CN112972374B

CN112972374B - Preparation method of emulsion containing oleum fructus Bruceae

Info

Publication number: CN112972374B
Application number: CN201911290063.4A
Authority: CN
Inventors: 张宇; 周浩; 罗岩; 姚立龙; 高玥媛; 刘晓庆; 杨颖�; 李薇; 薛春梅
Original assignee: Shenyang Yaoda Leiyunshang Pharmaceutical Co ltd
Current assignee: Shenyang Yaoda Leiyunshang Pharmaceutical Co ltd
Priority date: 2019-12-16
Filing date: 2019-12-16
Publication date: 2022-11-04
Anticipated expiration: 2039-12-16
Also published as: CN112972374A

Abstract

The invention provides a preparation method of an emulsion containing oleum fructus bruceae, which comprises the following steps: the method comprises the following steps of (1) circularly emulsifying and shearing a water-phase material and an oil-phase material to form primary emulsion, and circularly homogenizing the primary emulsion to obtain uniform emulsion which can be filtered by a sterilizing filter; wherein the circulating emulsifying and shearing comprises the circulating shearing of the materials in an emulsifying and shearing tank and a pipeline shearer. The emulsion containing the oleum fructus bruceae prepared by the method has the advantages that the average particle size is obviously reduced, the emulsion can be filtered by a sterilization-grade filter, the requirement of sterile inspection is met, and the stability is greatly improved.

Description

Preparation method of emulsion containing oleum fructus Bruceae

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of an emulsion containing brucea javanica oil.

Background

The fructus Bruceae is dry mature fruit of Brucea javanica (L.) Merr of Brucea of Simaroubaceae. Collected in autumn when the fruit is ripe, removed of impurities and dried in the sun. Brucea javanica was recorded in Ben Cao gang mu Shi Yi (supplement to compendium of materia Medica) written by Zhao Chi Ming Dynasty in Qing Dynasty. The efficacy recorded in pharmacopoeia of the people's republic of China is to clear away heat and toxic material, prevent malaria, stop dysentery and corrode proud warts. Can be used for treating dysentery and malaria, and wart and clavus.

The organic component of fructus Bruceae contains water soluble component and oil soluble component, and its toxic component is present in water soluble bitter component; the oil-soluble component, namely the oleum fructus bruceae, has better treatment effect and is widely applied to clinic. At present, the common extraction method of brucea javanica oil (or brucea javanica total fatty oil) is to crush brucea javanica medicinal materials, extract with petroleum ether, recover the petroleum ether from the extract, and simply refine the obtained petroleum ether extract.

In the 70 s of the 20 th century, the anti-tumor effect of the oleum fructus brucease is gradually discovered and recognized, wherein the oleum fructus brucease emulsion injection and the oleum fructus brucease oral emulsion which are sold in the market in the 80 s of the 20 th century are more widely used for clinical treatment of lung cancer, brain metastasis of lung cancer, digestive tract tumor and liver cancer.

Because the preparation process level is limited at that time, the oleum fructus Bruceae emulsion injection is easy to reduce emulsion stability and cause colostrum layering phenomenon after long-time heating, damp heat sterilization (100 deg.C, 30 min) is adopted as product sterilization process in production, and the sterilization process F ₀ Values less than 8 are non-terminally sterilized formulations. The sterilization process may cause incomplete sterilization, so that the oleum fructus brucease emulsion injection has safety risk in clinical use.

To achieve the desired level of sterility, additional sterilization steps may be taken. The method is characterized in that a filtering and sterilizing step is added in the preparation process of the oleum fructus bruceae emulsion injection, namely, the prepared oleum fructus bruceae emulsion injection passes through a sterilizing grade filter with the pore size of 0.22 mu m or smaller or the same filtering efficiency, and then is subjected to damp-heat sterilization which is the same as the preparation process of the original oleum fructus bruceae emulsion injection, so that the sterility of the oleum fructus bruceae emulsion injection can be realized.

The step of filtration sterilization is added to require the particle diameter D of the emulsion particles of the oleum fructus brucease injection ₉₀ Smaller than the pore size of the sterilizing grade filter, i.e. smaller than 0.22 μm. However, the brucea javanica oil emulsion injection obtained by the current production process has high large particle ratio and cannot pass through a sterilization grade filter with the particle size of 0.22 μm, so that the sterile grade of the brucea javanica oil emulsion injection cannot be realized by adding a filtration sterilization step, and the brucea javanica oil emulsion injection has the problem of high safety risk in clinical use.

Disclosure of Invention

In order to reduce the particle size of brucea javanica oil emulsion particles to be filtered by a sterilization-grade filter, achieve an aseptic grade and reduce the increase of production cost, the invention provides a preparation method of brucea javanica oil emulsion.

In the present invention, the term "brucea javanica oil" is an extract obtained by extracting brucea javanica (or after shelling brucea javanica) with petroleum ether, and the extract can be processed by refining, purifying and the like.

In the present invention, the term "brucea javanica oil-containing emulsion" is also referred to as "brucea javanica oil emulsion", "brucea javanica oil emulsion composition" and the like, which are emulsions containing brucea javanica oil as an active ingredient, including brucea javanica oil emulsion injection, brucea javanica oil oral emulsion and the like. The formula process of the oleum fructus bruceae emulsion injection and the oleum fructus bruceae oral emulsion are basically the same, the difference is that the production environment requirements of the two are different, and the oleum fructus bruceae oral emulsion is not injected in vivo, and usually no osmotic pressure regulator is selected.

In order to achieve the object of the present invention, the present inventors tried to seek improvement in the process of emulsifying homogenization of a product. It is common practice to emulsify and homogenize an emulsion using an emulsification shear tank and a high-pressure homogenizer, and to achieve a reduction in the particle size of the emulsion particles by increasing the number of homogenization times of the high-pressure homogenizer and the number of shearing times of the emulsification shear tank. However, through a great deal of experimental research, the inventor finds that the emulsion particle size of the brucea javanica oil emulsion cannot be reduced to the expected target particle size by increasing the homogenization times of the high-pressure homogenizer and the shearing times of the emulsification shearing tank. And too many times of shearing or too long time of shearing can cause the temperature of the sheared mixed solution to rise, which is not beneficial to the formation and the stability of the emulsion and also increases the production cost. The present inventors have unexpectedly found that by subjecting the material to cyclic shearing in the emulsification shearing tank and the line shears and then to cyclic homogenization by the method of the present invention, the particle size of the emulsion particles can be reduced to a desired level while the increase in production cost can be reduced.

The purpose of the invention is realized by the following technical scheme:

in one aspect, the present invention provides a method for preparing an emulsion containing oleum fructus bruceae, comprising the steps of: the method comprises the following steps of (1) circularly emulsifying and shearing a water-phase material and an oil-phase material to form primary emulsion, and circularly homogenizing the primary emulsion to obtain uniform emulsion which can be filtered by a sterilizing filter; wherein the circulating emulsifying and shearing comprises the circulating shearing of the materials in an emulsifying and shearing tank and a pipeline shearer.

In certain embodiments of the invention, the aqueous phase material comprises water for injection, an emulsifier, and optionally an osmotic pressure regulator, a stabilizer, and/or a pH regulator, and the oil phase material comprises brucea javanica oil.

In certain embodiments of the invention, the method further comprises the step of sterilizing the emulsion, preferably the sterilizing step comprises filtering the emulsion through a sterilizing filter followed by moist heat sterilization.

In certain embodiments of the invention, the sterilizing filter is a sterilizing filter of 0.22 μm or smaller pore size or the same filtration efficiency.

In certain embodiments of the present invention, the circulating emulsification shearing is performed in a circulating path of emulsification shearing, the circulating path of emulsification shearing includes an emulsification shearing tank 5, a line cutter 7, and a material pipe communicating the emulsification shearing tank 5 and the line cutter 7, and the circulating emulsification shearing is accomplished by: enabling the materials to flow in the emulsifying and shearing circulation path and sequentially carrying out emulsifying and shearing by the emulsifying and shearing tank 5 and the pipeline shearer 7, and circulating the materials in the emulsifying and shearing circulation path for one circle to complete one-time circulating emulsifying and shearing; and/or the circulation homogenization is carried out in a homogenization circulation path, wherein the homogenization circulation path comprises an emulsification shearing tank 5, a homogenizer 6, a transfer tank 11 and a material pipe which is communicated with the emulsification shearing tank 5, the homogenizer 6 and the transfer tank 11; and the cyclic homogenization is completed by the following steps: and (3) enabling the primary emulsion to flow into the homogenizer 6 from the emulsifying and shearing tank 5 for homogenization, enabling the homogenized material to flow into the transfer tank 11 from the homogenizer 6 so as to complete primary circulation homogenization, then enabling the material flowing into the transfer tank 11 to flow back into the homogenizer 6 again for re-homogenization, and enabling the re-homogenized material to flow into the emulsifying and shearing tank 5 from the homogenizer 6 so as to complete secondary circulation homogenization.

In certain embodiments of the present invention, the aqueous phase material is recycled emulsified and sheared by batch addition, preferably, part of the aqueous phase material is added for recycled emulsified and sheared first, then the oil phase material is added for recycled emulsified and sheared, and the rest of the aqueous phase material is added for recycled emulsified and sheared.

In certain embodiments of the invention, the cyclic emulsification shearing comprises the steps of: emulsifying and shearing the water-phase materials through the emulsifying and shearing tank 5, and then emulsifying and shearing through the pipeline shearer 7; and the oil phase materials are emulsified and sheared through the pipeline shearer 7 and then through the emulsifying and shearing tank 5.

Through repeated experiments, the inventor unexpectedly finds that the water phase material is added in batches, particularly part of the water phase material is added firstly, is uniformly mixed with the oil phase material and then is added with the rest part of the water phase material for emulsification, and/or the water phase material is firstly emulsified and sheared through the emulsification shearing tank and then is emulsified and sheared through the pipeline shearer; and the mode that the oil phase materials are firstly emulsified and sheared by the pipeline shearer, then emulsified and sheared by the emulsifying and shearing tank are separately added and circularly emulsified and sheared can ensure that the emulsifying effect of the materials is better, thereby being beneficial to the formation of the emulsion and further improving the stability of the emulsion.

In certain embodiments of the present invention, the process for preparing an emulsion comprising oleum fructus brucease comprises the steps of:

1) Adding an aqueous phase material containing water for injection, an emulsifier and an optional osmotic pressure regulator into the emulsification shear tank 5, and performing circulating emulsification shear through a circulation path of the emulsification shear to sufficiently mix the material, wherein the material flows in the circulation path of the emulsification shear and is subjected to circulating emulsification shear by the emulsification shear tank 5 and the pipeline shears 7 in sequence.

In certain embodiments of the present invention, the method of preparing an emulsion comprising oleum fructus brucease further comprises the steps of:

2) Adding the oil phase material into the pipeline shearing device 7, mixing the oil phase material with the water phase material in the step 1) in the pipeline shearing device 7 to obtain an oil-water mixture material, enabling the oil-water mixture material to flow in a circulation path of emulsification shearing, and sequentially carrying out circulation emulsification shearing by the pipeline shearing device 7 and the emulsification shearing tank 5 to obtain a uniform oil-water mixture material.

In certain embodiments of the present invention, the process for preparing an emulsion comprising oleum fructus brucease further comprises the steps of:

3) Optionally, a stabilizer and/or a pH regulator is added into the uniformly mixed material obtained in the step 2) in the emulsification shearing tank 5, the rest of water for injection is added into the emulsification shearing tank 5 to obtain a full-amount liquid medicine, the obtained full-amount liquid medicine flows in a circulation path of the emulsification shearing, and the emulsification shearing is sequentially carried out by the emulsification shearing tank 5 and the pipeline shearer 7 to obtain colostrum.

In certain embodiments of the present invention, in the step 1), the emulsifier and the first part of the water for injection are added into the emulsification shear tank 5, and the emulsifier and the first part of the water for injection are subjected to first circulation emulsification shear in the circulation path of the emulsification shear, and then a second part of the water for injection or the aqueous solution for injection containing an osmotic pressure regulator is added into the emulsification shear tank 5, and the resulting mixture is subjected to second circulation emulsification shear in the circulation path of the emulsification shear; wherein, the first circulation emulsification shearing is carried out for 1 time, and the time is 10 to 80 minutes; the second circulation emulsification shearing is carried out for 2 to 4 times, and each time lasts for 10 to 60 minutes; preferably, in the step 1), the temperature of the first part of water for injection, the second part of water for injection or the water solution for injection containing the osmotic pressure regulator is 40-100 ℃.

In certain embodiments of the present invention, in the step 2), the oil phase material is oleum fructus bruceae, and the circulating emulsification shearing of the oil-water mixture material in the circulating path of the emulsification shearing is a third circulating emulsification shearing, and the third circulating emulsification shearing is carried out for 2-4 times for 10-60 minutes each time; preferably, in the step 2), the temperature of the oleum fructus brucease is 50-100 ℃.

In certain embodiments of the present invention, in the step 3), the circulating emulsification shearing performed by the full amount of the liquid medicine in the circulation path of the emulsification shearing is a fourth circulating emulsification shearing, and the fourth circulating emulsification shearing is performed for 1 time for 10 to 60 minutes; preferably, in the step 3), the temperature of the rest of the water for injection is above 70 ℃, and the pH regulator is added to adjust the pH value of the liquid medicine to 4.0-6.0.

In certain embodiments of the invention, said cyclic homogenization is performed 2 to 6 times in a homogenizer 6 at a pressure of 400 to 1200bar.

In certain embodiments of the invention, the shear frequency of the shear emulsification tank is 40 to 60Hz, preferably 50Hz; the shearing frequency of the pipeline shearer 7 is 40-60 Hz, and preferably 50Hz.

In certain embodiments of the invention, the filtration is performed through a sterilizing filter having a filter element with a pore size of less than 0.22 μm at a filtration pressure of 30 to 120 psi; and/or the moist heat sterilization is carried out under live steam at 100 ℃.

In certain embodiments of the invention, the amount of emulsifier is from 40 to 500g, preferably from 80 to 250g, based on 1000ml of oleum fructus bruceae; the amount of the first part of water for injection is 200-10000 g, preferably 1000-3000 g; the amount of the second part of the water for injection or the water solution for injection containing the osmotic pressure regulator is 0.15 to 3500g, preferably 5 to 3500g; the amount of the osmotic pressure regulator is 0 to 700g, preferably 0 to 300g; the amount of the stabilizer is 0 to 100g, preferably 5 to 10g; the amount of the residual water for injection is 3000-20000 ml, preferably 10000ml.

In certain embodiments of the invention, the emulsifier is selected from one or more of soy lecithin, egg lecithin, poloxamers, monoglycerides of acetic acid, polysorbates, or polyoxyethylene castor oil; the osmotic pressure regulator is selected from one or more of glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, mannitol or xylitol; the stabilizer is selected from one or more of vitamin E, ascorbic acid, oleic acid, sodium oleate, cholic acid, deoxycholic acid or sodium deoxycholate; and/or the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, phosphoric acid and salts thereof, carbonic acid and salts thereof, lactic acid, citric acid or acetic acid.

In certain embodiments of the invention, the aqueous phase material and the oil phase material are filter sterilized prior to being subjected to cyclic emulsification shearing.

In certain embodiments of the present invention, the number of the line cutters 7 is one or more, preferably 2; and when the number of the line cutters 7 is plural, the line cutters 7 are connected in series.

The invention has the following beneficial effects:

the average particle size of the brucea javanica oil emulsion prepared by the method is remarkably reduced, the D90 is reduced to be below 200nm, the brucea javanica oil emulsion can be filtered by a sterilization-grade filter, and the prepared brucea javanica oil emulsion meets the requirement of sterile inspection. In addition, the brucea javanica oil emulsion prepared by the method provided by the invention has the advantages that the centrifugal stability constant (Ke value) is obviously reduced, the stability of the emulsion is obviously improved, and the emulsion meets the quality standard requirements in an acceleration test and a long-term stability test.

Drawings

Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:

FIG. 1 is a schematic view showing the construction of a production apparatus used in the method for preparing an emulsion containing oleum fructus Bruceae of examples 1 and 2 of the present invention, wherein the number of line cutters is 2 in the apparatus used in example 1, the number of line cutters is 3 in the apparatus used in example 2, and the line cutters are connected in series, and only one line cutter is shown in the figure for simplicity;

FIG. 2 is a schematic view of the construction of the production apparatus used in the process for producing an emulsion containing oleum fructus Bruceae in example 3 of the present invention;

FIG. 3 is a schematic structural view of a production apparatus used in the process for preparing an emulsion containing oleum fructus Bruceae in example 4 of the present invention;

FIG. 4 is a schematic view of the circulating emulsifying shear of the first production apparatus provided in FIG. 1 according to the present invention;

FIG. 5 is a schematic view of the first embodiment of the apparatus of FIG. 1 according to the present invention;

in the figure: 1-a water phase tank; 2-oil phase tank; 3-a first filtration device; 4-a second filtration device; 5-emulsifying and shearing tank; 6-a homogenizer; 7-a pipeline cutter; 8-a first water pump; 9-a first check valve; 10-a second check valve; 11-a transfer tank; 12-a receiving tank; 13-an emulsifying shearing device; 16-a material tank; 17-a heat exchanger; 18-a first control valve; 19-a second control valve; 20-a third control valve; 21-a fourth control valve; 22-a fifth control valve; 23-a sixth control valve; 24-a seventh control valve; 25-an eighth control valve; 26-a ninth control valve; 27-a tenth control valve; 28-eleventh control valve; 29-a twelfth control valve; 30-a thirteenth control valve.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given by way of illustration only and are not intended to limit the scope of the present invention.

In the following embodiments 1 to 4, the emulsification shear tank communicates with the line cutter and forms a circulation path for emulsification shear, and the emulsification shear tank communicates with the homogenizer and forms a homogenization circulation path. Three kinds of production apparatuses used in the method for preparing an emulsion containing oleum fructus bruceae in examples 1 to 4 of the present invention are respectively shown in schematic structural views in FIGS. 1 to 3.

The oil phase material of brucea javanica oil emulsion passes through pipeline shears 7 and flows into emulsification shear tank 5 in, the oil phase material of brucea javanica oil emulsion is advanced to go into pipeline shears 7 promptly, pipeline shears 7 can cut the oil phase material of brucea javanica oil earlier, the oil phase material of brucea javanica oil after 7 shears of pipeline shears gets into emulsification shear tank 5 from pipeline shears 7 again, pipeline shears 7 can carry out preliminary shearing to the oil phase material of brucea javanica oil to the particle size of particle in the oil phase material of preliminary reduction brucea javanica oil.

The emulsifying and shearing tank 5 is communicated with the pipeline shears 7 and forms an emulsifying and shearing circulation path, namely, an oil emulsion mixture in the brucea javanica oil can be sheared in a circulating mode through the emulsifying and shearing tank 5 and the pipeline shears 7, so that the oil emulsion mixture of the brucea javanica oil can be sufficiently sheared.

The emulsifying and shearing tank 5 is communicated with the homogenizer 6 to form a homogeneous circulation path, the oil emulsion composition of the brucea javanica oil is sufficiently sheared by the emulsifying and shearing tank 5 and the pipeline shearer 7, the brucea javanica oil enters the homogenizer 6 from the emulsifying and shearing tank 5 to be homogenized, the emulsifying and shearing tank 5 and the homogenizer 6 form a homogeneous circulation path, namely, the oil emulsion composition of the brucea javanica oil after being sufficiently sheared can be circularly homogenized by the emulsifying and shearing tank 5 and the homogenizer 6, so that the oil emulsion composition of the brucea javanica oil can be sufficiently homogenized, the particle size of particles of the oil emulsion composition of the brucea javanica oil after being circularly homogenized is equal to or smaller than 0.22 mu m, and the degerming and filtering device of the brucea javanica oil emulsion composition with the filter element aperture of 0.22 mu m can be used for degerming and filtering the oil emulsion composition of the brucea javanica oil, so as to reduce the incidence rate of bacteria in the brucea javanica oil emulsion composition.

The production facility of brucea javanica oil emulsion composition that this embodiment provided still includes aqueous phase jar 1 and oil phase jar 2, and aqueous phase jar 1 and emulsification shear tank 5 intercommunication are provided with first filter equipment 3 between aqueous phase jar 1 and the emulsification shear tank 5. The oil phase tank 2 is communicated with the pipeline shears 7, and a second filtering device 4 is arranged between the oil phase tank 2 and the pipeline shears 7.

The water phase tank 1 is filled with water phase materials, the water phase materials in the water phase tank 1 can enter the emulsifying and shearing tank 5 through the first filtering device 3, and the first filtering device 3 can perform preliminary sterilization and filtration on the water phase materials. Because the emulsification shearing tank 5 is communicated with the pipeline shears 7, the water phase materials entering the emulsification shearing tank 5 can be circularly sheared by the pipeline shears 7.

The oil phase tank 2 is filled with oil phase materials, the oil phase materials in the oil phase tank 2 can enter the pipeline shearer 7 through the second filtering device 4, and the second filtering device 4 can perform preliminary sterilization and filtration on the oil phase materials. Because the oil phase tank 2 is communicated with the pipeline shears 7, the oil phase materials in the oil phase tank 2 can enter the pipeline shears 7 for shearing, and the oil phase materials sheared by the pipeline shears 7 enter the emulsification shearing tank 5.

Specifically, the water phase material in the water phase tank 1 firstly enters the emulsification shear tank 5, and is circularly sheared through the emulsification shear tank 5 and the pipeline shears 7, when the water phase material is circularly sheared through the emulsification shear tank 5 and the pipeline shears 7, the oil phase material in the oil phase tank 2 enters the pipeline shears 7, that is, the water phase material and the oil phase material are mixed in the pipeline shears 7, the pipeline shears 7 shears a mixed material formed by the water phase material and the oil phase material, the mixed material is sheared through the pipeline shears 7 and then enters the emulsification shear tank 5, and the emulsification shear tank 5 and the pipeline shears 7 circularly shear the mixed material, so that the mixed material can be sufficiently circularly sheared to form the colostrum of the brucea javanica oil emulsion composition.

It should be noted that the number of the pipeline cutters 7 is one or more, wherein, preferably, the number of the pipeline cutters 7 is 1-3, when the number of the pipeline cutters 7 is one, the pipeline cutters 7 can be respectively communicated with the emulsification shear tank 5 and the homogenizer 6 in the above-mentioned connection manner, when the number of the pipeline cutters 7 is 2 or 3, 2/3 pipeline cutters 7 are connected in series, and the head-most pipeline cutter 7 and the tail-most pipeline cutter 7 are respectively communicated with the emulsification shear tank 5 to form an emulsification shear circulation path. Similarly, when the number of the pipeline cutters 7 is plural, the pipeline cutters 7 are sequentially connected in series to cut the oil emulsion composition for a plurality of times. In this embodiment, the number of the pipeline shears 7 is preferably 2, and after the pipeline shears 7 shear twice and the emulsification shearing circulation path and the homogenization circulation path act simultaneously, the oil emulsion composition can pass through a sterilization and filtration device of the oil emulsion composition with the filter element aperture of 0.22 μm, so that the preparation condition is ensured, and the process is saved to the maximum extent.

Specifically, a second water pump (not shown in the figure) is arranged between the water phase tank 1 and the first filtering device 3, and the second water pump can convey the water phase materials in the water phase tank 1 to the emulsifying and shearing tank 5; a third water pump (not shown in the figure) is arranged between the oil phase tank 2 and the second filtering device 4, and the third water pump can convey the oil phase materials in the oil phase tank 2 to the pipeline shearer 7.

The number of the second water pumps and the number of the third water pumps can be multiple, and the number is not particularly limited and can be set according to actual conditions.

Optionally, temperature control layers are disposed on the outer side wall of the water phase tank 1, the outer side wall of the oil phase tank 2, and the outer side wall of the emulsification shear tank 5, and in order not to destroy the temperature control layers on the water phase tank 1, the oil phase tank 2, and the emulsification shear tank 5, preferably, the inlet of the water phase tank 1 is disposed on the top of the water phase tank 1, the inlet of the oil phase tank 2 is disposed on the top of the oil phase tank 2, and the inlet of the emulsification shear tank 5 is disposed on the top of the emulsification shear tank 5.

In order to facilitate the materials in the water phase tank 1, the oil phase tank 2 and the emulsification shear tank 5 to flow out completely, preferably, the outlet of the water phase tank 1 is arranged at the bottom of the water phase tank 1, the outlet of the oil phase tank 2 is arranged at the bottom of the oil phase tank 2, and the outlet of the emulsification shear tank 5 is arranged at the bottom of the emulsification shear tank 5.

In this embodiment, the filter pores of the first filter device 3 and the filter pores of the second filter device 4 are both smaller than or equal to 0.22 μ M and larger than or equal to 0.1 μ M, so that the first filter device 3 and the second filter device 4 have better sterilization effect.

The production facility of brucea javanica oil emulsion composition that this embodiment provided still includes turnover tank 11, and emulsification shearing jar 5, homogenizer 6 and turnover tank 11 communicate in proper order, are provided with heat exchanger 17 between homogenizer 6 and the turnover tank 11.

The materials in the emulsification shearing tank 5 sequentially pass through the emulsification shearing tank 5, the homogenizer 6 and the heat exchanger 17 to flow into the transfer tank 11, and the materials in the transfer tank 11 sequentially pass through the homogenizer 6 and the heat exchanger 17 to flow into the emulsification shearing tank 5, so that the materials are homogenized.

Colostrum in the emulsification shearing tank 5 carries out the homogeneity through homogenizer 6, the colostrum in the emulsification shearing tank 5 passes through homogenizer 6 and flows into turnover tank 11, in order to carry out abundant homogeneity with the colostrum, the colostrum in the turnover tank 11 flows into emulsification shearing tank 5 through homogenizer 6 again, that is to say, the colostrum in the emulsification shearing tank 5 flows into turnover tank 11 through homogenizer 6 in, the colostrum in the turnover tank 11 flows into emulsification shearing tank 5 through homogenizer 6 in, so circulate the homogeneity, make the colostrum can obtain abundant homogeneity, form the emulsion.

Preferably, since the homogenized emulsion has a high temperature, a heat exchanger 17 is disposed between the homogenizer 6 and the transfer tank 11, so that the homogenized emulsion can be subjected to a temperature reduction treatment.

The production equipment of the brucea javanica oil emulsion composition provided by the embodiment further comprises a first water pump 8, and the emulsifying and shearing tank 5, the first water pump 8 and the pipeline shearer 7 are sequentially communicated to form an emulsifying and shearing circulation passage; the emulsification shearing tank 5, the first water pump 8 and the homogenizer 6 are communicated in sequence.

Specifically, emulsification shear tank 5, first water pump 8 and pipeline clipper 7 communicate in proper order and form the circulation route of emulsification shearing, that is to say, emulsification shear tank 5 is through first water pump 8 and pipeline clipper 7 intercommunication, and first water pump 8 can carry the material in the emulsification shear tank 5 to in the pipeline clipper 7. Emulsification shearing jar 5, first water pump 8 and isotropic symmetry 6 communicate in proper order, and first water pump 8 can carry the colostrum in the emulsification shearing jar 5 to isotropic symmetry 6, carries out the homogeneity.

Optionally, the number of the first water pumps 8 is not specifically limited, and may be specifically set according to actual needs.

The production facility of brucea javanica oil emulsion composition that this embodiment provided still includes receiving tank 12, and receiving tank 12 and turnover tank 11 intercommunication, the material in the turnover tank 11 flows into in receiving tank 12 through first water pump 8. That is, the transfer tank 11, the first water pump 8, and the receiving tank 12 are sequentially communicated, and the emulsion homogenized in the transfer tank 11 flows into the receiving tank 12 through the first water pump 8.

In a preferred embodiment of this embodiment, a first check valve 9 is provided between the emulsification shear tank 5 and the first filtering device 3, and a second check valve 10 is provided between the second filtering device 4 and the line cutter 7.

After the water phase material in the water phase tank 1 passes through the first filtering device 3, the components of the water phase material subjected to the sterilization filtration by the first filtering device 3 can be detected through the first detection valve 9, and the sterilization effect of the first filtering device 3 can be known through the components of the water phase material subjected to the sterilization filtration by the first filtering device 3. After the oil phase material in oil phase jar 2 passes through second filter equipment 4, can detect the composition of the oil phase material after the aseptic filtration of second filter equipment 4 through second check valve 10, can learn the degerming effect of second filter equipment 4 through the composition of the oil phase material after the aseptic filtration of second filter equipment 4.

In this embodiment, emulsification shear tank 5 is provided with emulsification shearing mechanism 13, and emulsification shearing mechanism 13 includes axis of rotation and first stirring rake, and in the axis of rotation stretched into emulsification shear tank 5, the axis of rotation had a plurality of first stirring rakes along axial interval connection.

The number of the first stirring paddles may be 1, 2 or more, and is not particularly limited herein, and may be specifically set according to specific situations.

Further, stirring devices are provided on the water phase tank 1, the oil phase tank 2, the transfer tank 11, and the receiving tank 12. Agitating unit includes motor and second stirring rake, and the second stirring rake sets up in the output shaft of motor, and the second stirring rake includes a plurality of paddles.

In a preferred embodiment of this embodiment, the number of the first filter devices 3 and the second filter devices 4 is plural.

Specifically, a plurality of first filtering devices 3 can be arranged between the water phase tank 1 and the emulsifying and shearing tank 5 at intervals, and the water phase material in the water phase tank 1 can be sufficiently filtered by the plurality of first filtering devices 3. But a plurality of second filter equipment 4 of interval setting between oil phase jar 2 and the emulsification shearing jar 5, the oil phase material in oil phase jar 2 can carry out abundant filtration through a plurality of second filter equipment 4.

During specific implementation, the water phase tank 1 is communicated with the first filtering device 3 through a first material pipe, the first filtering device 3 is communicated with the emulsification shear tank 5 through a second material pipe and a third material pipe, namely the water phase tank 1, the first material pipe, the first filtering device 3, the second material pipe, the third material pipe and the emulsification shear tank 5 are sequentially communicated, wherein the second material pipe is provided with a first control valve 18, and the third material pipe is provided with a second control valve 19.

The emulsification shearing tank 5 is communicated with the first water pump 8 through a fourth material pipe, a third control valve 20 is arranged on the fourth material pipe, the first water pump 8 is communicated with the pipeline shearing device 7 through a fifth material pipe, a fourth control valve 21 is arranged on the fifth material pipe, the pipeline shearing device 7 is communicated with the emulsification shearing tank 5 through a sixth material pipe, and a fifth control valve 22 is arranged on the sixth material pipe.

As shown in fig. 1, the aqueous phase material in the aqueous phase tank 1 flows into the first filtering device 3 through the first material pipe, the first control valve 18 and the second control valve 19 are opened, and the aqueous phase material in the first filtering device 3 flows into the emulsification shear tank 5 through the second material pipe and the third material pipe. And opening the third control valve 20, enabling the water-phase material in the emulsification shear tank 5 to flow into the first water pump 8 through the fourth material pipe, opening the fourth control valve 21, enabling the first water pump 8 to convey the water-phase material to the pipeline shears 7 through the fifth material pipe, enabling the pipeline shears 7 to convey the sheared water-phase material to the emulsification shear tank 5 through the sixth material pipe, and enabling the fifth control valve 22 to be in an open state.

The oil phase tank 2 is communicated with the second filtering device 4 through a seventh material pipe, and the second filtering device 4 and the pipeline shears 7 can be communicated through an eighth material pipe, a third material pipe and a ninth material pipe in sequence as shown in figure 1. A sixth control valve 23 is arranged on the eighth material pipe, a seventh control valve 24 is arranged at one end of the ninth material pipe communicated with the third material pipe, and an eighth control valve 25 is arranged at one end of the ninth material pipe communicated with the fifth material pipe.

The oil phase material in the oil phase tank 2 flows into the second filtering device 4 through the seventh material pipe, the sixth control valve 23, the seventh control valve 24 and the eighth control valve 25 are opened, and the oil phase material in the second filtering device 4 flows into the pipeline shearer 7 through the eighth material pipe, the third material pipe and the ninth material pipe.

The water phase material gets into emulsification shearing jar 5 earlier, through emulsification shearing jar 5 and pipeline shears 7 circulation shearing, then the oil phase material gets into pipeline shears 7 again and shears, because ninth material pipe and fifth material pipe intercommunication, the oil phase material in the ninth material pipe mixes at pipeline shears 7's entrance with the water phase material in the fifth material pipe promptly, the mixed material after the mixture gets into pipeline shears 7, cuts, the mixture material of cutting through pipeline shears 7 gets into emulsification shearing jar 5 through sixth material pipe. The mixed material is circularly sheared by an emulsifying shearing tank 5 and a pipeline shearer 7.

The second water pump is arranged on the first material pipe, and the third water pump is arranged on the seventh material pipe.

Wherein, optionally, an additional pipeline cutter 7 can be arranged on the sixth material pipe between the pipeline cutter 7 and the emulsification shear tank 5. Preferably, 1-2 pipeline cutters 7 are arranged on the sixth material pipe between the pipeline cutter 7 and the emulsification shear tank 5. More preferably, 1 pipeline shearing device 7 is arranged on the sixth material pipe between the pipeline shearing device 7 and the emulsification shearing tank 5, so that the emulsion can be sufficiently sheared, the particle size of the sheared emulsion can reach a preset size, and the sheared emulsion can smoothly pass through each filtering device, each degerming device and the like.

Alternatively, the connection between the second filter device 4 and the pipeline cutter 7 may be changed to: the second filtering device 4 is directly communicated with the pipeline cutter 7 through an eighth material pipe (see figure 2).

The emulsification shearing tank 5 is communicated with the homogenizer 6 through a fourth material pipe, a fifth material pipe and a tenth material pipe, wherein the first water pump 8 is positioned between the fourth material pipe and the fifth material pipe, and the tenth material pipe is provided with a ninth control valve 26. The homogenizer 6 is communicated with the heat exchanger 17 through an eleventh material pipe, the heat exchanger 17 is communicated with the turnover tank 11 through a twelfth material pipe, and a tenth control valve 27 is arranged on the twelfth material pipe.

The colostrum sheared by the emulsification shearing tank 5 flows into the first water pump 8 through the fourth material pipe, the fourth control valve 21 is closed, the ninth control valve 26 is opened, the colostrum in the first water pump 8 flows into the homogenizer 6 through the fifth material pipe and the tenth material pipe, the colostrum in the homogenizer 6 flows into the heat exchanger 17 through the eleventh material pipe, the tenth control valve 27 is opened, and the colostrum in the heat exchanger 17 enters the turnover tank 11 through the twelfth material pipe.

In order to circularly homogenize the colostrum, the colostrum in the turnover tank 11 flows back to the emulsification shear tank 5 through the first water pump 8, the homogenizer 6 and the heat exchanger 17, the turnover tank 11 is communicated with the first water pump 8 through a thirteenth material pipe and a fourth material pipe in sequence, an eleventh control valve 28 is arranged on the thirteenth material pipe, the heat exchanger 17 is communicated with the emulsification shear tank 5 through a fourteenth material pipe, and a twelfth control valve 29 is arranged on the fourteenth material pipe.

The colostrum in the turnover tank 11 flows into the first water pump 8 through the thirteenth material pipe and the fourth material pipe, at this time, the eleventh control valve 28 is in an open state, the third control valve 20 is in a closed state, the colostrum in the first water pump 8 enters the homogenizer 6 through the fifth material pipe and the tenth material pipe, the colostrum in the homogenizer 6 enters the heat exchanger 17 through the eleventh material pipe, the twelfth control valve 29 is opened, the tenth control valve 27 is closed, and the colostrum in the heat exchanger 17 flows into the emulsification shearing tank 5 through the fourteenth material pipe. The colostrum in the emulsification shearing tank 5 flows into the turnover tank 11 through the homogenizer 6, and the colostrum in the turnover tank 11 flows into the emulsification shearing tank 5 through the homogenizer 6, and is homogenized in a reciprocating circulation manner to form an emulsion.

The turnover tank 11 is communicated with a fifteenth material pipe through a thirteenth material pipe, a fourth material pipe, a fifth material pipe and a fifteenth material pipe, and a thirteenth control valve 30 is arranged on the fifteenth material pipe. The emulsion in the turnover tank 11 flows into the first water pump 8 through the thirteenth material pipe and the fourth material pipe, the thirteenth control valve 30 is opened, the ninth control valve 26 is closed, and the emulsion in the first water pump 8 flows into the receiving tank 12 through the fifth material pipe and the fifteenth material pipe.

Figure 3 shows another production facility for an oil brucea javanica emulsion composition for use in an embodiment of the invention, the production facility for an oil brucea javanica emulsion composition provided in figure 3 being substantially identical to the production facility for an oil brucea javanica emulsion composition provided in figure 1, except that the aqueous phase tank 1 and the oil phase tank 2 are replaced by a single material tank 16.

The production equipment for the brucea javanica oil emulsion composition shown in fig. 3 comprises a material tank 16, wherein the material tank 16 is respectively communicated with an emulsification shearing tank 5 and a pipeline shearing device 7, a first filtering device 3 is arranged between the material tank 16 and the emulsification shearing tank 5, and a second filtering device 4 is arranged between the material tank 16 and the pipeline shearing device 7.

In specific implementation, firstly, the water-phase material is introduced into the material tank 16, the water-phase material flows into the emulsification shearing tank 5 through the first filtering device 3, then the oil-phase material is introduced into the material tank 16, and the oil-phase material flows into the pipeline shearing device 7 through the second filtering device 4. By the arrangement, the use of the material tank 16 can be reduced, and the cost is saved.

The invention is described in further detail below with reference to specific examples, in which the equipment used is as follows:

the emulsification shear tank was purchased from huadi pharmaceutical equipment ltd, gilin, model: MT500V3.

Emulsion tank shears were purchased from ai ka (guangzhou) instruments and equipment limited (IKA china) model: UTS TM150/2KT. Fixed frequency 50Hz, rotor speed (50 Hz): 2800rpm, rotor outboard circumferential velocity: 21m/s, maximum allowable working pressure: 16bar.

Pipeline shears were purchased from ai ka (guangzhou) instruments and equipment limited (IKA china), model: DRS2000/05. Fixed frequency 50Hz, maximum rotor speed (at 50 Hz): 7300rpm, maximum linear velocity (at 50 Hz): 42m/s, maximum pressure: 16bar, maximum heating temperature: 120 ℃, maximum heating jacket pressure: 2.5bar.

The homogenizer was purchased from shanghai hangjie biotechnology limited, model number: NS3110H.

Example 1

Preparation of an oil emulsion of brucea javanica (sample 1)

(1) Adding 150g of soybean phospholipid emulsifier into an emulsifying and shearing tank, adding 3000g of water for injection at 50 ℃, and circularly emulsifying and shearing the emulsifier and the water for injection for 40 minutes once through the emulsifying and shearing tank and a pipeline cutter so as to fully mix the emulsifier and the water for injection. Then 600g of an 80 ℃ glycerol aqueous solution (wherein glycerol and water for injection are uniformly mixed according to the mass ratio of 1: 1) is added, and the mixture is continuously subjected to circulating emulsification and shearing for 3 times, namely 20 minutes for the first time, 20 minutes for the second time and 10 minutes for the third time through an emulsification shearing tank and a pipeline shearing device.

(2) Heating 1000ml of oleum fructus bruceae to 80 ℃, slowly adding into the pipeline shearer, mixing with the mixture in the step (1) in the pipeline shearer to obtain an oil-water mixture, enabling the oil-water mixture to flow in a circulating path of emulsification shearing, and carrying out circulating emulsification shearing on the oil-water mixture sequentially by the pipeline shearer and the emulsification shearing tank for 3 times, wherein each time lasts for 10 minutes to obtain a uniform oil-water mixture.

(3) And (3) gradually adding injection water with the temperature of 70 ℃ to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, enabling the full amount of liquid medicine to flow in the circulation path of emulsification shearing, and carrying out once 30-minute circulation emulsification shearing by the emulsification shearing tank and the pipeline shearing device in sequence to obtain primary emulsion.

(4) And (4) circularly homogenizing the primary emulsion obtained in the step (3) for 3 times through a homogenizing circulation passage comprising an emulsifying shearing tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 1200bar.

(5) Filtering the uniform emulsion obtained in the step (4) through a sterilizing filter with a filter element with the pore diameter of 0.22 mu m under the filtering pressure of 30 psi.

(6) Encapsulating the filtrate, and sterilizing with 100 deg.C flowing steam for 30 min.

Example 2

Preparation of an oil emulsion of brucea javanica (sample 2)

(1) Adding 250g of emulsifier (yolk lecithin and poloxamer in a mass ratio of 1: 1) into an emulsification shearing tank, adding 3750g of 90 ℃ water for injection, and circularly emulsifying and shearing the emulsifier and the water for injection for 80 minutes once through the emulsification shearing tank and a pipeline shearer to fully mix the emulsifier and the water for injection. 375g of a 100 ℃ uniformly mixed solution of propylene glycol, mannitol and water for injection (wherein the mass ratio of propylene glycol, mannitol and water for injection is 2: 1.

(2) Heating 3000ml of oleum fructus bruceae to 100 ℃, slowly adding into the pipeline shearer, mixing with the mixture in the step (1) in the pipeline shearer to obtain an oil-water mixture, enabling the oil-water mixture to flow in a circulating path of emulsification shearing, and carrying out circulating emulsification shearing on the oil-water mixture sequentially by the pipeline shearer and the emulsification shearing tank for 2 times, wherein each time lasts for 60 minutes to obtain a uniform oil-water mixture.

(3) Adding 25g of vitamin E and hydrochloric acid into the uniform oil-water mixture obtained in the step (2) to adjust the pH value to 4.0-6.0, gradually adding 90 ℃ injection water to 10000ml to obtain a full amount of liquid medicine, enabling the full amount of liquid medicine to flow in the circulation path of emulsification shearing, and carrying out one-time 60-minute circulation emulsification shearing by the emulsification shearing tank and the pipeline shearing device in sequence to obtain colostrum.

(4) And (4) circularly homogenizing the primary emulsion obtained in the step (3) for 4 times through a homogenizing circulation passage comprising an emulsifying shear tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 800bar.

(5) Filtering the uniform emulsion obtained in the step (4) through a sterilizing filter with a filter element with the pore diameter of 0.1-0.22 mu m under the filtering pressure of 120 psi.

Example 3

Preparation of an oil emulsion of brucea javanica (sample 3)

(1) Adding 120g of soybean lecithin serving as an emulsifier into an emulsifying and shearing tank, adding 600g of water for injection at 40 ℃, and carrying out circulating emulsifying and shearing on the emulsifier and the water for injection for 10 minutes once through the emulsifying and shearing tank and a pipeline shearing device so as to fully mix the emulsifier and the water for injection. 1750ml of 50 ℃ water for injection was added thereto, and the mixture was subjected to cyclic emulsification shearing by passing through an emulsification shearing tank and a line cutter for 2 times each for 60 minutes.

(2) Heating 500ml of oleum fructus bruceae to 50 ℃, slowly adding into the pipeline shearer, mixing with the mixture in the step (1) in the pipeline shearer to obtain an oil-water mixture, enabling the oil-water mixture to flow in a circulating path of emulsification shearing and to be sequentially subjected to circulation emulsification shearing by the pipeline shearer and the emulsification shearing tank for 4 times, and obtaining a uniform oil-water mixture after 10 minutes each time.

(3) And (3) adding 50g of oleic acid and sodium hydroxide into the uniform oil-water mixture obtained in the step (2) to adjust the pH value to 4.0-6.0, gradually adding 100 ℃ of water for injection to 10000ml to obtain a full amount of liquid medicine, enabling the full amount of liquid medicine to flow in the circulation path of emulsification shearing, and performing circulation emulsification shearing for 10 minutes once by the emulsification shearing tank and the pipeline shearing device in sequence to obtain primary emulsion.

(4) And (4) circularly homogenizing the primary emulsion obtained in the step (3) for 6 times through a homogenizing circulation passage comprising an emulsifying shear tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 400bar.

(5) Filtering the uniform emulsion obtained in the step (4) through a sterilizing filter with a filter element with the pore diameter of 0.22 mu m under the filtering pressure of 80 psi.

Example 4

Preparation of an oil emulsion of brucea javanica (sample 4)

(1) Adding 200g of polysorbate emulsifier into an emulsifying and shearing tank, adding 2000g of water for injection at 70 ℃, and performing circulating emulsifying and shearing on the emulsifier and the water for injection for 60 minutes once through the emulsifying and shearing tank and a pipeline shearer to fully mix the emulsifier and the water for injection. Then, 6g of a 70 ℃ uniform mixed solution of polyethylene glycol and water for injection (wherein the mass ratio of polyethylene glycol to water for injection is 1.

(2) Heating 1000ml of oleum fructus bruceae to 70 ℃, slowly adding the oleum fructus bruceae into the pipeline shearing device, mixing the oleum fructus bruceae and the mixture obtained in the step (1) in the pipeline shearing device to obtain an oil-water mixture, enabling the oil-water mixture to flow in a circulating path of emulsification shearing, and carrying out circulating emulsification shearing on the oil-water mixture sequentially by the pipeline shearing device and the emulsification shearing tank for 2 times, wherein the first time is 30 minutes, and the second time is 60 minutes, so as to obtain a uniform oil-water mixture.

(3) And (3) gradually adding 80 ℃ injection water to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, enabling the full amount of liquid medicine to flow in the emulsification shearing circulation path, and performing one-time 60-minute circulation emulsification shearing by the emulsification shearing tank and the pipeline shearing device in sequence to obtain primary emulsion.

(4) And (4) circularly homogenizing the primary emulsion obtained in the step (3) for 5 times through a homogenizing circulation passage comprising an emulsifying shearing tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 600bar.

(5) And (4) filtering the uniform emulsion obtained in the step (4) through a sterilizing filter with a filter element with the pore diameter of 0.22 mu m under the filtering pressure of 60 psi.

In the following comparative examples 1 to 2, the material was emulsified and sheared only by using the emulsifying and shearing tank without using the line cutter, and emulsified and homogenized by using the homogenizing circulation path formed by the emulsifying and shearing tank communicating with the homogenizer and the transfer tank.

Comparative example 1

Preparation of a brucea javanica oil emulsion control (control 1)

The same formula and process parameters as in example 1 were used to prepare an oil emulsion of brucea javanica, except that a pipeline cutter was not used, but only an emulsification shear tank was used to emulsify and shear the material, and the specific procedure was as follows:

(1) 150g of soybean phospholipid as an emulsifier was put into an emulsifying and shearing tank, 3000g of water for injection at 50 ℃ was added, and the emulsifier and the water for injection were emulsified and sheared by the emulsifying and shearing tank for 40 minutes to be sufficiently mixed. Then 600g of an 80 ℃ glycerol aqueous solution (wherein glycerol and water for injection are uniformly mixed in a mass ratio of 1: 1) was added, and the mixture was further subjected to emulsification shearing by an emulsification shearing tank for 3 times, the first 20 minutes, the second 20 minutes and the third 10 minutes.

(2) Heating 1000ml of oleum fructus bruceae to 80 ℃, slowly adding into the emulsification shearing tank to obtain an oil-water mixture, and emulsifying and shearing the oil-water mixture in the emulsification shearing tank for 3 times, 10 minutes each time to obtain a uniform oil-water mixture.

(3) And (3) gradually adding injection water with the temperature of 70 ℃ to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, and emulsifying and shearing the full amount of liquid medicine in the emulsifying and shearing tank for 30 minutes to obtain primary emulsion.

(5) Encapsulating the emulsion, and sterilizing with 100 deg.C flowing steam for 30 min.

In this comparative example, since the homogeneous emulsion obtained in step (4) had too large a particle size to be filtered through a sterilizing filter having a filter element with a pore size of 0.22 μm, the emulsion was directly filled without filtration and sterilized with flowing steam at 100 ℃ for 30 minutes to obtain a brucea javanica oil emulsion (comparative sample 1).

Comparative example 2

Preparation of brucea javanica oil emulsion comparative sample (comparative sample 2)

The same formulation and equipment as in comparative example 1 were used to prepare an oil emulsion of brucea javanica, except that the time for emulsification shear and homogenization was increased, as follows:

(1) 150g of soybean phospholipid as an emulsifier was put into an emulsifying and shearing tank, 3000g of water for injection at 50 ℃ was added, and the emulsifier and the water for injection were emulsified and sheared by the emulsifying and shearing tank for 90 minutes to be sufficiently mixed. Then 600g of an aqueous solution of 80 ℃ glycerin (wherein glycerin and water for injection were uniformly mixed at a mass ratio of 1: 1) was added thereto, and the mixture was further subjected to emulsification shearing by an emulsification shearing tank for 5 times, each for 90 minutes.

(2) Heating 1000ml of oleum fructus bruceae to 80 ℃, slowly adding into the emulsification shearing tank to obtain an oil-water mixture, and emulsifying and shearing the oil-water mixture in the emulsification shearing tank for 5 times, each time for 90 minutes, to obtain a uniform oil-water mixture.

(3) And (3) gradually adding injection water with the temperature of 70 ℃ to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, and emulsifying and shearing the full amount of liquid medicine in the emulsifying and shearing tank for 90 minutes to obtain primary emulsion.

(4) And (4) circularly homogenizing the primary emulsion obtained in the step (3) for 8 times through a homogenizing circulation passage comprising an emulsifying shearing tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 1200bar.

In this comparative example, since the homogeneous emulsion obtained in step (4) had too large a particle size to be filtered through a sterilizing filter having a 0.22 μm pore size filter, the emulsion was directly filled without filtration and sterilized with 100 ℃ circulating steam for 30 minutes to obtain an oil emulsion of brucea javanica (comparative sample 2).

Comparative example 3

Preparation of brucea javanica oil emulsion control sample (control sample 3)

The same formulation and process parameters as in example 1 were used to prepare an oil emulsion of brucea javanica, except that no emulsification shear tank was used, but the material was emulsified and sheared only by two pipeline shears connected in series, the specific procedure was as follows:

(1) 150g of soybean phospholipid as an emulsifier was put in a line cutter, 3000g of water for injection at 50 ℃ was added, and the emulsifier and the water for injection were emulsified and cut by the line cutter for 40 minutes to be mixed sufficiently. Then 600g of an 80 ℃ glycerol aqueous solution (wherein glycerol and water for injection are uniformly mixed in a mass ratio of 1: 1) was added, and the mixture was further emulsified and sheared by a pipeline shearer for 3 times, first 20 minutes, second 20 minutes, and third 10 minutes.

(2) Heating 1000ml of oleum fructus bruceae to 80 ℃, slowly adding into the pipeline shearer to obtain an oil-water mixture, and emulsifying and shearing the oil-water mixture in the pipeline shearer for 3 times, 10 minutes each time, to obtain a uniform oil-water mixture.

(3) And (3) gradually adding injection water with the temperature of 70 ℃ to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, and emulsifying and shearing the full amount of liquid medicine in the pipeline shearing device for 30 minutes to obtain primary emulsion.

(4) Homogenizing the primary emulsion obtained in the step (3) for 3 times through a homogenizing circulation passage comprising an emulsifying shear tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 1200bar.

In this comparative example, since the homogeneous emulsion obtained in step (4) had too large a particle size to be filtered through a sterilizing filter having a filter element with a pore size of 0.22 μm, the emulsion was directly filled without filtration and sterilized with flowing steam at 100 ℃ for 30 minutes to obtain a brucea javanica oil emulsion (comparative sample 3).

Comparative example 4

Preparation of brucea javanica oil emulsion comparative sample (comparative sample 4)

The same formulation and equipment as in comparative example 3 was used to prepare an oil emulsion of brucea javanica, except that the time for emulsification shear and homogenization was increased, as follows:

(1) 150g of soybean phospholipid as an emulsifier was put in a line cutter, 3000g of water for injection at 50 ℃ was added, and the emulsifier and the water for injection were emulsified and cut by the line cutter for 90 minutes to be mixed thoroughly. Further 600g of an 80 ℃ aqueous solution of glycerin (wherein glycerin and water for injection were uniformly mixed in a mass ratio of 1: 1) was added, and the mixture was further emulsified and sheared by a line cutter for 5 times of 90 minutes each time.

(2) Heating 1000ml of oleum fructus bruceae to 80 ℃, slowly adding into the pipeline cutter to obtain an oil-water mixture, and emulsifying and shearing the oil-water mixture in the pipeline cutter for 5 times, each time for 90 minutes, to obtain a uniform oil-water mixture.

(3) And (3) gradually adding injection water with the temperature of 70 ℃ to 10000ml into the uniform oil-water mixture obtained in the step (2) to obtain a full amount of liquid medicine, and emulsifying and shearing the full amount of liquid medicine in the pipeline shearing device for 90 minutes to obtain primary emulsion.

(4) Homogenizing the primary emulsion obtained in the step (3) for 8 times through a homogenizing circulation passage comprising an emulsifying shear tank, a homogenizer and a transfer tank to obtain a uniform emulsion, wherein the pressure of the homogenizer is 1200bar.

In this comparative example, since the homogeneous emulsion obtained in step (4) had too large a particle size to be filtered through a sterilizing filter having a filter element with a pore size of 0.22 μm, the emulsion was directly filled without filtration and sterilized with flowing steam at 100 ℃ for 30 minutes to obtain a brucea javanica oil emulsion (comparative sample 4).

Test example 1

Determination of emulsion stability constant (Ke value):

the smaller the Ke value, the less the dispersed droplets in the emulsion float up by the centrifugal force, and the more stable the emulsion, and the Ke value was used to evaluate the physical stability of the emulsion.

Samples 1-4 and comparative samples 1-4 were taken, 7ml each, and placed in centrifuge tubes. Centrifuging at 4000r/min for 15 min, collecting lower layer emulsion, diluting with water for injection until the absorbance of the sample is 0.3-0.7, respectively placing into sample placing region of UV-2550 sample cell of Shimadzu ultraviolet-visible spectrophotometer, and using water for injection as blank solvent. The absorbance of the sample before centrifugation and the lower layer solution after centrifugation were measured at a wavelength of 500nm, and the Ke value was calculated.

Calculating the formula:

(in the formula A) ₀ Is the absorbance of the sample before centrifugation, A is the absorbance of the lower layer solution sample after centrifugation)

The results are shown in Table 1.

TABLE 1

As can be seen from the results in Table 1, the Ke values of samples 1-4 prepared by the method of the present invention are significantly lower than the Ke values of comparative samples 1-4 prepared by the method of the comparative example. This indicates that the emulsions prepared by the method of the present invention are significantly more stable than the emulsions prepared by the comparative method.

Test example 2

The particle size measuring method comprises the following steps:

samples 1-4 and comparative samples 1-4 were taken 11. Mu.l each and placed in centrifuge tubes to which 10ml of water for injection had been added. Shake gently until uniform. The PSS laser particle analyzer (purchased from Shanghai Orphajia Biotechnology Co., ltd.) is opened, a sample to be detected is placed in a sample cell detection position, the light intensity value is adjusted to be 300 +/-30 KHz, the circulation is set for 2 weeks, the detection is clicked, a report is printed, and data are recorded. The results are given in Table 2 below:

TABLE 2

As shown in Table 2, the method provided by the invention can reduce the D90 of the brucea javanica oil emulsion to below 200nm, and the brucea javanica oil emulsion prepared by the method can be filtered by a sterilization-grade filter, and meets the requirement of sterility test.

Test example 3

1. Stability test

Samples 1 to 4 and comparative samples 1 to 4 were taken, respectively, and an accelerated test and a long-term stability test were conducted under the same conditions.

The accelerated test is that eight groups of samples are placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the humidity is 75% +/-5%, sampling detection is respectively carried out at the end of 1 st, 2 nd, 3 rd and 6 th months, and the detection results are compared with the detection results of 0 month; the long-term stability test is to place the sample at 20 ℃ and 60% +/-10% humidity, sample and test at 3 rd, 6 th, 9 th, 12 th, 18 th and 24 th months respectively, and compare the test result with that of 0 month. The appearance of the sample was observed, and the Ke value, D90, p.i. of the sample were measured and calculated according to the methods of test example 1 and test example 2.

2. Results of accelerated test

TABLE 3 stability test results under accelerated test (n = 8)

The comparative sample 1-2 showed oil appearance from the 3 rd month, and the oil appearance of the comparative sample 1 was increased with the increase of the standing time, and an oil layer was formed; the oil production phenomenon begins to appear in the 6 th month of the comparative sample 3; comparative sample 4 and samples 1-4 both met the quality standard requirements.

3. Long term stability test results

Table 4 long term stability test results (n = 8)

The comparative sample 1 showed oil evolution from the 9 th month, and the comparative sample 2 showed oil evolution from the 12 th month, and the oil evolution was significant with the time. The comparative samples 3-4 exhibited oil evolution from month 18 with no delamination. Samples 1-4 all met the quality standard requirements.

Claims

1. A method for preparing emulsion containing oleum fructus Bruceae comprises the following steps: the method comprises the following steps of (1) circularly emulsifying and shearing a water-phase material and an oil-phase material to form primary emulsion, and circularly homogenizing the primary emulsion to obtain uniform emulsion which can be filtered by a sterilizing filter;

wherein the circulating emulsification shearing is carried out in a circulating path of emulsification shearing, the circulating path of emulsification shearing comprises an emulsification shearing tank (5), a pipeline shearing device (7) and a material pipe for communicating the emulsification shearing tank (5) with the pipeline shearing device (7), and the circulating emulsification shearing is completed by the following steps: the materials flow in the circulation path of the emulsification shearing and are sequentially emulsified and sheared by the emulsification shearing tank (5) and the pipeline shearing device (7), and the materials circulate in the circulation path of the emulsification shearing for one circle to complete one-time circulation emulsification shearing; and

the circulation homogenization is carried out in a homogenization circulation path, and the homogenization circulation path comprises an emulsification shearing tank (5), a homogenizer (6), a transfer tank (11) and a material pipe which is communicated with the emulsification shearing tank (5), the homogenizer (6) and the transfer tank (11); and the cyclic homogenization is completed by the following steps: the primary emulsion flows into the homogenizer (6) from the emulsifying and shearing tank (5) for homogenization, the homogenized material flows into a transfer tank (11) from the homogenizer (6) so as to complete primary circulation homogenization, then the material flowing into the transfer tank (11) flows back to the homogenizer (6) again for re-homogenization, and the re-homogenized material flows into the emulsifying and shearing tank (5) from the homogenizer (6) so as to complete secondary circulation homogenization;

wherein the colostrum is formed by a method comprising the steps of:

1) Adding an aqueous phase material containing water for injection, an emulsifier and an optional osmotic pressure regulator into the emulsification shearing tank (5), and performing circulating emulsification shearing through a circulating path of the emulsification shearing to fully mix the material, wherein the material flows in the circulating path of the emulsification shearing and is subjected to circulating emulsification shearing by the emulsification shearing tank (5) and the pipeline shearer (7) in sequence;

2) Adding the oil-phase material into the pipeline shearing device (7), mixing the oil-phase material with the water-phase material in the step 1) in the pipeline shearing device (7) to obtain an oil-water mixed material, enabling the oil-water mixed material to flow in a circulation path of emulsification shearing, and performing circulation emulsification shearing on the oil-water mixed material through the pipeline shearing device (7) and the emulsification shearing tank (5) in sequence to obtain a uniform oil-water mixed material;

3) Optionally adding a stabilizer and/or a pH regulator into the uniformly mixed material in the step 2) in the emulsifying and shearing tank (5), adding the rest of water for injection into the emulsifying and shearing tank (5) to obtain a full-amount liquid medicine, making the full-amount liquid medicine flow in a circulating path of the emulsifying and shearing, and performing circulating emulsifying and shearing by the emulsifying and shearing tank (5) and the pipeline shearer (7) in sequence to obtain a primary emulsion;

wherein:

in the step 1), the emulsifier and the first part of water for injection are added into the emulsification shearing tank (5), the emulsifier and the first part of water for injection are subjected to first circulation emulsification shearing in a circulation path of the emulsification shearing, then a second part of water for injection or an aqueous solution for injection containing an osmotic pressure regulator is added into the emulsification shearing tank (5), and the obtained mixture is subjected to second circulation emulsification shearing in the circulation path of the emulsification shearing; wherein, the first circulation emulsification shearing is carried out for 1 time, and the time is 10 to 80 minutes; the second circulation emulsification shearing is carried out for 2 to 4 times, and each time lasts for 10 to 60 minutes;

in the step 2), the oil-phase material is oleum fructus brucease, the circulating emulsification and shearing of the oil-water mixture in the circulating path of the emulsification and shearing is a third circulating emulsification and shearing, and the third circulating emulsification and shearing is carried out for 2-4 times and each time lasts for 10-60 minutes; and/or

In the step 3), the circulating emulsification shearing of the full amount of the liquid medicine in the circulation passage of the emulsification shearing is fourth circulating emulsification shearing, and the fourth circulating emulsification shearing is carried out for 1 time and 10-60 minutes in total.

2. The method according to claim 1, wherein the temperature of the first portion of water for injection, the second portion of water for injection or the aqueous solution for injection containing the osmotic pressure regulator in step 1) is 40 ℃ to 100 ℃;

in the step 2), the temperature of the oleum fructus bruceae is 50-100 ℃; and/or

In the step 3), the temperature of the rest of the water for injection is above 70 ℃, and the pH regulator is added to regulate the pH value of the liquid medicine to 4.0-6.0.

3. The method of claim 1, further comprising the step of sterilizing the emulsion.

4. The method of claim 3, wherein the sterilizing step comprises filtering the emulsion through a sterilizing filter followed by moist heat sterilization.

5. The method of claim 1, wherein the sterilizing filter is a sterilizing filter of 0.22 μ ι η or smaller pore size or the same filtration efficiency.

6. The method according to any one of claims 1 to 5, wherein said cyclic homogenization is carried out 2 to 6 times in a homogenizer (6) at a pressure of 400 to 1200 bar; and/or

The shearing frequency of the emulsification shearing tank (5) is 40-60 Hz; the shearing frequency of the pipeline shearer (7) is 40-60 Hz.

7. The method according to claim 6, wherein the shear frequency of the emulsification shear tank (5) is 50Hz; and/or

The shearing frequency of the pipeline shearer (7) is 50Hz.

8. The process according to claim 4, wherein the filtration is carried out at a filtration pressure of 30-120 psi through a sterilizing filter having a filter element with a pore size of 0.22 μm or less; and/or

The moist heat sterilization is carried out under live steam at 100 ℃.

9. The method of claim 1, wherein the amount of emulsifier is 40-500 g based on 1000ml of oleum fructus bruceae; the amount of the first part of the water for injection is 200 to 10000g; the amount of the second part of water for injection or the water solution for injection containing the osmotic pressure regulator is 0.15-3500 g; the amount of the osmotic pressure regulator is 0-700 g; the amount of the stabilizer is 0 to 100g; the amount of the residual water for injection is increased to 3000-20000 ml.

10. The process according to claim 9, wherein the amount of emulsifier is 80 to 250g; the amount of the first part of water for injection is 1000-3000 g; the amount of the second part of water for injection or the water solution for injection containing the osmotic pressure regulator is 5-3500 g; the amount of the osmotic pressure regulator is 0-300 g; the amount of the stabilizer is 5-10 g; and/or the amount of the rest water for injection is added to 10000ml.

11. The method of any one of claims 1 to 5, wherein the emulsifier is selected from one or more of soy phospholipid, soy lecithin, egg lecithin, poloxamer, monoglyceryl acetate, polysorbate, or cremophor EL;

the osmotic pressure regulator is selected from one or more of glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, mannitol or xylitol;

the stabilizer is selected from one or more of vitamin E, ascorbic acid, oleic acid, sodium oleate, cholic acid, deoxycholic acid or sodium deoxycholate; and/or

The pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, phosphoric acid and salts thereof, carbonic acid and salts thereof, lactic acid, citric acid or acetic acid.

12. The method according to any one of claims 1 to 5, wherein the aqueous phase material and the oil phase material are subjected to a filter sterilization treatment before being subjected to the cyclic emulsification shearing.

13. A method according to any one of claims 1 to 5, wherein the number of line cutters (7) is one or more; and when the number of the pipeline shears (7) is multiple, the pipeline shears (7) are connected in series.

14. A method according to claim 13, wherein the number of line cutters (7) is 2.