer for emulsification, homogenization pressure 1000 bar, 3 cycles;

(6) Filtration: the fine milk is filtered through a 0.45 μm microporous membrane membrane and potted;

(7) Damp heat sterilization (F0>8), that is.

The substance was determined to be 0.060% and the average particle diameter was 226 nm.

Claims (10)

1. The present invention relates to a pharmaceutical composition of piranil, which comprises pirinil, an oil for injection, a phospholipid and water for injection, wherein the content of acrylonitrile is 1 to 10 parts by weight, and the weight of oil for injection is 10 parts by weight. 60. The weight fraction of the phospholipid is 1 to 4, and the weight of the water for injection is 100 to 200.
2. The pharmaceutical composition of Promethazine according to claim 1, which comprises 1 to 6 parts by weight of an injection oil, 0.1 to 0.4 parts by weight of a phospholipid per 10 parts by weight of the propranil, and 10 to 10 parts by weight. 20 parts by weight of water for injection.
3. The pharmaceutical composition of Promethazine according to claim 1 or 2, wherein the phospholipid contains phosphatidylcholine, phosphatidylethanolamine, phosphatidylcholine content of 80% or more (w/w), phosphatidylethanolamine The content is below 14% (w/w).
4. The pharmaceutical composition of Promethazine according to claim 3, wherein the content of phosphatidylethanolamine in the phospholipid is from 11% to 14% (w/w).
5. The pharmaceutical composition of Promethazine according to claim 3, wherein the phospholipid further contains phosphatidylinositol, and the phosphatidylinositol content is 0.5 to 5% (w/w).
6. The pharmaceutical composition of Promethazine according to claim 5, wherein the phosphatidylinositol content is from 0.5 to 3% (w/w).
7. The pharmaceutical composition of Promethazine according to claim 6, wherein the phosphatidylethanolamine content is 8% (w/w) or less, and the phosphatidylinositol content is 0.5 to 1% (w/w).
8. The pharmaceutical composition of Promethazine according to claim 1 or 2, further comprising a pH adjusting agent selected from the group consisting of sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, and citric acid. Salt, acetic acid, acetate or a combination thereof.
9. The pharmaceutical composition of Promethazine according to claim 1 or 2, further comprising an isotonicity adjusting agent selected from the group consisting of glycerin, glucose, mannitol, propylene glycol or a combination thereof.
10. A method of preparing a pharmaceutical composition of the present invention according to claim 9, comprising the steps of:

    (1) Preparation of oil phase: adding propofol, a phospholipid to an oil for injection, stirring and dissolving it as an oil phase;

    (2) Preparation of colostrum: the oil phase of step (1) is added to water containing isotonicity adjusting agent for injection, and is sheared at high speed to form colostrum;

    (3) High-pressure homogenization: step (2) colostrum high-pressure homogenization to obtain fine milk;

    (4) Filtration, potting, sterilization, that is.