KR101981606B1 - Infant liquid formula composition and its manufacturing process - Google Patents

Abstract

The present invention relates to a liquid pharmaceutical composition having excellent production efficiency, phase stability, aging stability and microbial safety, and a process for producing the same. The process for producing a liquid pharmaceutical composition according to the present invention has a step of producing a concentrated mixture liquid as a semi-finished product, so that a utility, a time and the like required compared to a process for collectively preparing an initially diluted finished product are reduced and the production efficiency is excellent. Further, the liquid pharmaceutical composition according to the present invention has superior phase stability and long-term stability according to emulsification and dispersion stabilization, and is superior in microbial safety through ultrahigh-temperature short-time sterilization (UHT) treatment and the like. Further, the liquid pharmaceutical product according to the present invention can be easily nursed by using the plastic container of the direct coupling type with the nipple.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to an infant liquid formula composition,

More particularly, the present invention relates to a liquid preparation oil composition and a liquid preparation composition thereof having excellent production efficiency, phase stability, aging stability and microbial safety through emulsification and dispersion stabilization and preheating, homogenization and sterilization processes. And a manufacturing method thereof.

In case of powdered milk powder, which is usually distributed in the market, when nutrients are dissolved in liquid form for lactation, nutrients are designed so as to be similar to the components of milk, and after various mixing, concentration, sterilization or sterilization processes, To form a powder. However, differences in concentration, solubility, dispersibility, temperature, and so on are inevitably different from the actual milking concentration depending on the actual usage method of lactating milk. In addition, there is a problem in that there is a substantial difference in terms of realizing the proper nutritional composition of mother's milk and constant milking concentration. In addition, the formulation of powdered milk powder has a problem that the loss of nutritional components due to heat treatment such as spray drying is a problem.

Also, in order to solve the above problems, it has been found that even in the production of the liquid type preparation milk having a constant milking concentration, the mixing of the raw materials such as milk, protein, vitamins and minerals, the instability of emulsification and dispersion due to homogenization, Phase separation due to protein denaturation, etc., or precipitation, etc., have not reached the level that can safely feed within the distribution period. In addition, there are problems such as a large number of compounding, homogeneous, and low yield of product due to the heat treatment step, and an increase in processing cost, thereby causing the burden of manufacturing cost to be passed on to consumers.

The concentrating step before the preparation of the preparation oil (the step of preparing a concentrated mixture liquid) generally includes a number of processing steps such as mixing, preheating, homogenization, sterilization, or sterilization, and is known as an efficient method in terms of time and cost reduction . However, since the intrinsic properties of dairy products cause severe problems such as poor stability, odor, or gelling, they are difficult to apply in practice.

Especially in the case of whey protein raw materials, which are inevitably used in dairy products, the main amino acids that constitute the muscles are abundant, which not only helps to produce muscles, but also has a higher content in milk than milk, Is a component that must be included in high amounts in milk. However, in terms of stabilization, the whey protein raw material is a three-dimensional three-dimensional structure formed by a combination of free amino, carboxyl groups, intermolecular ions and disulfide bonds, Or precipitation may occur, resulting in the loss of original properties and actions.

The main cause of protein denaturation in general dairy products is known as heating, but other mechanical forces such as agitation and high pressure may also be a factor in protein denaturation. Due to these physical and chemical factors, the tendency of crosslinking in the heat treatment condition must be suppressed to a great extent in the concentration step in the manufacturing process, and it is difficult to use the process and raw materials in order to solve this problem.

In the case of liquid formulated milk, delayed re-agglomeration due to selection of suitable emulsifier, fine dispersion of the dispersed particles, and coating of the particle surface as a complex form of emulsification, dispersion and dissolution processes is a very important factor for improving the stability. An emulsion, which is typically one of the characteristics of formula oil, refers to a colloid solution in which two phases are dispersed, that is, another liquid that is insoluble in a liquid, that is, a dispersion medium, is dispersed in a dispersed phase. Such an emulsion may lead to separation of the fat layer when the phase is unstable, but when the emulsion or dispersed phase is unstable, it may cause non-uniformity of the dispersed particles and may easily aggregate and adversely affect the sedimentation amount of the protein. It will not achieve its original purpose. In this case, it is very important to prevent re-aggregation of appropriate emulsifier and dispersed particles.

Emulsions in dairy products are characterized by protein stabilization in a different pattern from common emulsions. In the case of emulsifiers, it is used as a secondary role, but emulsifiers are very important because they are instantaneously arranged at the water interface to lower the interfacial tension. Particularly, emulsifiers commonly used are low molecular and ampholytic and are arranged at the interface of the oil phase and water phase to contribute to stabilization of the lipid spheres and phase stabilization. However, when the proper amount is not applied, the emulsions tend to be desorbed or too much emulsifier content adversely affects the phase stability .

One of the important stabilization factors in the manufacturing process is the homogenization of the particles and the homogenization of the particles. Minimization and homogenization of particles by proper homogenization minimizes agglomeration between particles due to aging, which is an effect of delaying agglomeration of particles considerably longer than that of relatively large and uneven particles, . However, micronized and homogeneous particles formed through homogenization may cause aggregation, separation, or sedimentation delay compared to a non-refined oil composition, but may cause problems due to re-aggregation at a time and at various temperature circulation and aging conditions. Therefore, it is very important to select appropriate emulsification, dispersion stabilizer, and protein that will not only refine and homogenize the particles properly under optimized homogeneous conditions, but also prevent re-aggregation during the distribution process.

In addition, the proper design of heat treatment conditions such as sterilization and sterilization for such liquid preparations reduces microbial safety and phase stability by reducing the denaturation of protein and other milk materials by heating, and improves odor, discoloration, and taste It is an essential element to maintain. In the case of existing commercially available liquid formulated milk, most of them are produced through an excessive heat treatment process in the retort type, which causes phase instability or partially causes taste, odor, or discoloration. In order to avoid such a phenomenon, it is also found that the protein content of the protein, which is an essential element, is lowered and commercialized, thereby failing to supply adequate nutrition to consumers.

The production of such liquid formulated milk as described above has many difficulties such as emulsification, dispersion stability, homogenization, and sterilization, and it is necessary to develop a method which can solve such a problem at one time in producing liquid formulated milk.

A problem to be solved by the present invention is to provide a liquid pharmaceutical composition having excellent production efficiency, phase stability, stability with time, and microbial safety and a method for producing the same.

As a result of intensive efforts to achieve the above technical object, the inventors of the present invention have found that, in the production of liquid preparation milk, a specific emulsifier, milk, protein and the like are added to and mixed with the fat and the preheating, homogenization and sterilization process To prepare a concentrated mixture liquid in which protein thermal denaturation was reduced and microbial safety was secured. Then, the concentrated mixture was diluted with water, and then subjected to preheating, homogenization, and ultrahigh-temperature short-time sterilization (UHT) to prepare a liquid preparation.

The liquid formulated milk produced by the above-mentioned method has high production efficiency, is uniform in particles due to emulsification and dispersion stabilization, has excellent phase stability and long-term stability because there is no phase separation and precipitation, and the microbial safety is remarkable due to an effective sterilization process And completed the present invention.

(S1) mixing and stirring at least one selected from the group consisting of milk, milk powder and proteins, and a fat, oil, or mixture thereof; (s2) homogenizing the product of step (s1); And (s3) sterilizing the product of the step (s2), and a concentrated liquid for the production of a liquid preparation oil prepared by the above production method.

In the production method of the present invention, the semi-finished product type concentrated liquid has a solid content of about 120 to less than 400% by weight (concentration), preferably 150 to 350% by weight (concentration) Preferably from 200 to 300% by weight (thickeness). If the concentration of the concentrate is less than 120 wt% (concentration), the production efficiency decreases. If the concentration of the concentrate is more than 400 wt% (concentration), the quality stability such as protein denaturation, microorganisms, or precipitation may be drastically lowered.

In the present invention, the emulsifier may be lecithin, glycerin fatty acid esters, or a mixture thereof. In the present invention, the glycerin fatty acid ester is a compound in which a fatty acid and glycerin or polyglycerin are esterified or a derivative thereof. More specifically, the glycerin fatty acid esters include glycerin fatty acid esters, glycerin acetic acid fatty acid esters, glycerin lactic acid fatty acid esters, glycerin citric acid fatty acid esters, glycerin succinic acid fatty acid esters, glycerin diacetyl tartaric acid fatty acid esters, glycerin acetic acid esters, polyglycerin fatty acid esters, Polyglycerol condensed ricinoleic acid ester, and the like.

In the above production process, the glycerin fatty acid esters are used in an amount of 1/25 to 1/1 (glycerin fatty acid esters / fat) weight ratio, preferably 1/15 to 1/5 (glycerin fatty acid esters / fat) . When the emulsifier is less than 1/25 (glycerin fatty acid esters / fat) weight ratio, it is difficult for the low molecular weight and amphipathic emulsifier to be effectively adsorbed on the liquid interface of the liquid preparation oil. If the weight ratio is 1/1 (glycerin fatty acid ester / fat) Excessive adsorption causes adverse effects on phase stability.

Lecithin which can be used in the present invention is a naturally occurring emulsifier and has a nutritive meaning of phospholipids. However, structurally, choline in the head portion has hydrophilic character and fatty acid in the body portion is oil-affinity, so amphoteric stabilizer having surfactant properties . In addition, lecithin has a cationic property in the hydrophilic portion, so that the lecithin adsorbs to the casein micelle negative charge, which is a characteristic of dairy products, to prevent agglomeration between the particles, thereby effectively stabilizing the dispersion of the composition.

The lecithin is used in an amount of 0.005 to less than 1.5% by weight, preferably 0.007 to 1.3% by weight, more preferably 0.01 to 1% by weight, based on the total weight of the liquid preparation composition. . When the content of lecithin is less than 0.005% by weight, the effect is extremely slight. When the content of lecithin is more than 1.5% by weight, it is difficult to apply the composition due to changes in color and taste of contents due to dark color inherent in lecithin.

In the present invention, the weight ratio of the lecithin and the glycerin fatty acid esters is in the range of 9: 1 to 1: 9, preferably 8: 2 to 2: 8, more preferably 7: 3 to 3: 7, : 4 to 4: 6 (lecithin: glycerin fatty acid esters). When the lecithin and the glycerin fatty acid esters are contained in the above weight ratio range, the emulsification and dispersion stabilizing effect of the liquid preparation milk of the present invention is remarkably excellent.

The manufacturing method of the present invention may further include a preheating step for increasing the homogenization effect, reducing the risk of solidification of milk casein during the sterilization process, and inactivating microorganisms. Specifically, the production method may further include a step of preheating the product of step (s1) to 50 ° C to 80 ° C, preferably 55 ° C to 75 ° C, before step (s2). At a preheating temperature of less than 50 ° C, the effect of homogenization of the particles is very poor, and at 80 ° C, phase instability due to protein denaturation may occur.

In the present invention, homogenization of the concentrated liquid mixture greatly influences phase stabilization depending on the treatment method. In the present invention, the ratio of the first pressure to the second pressure of the homogenizer is considered in order to realize particle refinement and homogenization. Generally, under homogenization conditions, the primary pressure increases through the valve and seat while the velocity increases and the pressure decreases, so that the fluid at high velocity forms a turbulent flow and consequently hinders homogenization efficiency and stable dispersion phase composition. In addition, the secondary pressure valve causes a back pressure in the direction of the primary pressure, causing a cavitation phenomenon caused by the primary pressure to cause a decrease in the homogeneous effect. Therefore, in the manufacturing method of the present invention, the step (s2) may be performed at a ratio of the first pressure to the second pressure of the homogenizer in the range of 5% to 30%, preferably 8% to 25%. If the ratio of the first pressure to the second pressure is less than 5%, the homogenization efficiency is lowered due to the cavitation phenomenon. If the ratio is more than 30%, the secondary pressure is excessively increased.

In addition, it is important to set the homogeneous pressure level in the present invention. In general, when the homogeneous pressure is higher, the particles are finer, but when the homogeneous pressure is set to be higher than that of the fluid, aggregation can occur. Therefore, in the present invention, the homogeneous pressure can be performed at 150 to 500 bar, preferably 200 to 400 bar.

In the present invention, the concentrate contains a large amount of carbohydrates, fats and proteins, and is a highly nutritious composition which is easy to propagate microorganisms when stored at room temperature for a long time. There is a difference depending on the raw materials to be added, but a large amount of microorganisms exist in the concentrated mixture liquid as in the case of general dairy products, and there exist cold tolerant bacteria that survive the refrigeration temperature and heat resistant bacteria that do not kill even at the high temperature heat treatment.

In the present invention, the sterilization process through the intermediate heat treatment was carried out during the manufacturing and storage of the concentrate solution, and the microbiological safety was maintained for over 48 hours. Through the sterilization process as described above, it was possible to obtain effects such as inhibition of growth of microorganisms and reduction of protein denaturation during storage of the concentrate for efficiency of production, and microorganism safety and phase stability were secured even after the final product was manufactured.

In the manufacturing method of the present invention, the sterilizing step (s3) may be sterilized at a temperature of 60 ° C or more and less than 100 ° C for 5 seconds or more and less than 60 seconds, preferably 70 to 90 ° C for 10 to 30 seconds It can be sterilized. When the sterilization process is less than 60 ° C, the sterilization effect is insignificant. When the sterilization process is 100 ° C or higher, the microbial safety is increased but the degree of precipitation increases due to thermal degeneration. In addition, even if the sterilization time is more than 60 seconds, the phase stability is deteriorated due to the continuous heat damage.

The proportion of the particle size of less than 10 mu m may be 90% or more in the concentrated blending solution in the production process. Preferably, the concentrated blending solution after the (s3) sterilization step may have a particle size ratio of less than 1 mu m of 90% or more. The above concentrated liquid mixture obtained by homogenizing and sterilizing the microcrystalline fine particles has excellent dispersion stability of the liquid liquid preparation composition, and the aggregation, separation, or precipitation is significantly improved.

In the present invention, the fat is used as a fat source for infants and to supply saturated fat, unsaturated fats, and essential fatty acids. More specifically, the fat can be used in a mixture of one or more selected from the group consisting of soybean oil, canola oil, palm olein oil, palm oil, palm kernel oil, sunflower oil, brown rice oil, corn oil and refined processed oil.

In the present invention, the milk, the milk powder, and the protein are components used as a source of various nutrients including proteins in liquid preparation milk. The milk may be one or more of sterilized milk (oil), sterilized milk, low-fat milk, non-fat milk, fortified milk, goat milk, or chlorine oil. The powdered milk may be a mixture of one or more kinds of skimmed milk powder, whole milk powder, sweetened milk powder, or mixed milk powder. The proteins include milk-derived proteins including milk protein, concentrated milk protein, isolated milk protein, whey protein, demineralized whey protein, concentrated whey protein, isolated whey protein, goat milk protein and goat milk protein; Vegetable protein (such as soybean protein); And meat-derived protein (chicken protein, etc.), and the like.

The fat-soluble vitamin may be added as a nutrient component of the liquid formula milk to the concentrated liquid preparation method. Specifically, at least one selected from the group of fat-soluble vitamins consisting of vitamins A, E, D, and K in step (s1) Can be added additionally.

(S4) diluting the concentrated liquid for preparing the liquid preparation oil in water; (s5) homogenizing the product of step (s4); And (s6) a step of sterilizing the product of step (s5), and a liquid pharmaceutical composition prepared by the method.

It is preferable that the method further comprises the step of preheating the product of step (s4) to 50 占 폚 to 80 占 폚 before step (s5) in the method of producing the liquid preparation formula composition to increase the homogeneous effect, reduce the risk of solidification of milk casein, It is desirable for activation.

(S5), the product of step (s4) is heated to a pressure of 150 to 500 bar so that the ratio of the first pressure to the second pressure of the homogenizer Homogenization can be carried out with 5% to 30%, preferably 8% to 25%.

(S6) sterilization treatment can be performed by ultra high temperature (UHT) treatment, which shortens all microorganisms completely by short and strong heating, thereby improving the stability over time, It is a process for preserving a liquid product so that the water-repellent property is not inhibited even when it is used. This is less protein denaturation, odor, or discoloration than the conventional retort method, and taste or color is better than retort type. The ultra-high temperature short-time sterilization treatment may be performed at 120 to 150 ° C for 1 to 60 seconds, preferably 125 to 140 ° C for 5 to 50 seconds. If the ultra-high temperature short-time sterilization treatment is performed at a temperature of less than 120 ° C or less than 1 second, the microbial killing effect is insignificant. If the temperature is more than 150 ° C or more than 60 seconds, the thermal degeneration results in precipitation or poor thermal stability.

In the method for preparing the liquid preparation composition, vitamins, minerals, or a mixture thereof may be further added in step (s4).

In the present invention, the mineral plays an important role not only in nutrition but also in stabilizing the preparation liquid during the manufacturing process. Specifically, the mineral may be one selected from the group consisting of calcium carbonate, potassium phosphate monobasic, potassium phosphate, potassium chloride, magnesium phosphate, sodium hydrogen carbonate, zinc oxide, ferric pyrophosphate, manganese sulfate, potassium iodide, Or more can be mixed and used. The use of such minerals can prevent denaturation and coagulation due to heat treatment of the protein, and potassium phosphate monobasic and potassium phosphate are most preferable because they also function as pH buffering agents for the preparation liquid.

In the process for preparing the liquid pharmaceutical composition, the water-soluble vitamin may be a mixture of one or more selected from the group consisting of vitamins B1, B2, B6, B12, C, pantothenic acid, niacin, folic acid and biotin .

The liquid formulated milk composition prepared by the process of the present invention preferably has a particle size ratio of less than 0.8 mu m at the final final product stage of 90% or more and a pH of 6 to 8.

(S1) mixing and stirring at least one selected from the group consisting of milk, milk powder and proteins, and a fat, oil, or mixture thereof; (s2) homogenizing the product of step (s1) at a pressure of 150 to 500 bar to a first pressure to a second pressure of the homogenizer at 5% to 30%; And (s3) sterilizing the product of step (s2) at a temperature of greater than or equal to 60 DEG C and less than 100 DEG C for greater than or equal to 5 seconds and less than 60 seconds, wherein the solubility of the product in the liquid phase (S4) diluting the concentrated liquid mixture with water after preparing a concentrated liquid mixture by the process for producing a liquid concentrate for producing liquid liquid having a concentrated degree; (s5) homogenizing the product of step (s4) at a pressure of 150 to 500 bar to a first pressure to a second pressure of the homogenizer in a range of 5% to 30%; And (s6) a step of subjecting the product of step (s5) to ultra-short-time sterilization (UHT) at 120 ° C to 150 ° C for 1 to 60 seconds.

The liquid pharmaceutical composition prepared by the above method has the highest production efficiency, phase stability, aging stability, and microbial safety.

The present invention provides a liquid pharmaceutical product product in which a plastic container having a fastening portion capable of directly fastening a milk-feeding nipple is filled with the liquid preparation milk composition. Preferably, the fastening portion can be a spiral fastening portion, and a configuration can be used in which the nipple or the plastic container can be rotated to easily fasten them to each other. The liquid formulated milk product is advantageous in that the user can conveniently feed the milk using a plastic container of a direct-fastening type with the nipple, without the need for a separate feeding bottle.

Plastic containers or glass bottles made of various materials such as HDPE, LDPE, PET, PP, PE, or PC can be used as the container, but it is preferable to fill the container with a plastic container because there is a risk of breaking glass bottles.

The process for producing a liquid pharmaceutical composition according to the present invention has a step of producing a concentrated mixture liquid as a semi-finished product, so that a utility, a time and the like required compared to a process for collectively preparing an initially diluted finished product are reduced and the production efficiency is excellent.

Further, the liquid pharmaceutical composition according to the present invention has superior phase stability and long-term stability according to emulsification and dispersion stabilization, and is superior in microbial safety through ultrahigh-temperature short-time sterilization (UHT) treatment and the like.

Further, the liquid pharmaceutical product according to the present invention can be easily nursed by using the plastic container of the direct coupling type with the nipple.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

Experimental Example  1: Production efficiency, sedimentation amount, and Phase separation  evaluation

A liquid pharmaceutical composition was prepared based on the concentration ratio and the process variation shown in Table 1 below. The production process is divided into two stages. First, in the semi-product thickening process, fat-soluble vitamins, emulsifiers, lecithin, etc. are added to a completely dissolved fat at a high temperature, and the mixture is stirred at high temperature to completely dissolve. And stirring was started with a homomixer. After stirring for a certain period of time, milk was added while stirring at a temperature of about 40 ° C, and whey protein powder, skim milk powder, pH adjusting agent, lactose, and dextrin were added and stirred after a certain period of time. The semi-finished concentrate was preheated, homogenized and sterilized at 85 ° C for 20 seconds using a UHT device.

After the semi-finished product is manufactured, the semi-finished product concentrate is mixed with water, water-soluble vitamins, minerals and the like by mixing and stirring the semi-finished product concentrate. The mixture is preheated and homogenized in the same manner as the semi-finished product concentration process, Short-term sterilization (UHT) was completed and completed.

Example Semi-finished product
Concentration ratio (%) Production efficiency Sedimentation amount Phase separation One 100 X ◎ ◎ 2 120 △ ◎ ◎ 3 150 ○ ○ ◎ 4 200 ○ ○ ○ 5 250 ○ ○ ○ 6 300 ○ △ △ 7 400 ◎ X X 8 450 ◎ X X 9 500 ◎ X X

As shown in Table 1, when the degree of enrichment is increased in terms of production efficiency, sedimentation amount, and phase separation according to the degree of enrichment, the yield of production increases but the phase stability portion tends to deteriorate. That is, in the case of Example 9, the production yield was increased as the degree of concentration increased, but it was poor in the stability portion and relatively good in the production yield and stability in Examples 3, 4 and 5. For this reason, the concentration ratio considering the production yield and stability is selected in the present invention.

Experimental Example  2: Addition of emulsifier and lecithin Degree of precipitation  And Phase separation  evaluation

According to the same manner as in Experimental Example 1, a concentrate milk liquid was prepared according to the composition ratios shown in Table 2 below, and the degree of precipitation and phase separation were evaluated.

Thickener composition Example One 2 3 4 5 6 7 8 Edible mixture preservation 5 5 5 5 5 5 5 5 Vitamin blend 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Glycerin fatty acid ester - 0.2 0.5 One 5 0.5 0.5 0.5 lecithin 0.01 0.5 1.5 Sterilization oil 20 20 20 20 20 20 20 20 Whey protein powder 2 2 2 2 2 2 2 2 Skim milk powder 4 4 4 4 4 4 4 4 Dextrin and lactose 10 10 10 10 10 10 10 10 Purified water To 100 wt%

Example One 2 3 4 5 6 7 8 Degree of precipitation X △ ○ ○ △ ○ ◎ ◎ Phase separation X △ ○ ○ △ ○ ◎ ◎

Table 2 and Table 3 show the examples and the phase stability results, respectively. As described in the present invention, it was confirmed that the stability of phase stability, such as precipitation and phase separation, was remarkably improved at a certain ratio of the glycerin fatty acid esters to the fat, and that the stability was further improved when mixed with lecithin. However, in the case of lecithin, as shown in Example 8, the phase stability showed an excellent tendency as shown at a certain ratio or more, but the change in hue and taste was evaluated and not suitable.

Experimental Example  3: Number of microorganisms according to sterilization temperature and sterilization time of semi-finished concentrate and Degree of precipitation  evaluation

When the concentrate was prepared by the method shown in Experimental Example 1 and the sterilization temperature and the sterilization time were changed as shown in Table 4, the number of microorganisms and the degree of precipitation thereof were evaluated.

Example Semi-finished product sterilization temperature (℃) Sterilization time (sec) Initial microbial count
(CFU / ml) After 24 hours the number of microorganisms (CFU / ml) Degree of precipitation One 70 5 13000 42000 ◎ 2 80 5 8000 31000 ◎ 3 90 5 4100 7000 ◎ 4 100 5 1000 1500 △ 5 70 15 7600 9000 ◎ 6 80 15 7300 7800 ◎ 7 90 15 1000 1400 ○ 8 100 15 800 1300 △ 9 70 30 7000 9000 ○ 10 80 30 6300 7000 ○ 11 90 30 900 900 △ 12 100 30 600 700 X 13 70 60 3000 8000 △ 14 80 60 2000 4700 X 15 90 60 800 800 X 16 100 60 300 500 X

As shown in Table 4, the higher the sterilization temperature of the concentrated semi-finished product, the more the microbial safety was increased, but the degree of precipitation tended to increase due to the thermal denaturation. In addition, even when the sterilization time is increased, the stability of the phase is degraded due to the continuous thermal damage. In the case of sterilization treatment at a low temperature and a short time, the phase stability is increased but the microbial safety is relatively low. For this reason, the optimum sterilization temperature and time of the semi-finished product are selected.

Experimental Example  4: Homogenization  In the step, the precipitation according to the primary and secondary pressure ratios and Phase separation  evaluation

The sedimentation and phase separation phenomena according to the changes of the primary and secondary pressure ratios during the production of the semi-finished product by the method shown in Experimental Example 1 are shown in Table 5 below.

Example The homogeneous pressure (bar) Primary and secondary pressure ratio Sedimentation Phase separation One 200 5 △ △ 2 200 10 ○ ○ 3 200 13 ◎ ◎ 4 200 17 ◎ ◎ 5 200 20 ○ ○ 6 200 27 ○ △ 7 200 30 △ △ 8 200 40 △ △

As shown in Table 5 above, the first and second homogeneous pressure ratios of the semi-finished products were tested. As a result of the evaluation of the same contents as the whole, the sedimentation and phase separation showed a similar tendency. As shown in the above examples, the best effects were obtained in Examples 3 and 4.

In the following evaluation methods of Experimental Examples 1 to 4, specific evaluation criteria are shown for production efficiency, degree of precipitation, degree of phase separation, particle size and uniformity, and method for measuring microorganism bacteria.

<Production efficiency evaluation>

The production efficiency of the final finished product according to the semi-finished product concentration is very good (◎), good level (○), normal level (△) when the production efficiency is the best in consideration of product production time, cost, , And the poor level was evaluated as poor (X).

&Lt; Precipitation degree &

After the product was prepared, the contents at room temperature according to the same aging period were filtered through 120 mesh, and the remaining amount of precipitate remaining was measured and written in numerical value. (△) and defective (X) at the level of ordinary commercial products, respectively, when the sedimentation amount remaining on the 120 mesh was the smallest (⊚) and when the sedimentation amount remained on the 120 mesh was the smallest (⊚).

< Phase separation  Degree>

The product was visually observed at room temperature according to the same aging period, and the phase separation height separated from the upper or lower layer was measured and written. (⊚) when the separation was the smallest (⊚), and when the separation was good (○), the average (△) and poor (X) were evaluated.

&Lt; Method for measuring microorganisms &

Standard agar medium was prepared and samples were aseptically collected and homogenized in a sterile petri dish with standard agar medium. The medium was allowed to solidify and then cultured at 35 to 37 DEG C for 24 to 48 hours, and the number of colonies formed was calculated. In the present invention, the number of microorganisms was evaluated in terms of the number of microorganisms (CFU / ml), and a very good level (⊚), a good level (∘), a normal level (△) The level was evaluated as poor (X).

Claims (17)

(s1) mixing and stirring at least one selected from the group consisting of milk, milk powder and proteins, and a fat, oil, or mixture thereof;
(s2) homogenizing the product of step (s1); And
(s3) sterilizing the product of step (s2)
A concentrated liquid of the intermediate stage for producing a final liquid liquid preparation having a concentration of 150 to 350% by weight based on the solid content of the liquid liquid preparation composition is prepared,
(s4) diluting the concentrated liquid mixture with water;
(s5) homogenizing the product of step (s4); And
(s6) Sterilizing the product of step (s5)
&Lt; / RTI &gt; delete The method according to claim 1, wherein the emulsifier is lecithin, a glycerin fatty acid ester, or a mixture thereof. 4. The method according to claim 3, wherein the glycerin fatty acid ester is a weight ratio of 1/25 or more to 1/1 or less (glycerin fatty acid esters / fat) relative to the weight of the fat. 4. The process according to claim 3, wherein the lecithin is present in an amount of from 0.005 to less than 1.5% by weight based on the total weight of the liquid preparation composition. The method according to claim 1, further comprising the step of preheating the product of step (s1) to 50 ° C to 80 ° C before the step (s2). The method according to claim 1, wherein the step (s2) comprises homogenizing the product of step (s1) at a pressure of 150 to 500 bar at a ratio of the first pressure to the second pressure of the homogenizer at 5% to 30% . 2. The method according to claim 1, wherein the step (s3) is sterilized at a temperature of 60 DEG C or more and less than 100 DEG C for not less than 5 seconds and less than 60 seconds. An intermediate-stage concentrated liquid for the final production of a liquid-formulated liquid prepared according to the production method of claim 1. delete The method according to claim 1, further comprising the step of preheating the product of step (s4) to 50 ° C to 80 ° C before the step (s5). The method according to claim 1, wherein the step (s5) comprises homogenizing the product of step (s4) at a pressure of 150 to 500 bar at a ratio of the first pressure to the second pressure of the homogenizer at 5% to 30% . The method according to claim 1, wherein the step (S6) comprises ultra-short-time (UHT) treatment at 120 to 150 ° C for 1 to 60 seconds. A liquid pharmaceutical composition prepared by the method of claim 1. 15. The liquid pharmaceutical composition according to claim 14, wherein the crude oil composition has a particle size ratio of 0.8 mu m or less of 90% or more. (s1) mixing and stirring at least one selected from the group consisting of milk, milk powder and proteins, and a fat, oil, or mixture thereof;
(s2) homogenizing the product of step (s1) at a pressure of 150 to 500 bar to a first pressure to a second pressure of the homogenizer at 5% to 30%; And
(s3) sterilizing the product of step (s2) at a temperature of 60 DEG C or more and less than 100 DEG C for not less than 5 seconds and less than 60 seconds,
A method for producing a liquid concentrate for preparing a liquid pharmaceutical preparation having a concentration of 150 to 350% by weight based on the solid content based on the weight of the liquid preparation composition,
(s4) diluting the concentrated liquid mixture with water;
(s5) homogenizing the product of step (s4) at a pressure of 150 to 500 bar to a first pressure to a second pressure of the homogenizer in a range of 5% to 30%; And
(s6) subjecting the product of step (s5) to ultra-short-time short-time sterilization (UHT) at 120 to 150 DEG C for 1 to 60 seconds
&Lt; / RTI &gt; Wherein the plastic container having a fastening portion capable of directly fastening the nipple is filled with the liquid make-up composition according to Claim 14.