JP3067810B2 - Method for producing dry powder of O / W emulsion for oral administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a fat-soluble vitamin O / W.
The present invention relates to a method of dry-pulverizing a type emulsion into a solid preparation for oral administration.

[0002]

2. Description of the Related Art It has already been of interest in the field of pharmacy that an emulsion of fat-soluble vitamins with a milk fat globule membrane component improves the absorption of fat-soluble vitamins in the intestinal tract. However, in practical use, liquid preparations such as emulsions have the following disadvantages. In a liquid state, the milk fat globule membrane component is liable to be rancid, and in order to prevent this, it is necessary to use a preservative and an antioxidant involuntarily. There are also general limitations on emulsion stability. Further, when the preparation is taken, it is necessary to measure it because it is in a liquid state, and it is generally inconvenient to handle the liquid preparation itself because it is generally stored in a container such as a bottle. Furthermore, it is not easy for a user to prepare a required amount of emulsion just before taking.

In recent years, while the importance of O / W emulsions in the pharmaceutical field has been increasing, several methods for producing dry powder preparations have been proposed (for example, Japanese Patent Application Laid-Open No. 52-1982).
No. 125615, JP-A-60-239417, etc.).

[0004]

However, the conventional O / W
In the type emulsion dry powdering technique, various additives are required to maintain physical stability and chemical stability during emulsion preparation and redispersion after dry powderization. Furthermore, despite the fact that the preparations maintain such stability, few emulsion particles have a resilience comparable to that at the time of emulsion preparation when redispersing after dry powder. However, even if the technology is described as good, its resilience is not always desirable. In addition, as the emulsifier used in the emulsion, an HCO60 or Tween-based emulsifier, which has practical problems such as side effects, is used. The use of these emulsifiers has not only a problem in use, but also a serious drawback that in most of the combinations with the oil phase due to physical properties, a dry powder is never obtained and a viscous product is obtained. Had.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve such disadvantages of the prior art, and as a result,
By using a milk fat globule membrane as an emulsifier and freeze-drying or spray-drying a fat-soluble vitamin in the form of an O / W emulsion, it was found that a dry powder that solved all of the above disadvantages could be obtained. Based on the above, the present invention has been completed. According to the present invention, the improvement effect of the absorption rate of the fat-soluble vitamin emulsion originally provided by the milk fat globule membrane component can be maintained, and at the same time, disadvantageous aspects such as rancidity can be eliminated. The details of the present invention are described below.

A feature of the present invention is that an orally administrable lipid obtained by dissolving a fat-soluble vitamin using a milk fat globule membrane component capable of promoting absorption of fat-soluble vitamin in the intestinal tract as an emulsifier,
The point is that the fat or oil or a mixture thereof is emulsified into as fine particles as possible under appropriate heating conditions, and then freeze-dried or spray-dried.

The milk fat globule coating component used in the present invention is a fat globule in milk (2 to 6 μm in diameter, average of 3.
4 μm) and form a milk fat globule membrane (Milk Fat G) that forms an interface between highly hydrophobic lipids and the surrounding aqueous phase.
Lobe Membrane (MFGM), which is usually obtained by washing a cream obtained by centrifuging milk several times with water and destroying fat globules in a charging step. . At this time, skim milk produced as a by-product when the cream is decomposed from milk and butter milk produced as a by-product when producing butter from the cream are obtained as dairy by-products having emulsifying activity. The main components of skim milk are lactose and casein, while buttermilk contains MFGM. Therefore, these dairy by-products can also be used as the emulsifier in the present invention and can be suitable excipients for the finally obtained dry powder. That is, in the present invention, the milk fat globule membrane component includes, in addition to pure MFGM, high-protein dairy by-product MFGM containing casein and whey protein, dairy by-product MFGM containing high lactose, and MFGM.
And dairy by-products such as buttermilk and the like, and also an appropriate combination thereof. Since dairy by-products are inexpensive, their proper use leads to a reduction in the cost of raw materials in the industrialization of the present invention.

When only pure MFGM is used as an emulsifier, the amount of the MFGM added and the quality of the dry powder obtained by the emulsification method differ depending on the emulsification conditions or the above-mentioned dairy by-products. By using MFGM in combination, it is possible to obtain a dry powder of superior quality.

In the dry powder production method of the present invention, the particle size (average particle size) when emulsifying using the milk fat globule coating component has a particularly important meaning. In order to obtain an excellent dry powder, the average particle size is preferably 3 μm or less. More preferably, a submicron (su
bmicron) or less, that is, 1 micron or less. However, since the numerical value of “3 μm or less” or “1 μm or less” is an average particle diameter based on statistical processing, the average particle system calculated based on the measurement result is, for example, 2.9 μm. However, it must be noted that it may not be possible to obtain an excellent dry powder. As the emulsification method, a commonly used high-pressure homogenizer (microfluidizer, Manton-Gaulin homogenizer, etc.) method, ultrasonic emulsification method, high-speed shear mixer method, and the like are used. The high-pressure homogenizer method is preferable from the viewpoint of operability and efficiency, and it is preferable to use a microfluidizer from the viewpoint of general performance of the apparatus. Next, the lipid or fat or oil that dissolves the fat-soluble vitamin used in the present invention is easy to handle a small amount of fat-soluble vitamin in the emulsification step and the dry powder step in the present invention, and is useful for maintaining good powder properties. . These oil phase components include triglycerides of fatty acids having 8 to 10 carbon atoms and triglycerides of saturated fatty acids having 12 to 18 carbon atoms extracted from coconut oil, and hydrogenated castor oil, cottonseed oil, sesame oil, soybean oil, and peanut oil. , Rapeseed oil, cocoa butter oil, and butter oil can be used alone or in combination. Preferably, particularly when freeze-drying is performed in the dry powder step of the present invention, it is desirable to select and use one having a melting point (freezing point) near body temperature from the above-mentioned oil phase components. This is desirable in order to maintain the powder properties after the connection and drying, and also in accordance with physiological conditions for restoring the emulsified and dispersed state upon redispersion. Regarding the restoration of the emulsified and dispersed state under physiological conditions, even in the case of a spray-dried powder, use of an oil or fat having a higher melting point (higher freezing point) than necessary for the oil phase component used in the production thereof should be avoided.

Further, the present invention provides an agent for oral ingestion as a health food and a medicine, which has improved intestinal absorption efficiency of fat-soluble vitamins. The mixing ratio of various fat-soluble vitamins is set based on the required amount of each vitamin, and is not particularly limited as long as it can be taken orally without difficulty. The following table shows the required amounts of various fat-soluble vitamins for adult men. Vitamin A contains 2,100 IU (630 μg
RE), 3,780 μg of β-carotene (2,100 IU
Vitamin A efficacy), Vitamin D is 100 IU (2.5μ
g), 10 mg (15 IU) of vitamin E and 100 μg of vitamin K are required based on nutritional effects. The standard dosage as a drug based on pharmacological effects is 5,000-50,000 IU of vitamin A, 20 IU-160 IU (0.5-4 μg) of vitamin D, and vitamin E
100-300mg (but tocopherol acetate), vitamin K 5-15mg, ubiquinone 300mg
It is. These vitamins can originally depend on endogenous foods such as daily food or vitamin D, but they tend to be insufficient due to various fluctuation factors in daily life. In order to improve symptoms due to deficiency, administration based on pharmacological effects is required. The biosaturated amount of these vitamins has a relatively large difference from the minimum required amount, and in general, aggressive ingestion from foods and management of administration as pharmaceuticals are easy from the viewpoint of safety. From such facts, a preparation which can ingest these fat-soluble vitamins simply and efficiently as in the present invention is extremely significant.

In the present invention, the amount of MFGM when used as an emulsifier is 1% or more, preferably 5 to 10%, based on the unit weight of the oil phase component. From the fat-soluble vitamin content and ingestible volume of the obtained dry powder, the amount of MFGM added or dairy by-products can be added and substituted for the purpose of adjusting the powder volume, which is considered to vary depending on the dry powdering conditions. The ratio of the addition to the total amount of the emulsified composition can be controlled by adjusting the amount of water.
In other words, M which has an intestinal absorption-promoting action of fat-soluble vitamins
FGM has the advantage of producing a good emulsion as an emulsifier, as well as the advantage that no additional excipients are required in dry powdering. In all of the patent applications relating to dry powdering of conventional emulsions, the addition of a large number of excipients to prevent the collapse of the emulsion system accompanying the dry powdering process, that is, the appearance of viscous powder and poor redispersibility. The effect is claimed. The addition of these excipients risks the destabilization of the emulsion system depending on the combination with the emulsifier, if care is not taken in the selection. In addition, when the resulting dry powder is formulated into tablets and granules, the addition of excipients for the purpose of the dry powdering process may limit the formulation of the formulation, or may result in the inability to formulate the formulation extremely. I will. In contrast, in the present invention, the MF
Such a situation can be avoided only by adjusting the amount of skim milk or buttermilk used for GM and dairy by-products.

As described in detail above, the present invention relates to a method of preparing a milk fat globule film to be used as an emulsifier in the amount and type (pure MF).
Whether GM is used alone or in combination with other dairy by-products), conditions for emulsification, and conditions for pulverization are appropriately selected and achieved. There are various modes of matching.

Hereinafter, the present invention will be described in more detail with reference to examples in which desired conditions are combined, but the present invention is not limited to these examples.

[0014]

[Example 1] 760 mg of MFGM was added to purified water 95
Disperse in ml. On the other hand, DL-α-tocopherol 100
mg of panassate in advance (manufactured by NOF Corporation; triglyceride of fatty acid having 8 to 10 carbon atoms extracted from coconut oil)
An oil layer dissolved in 5 g is prepared. The MFGM dispersion was added to the oil phase and emulsified by a homogenizer. The particle size immediately after emulsification is SUB-MICRONPAR
TICLE ANALYZER “COULTER ^R mo
del N4 "(COULTER ELECTRONI
CS, INC. Manufactured). This is referred to as emulsion 1. Further, the emulsion 1 was subjected to ultrasonic treatment (40 W, 3
min.), and the particle size was measured in the same manner. This is referred to as emulsion 2.

Emulsions 1 and 2 were each prepared immediately after preparation.
After being frozen under the condition of 0 to -30 ° C and left overnight, it was freeze-dried at room temperature. In comparison of the dried products after the freeze-drying operation for two days, the dried products 1 and 2 corresponding to the emulsions 1 and 2 respectively.
There was a difference in the powder properties of. As shown in Table 1, Emulsion 2 (average particle diameter of 567 nm) having a particle diameter of submicron or less immediately after emulsification was better in Emulsion 1 (average particle diameter of 237).
0 nm).

[Table 1] Powder property after freeze-drying immediately after emulsification Average particle size Emulsion 1 (Dry 1) 2370 nm Viscous Emulsion 2 (Dry 2) 567 nm Dried [Example 2] 760 mg MFGM and MFGM Higher protein dairy by-product MFGM-I 760 mg, 3
800 mg each is heated (50 ° C.) and dispersed in 95 ml of purified water. On the other hand, an oil layer is prepared by previously dissolving 100 mg of DL-α-tocopherol in 5 g of cocoa butter substitute fat (manufactured by Kaneka Corporation) at 40 ° C. The dispersion of MFGM and MFGM-I was added to this oil phase, emulsified by a homogenizer, and then subjected to ultrasonic treatment (40 W,
3 min.) To obtain emulsions 3, 4, and 5.
The particle size immediately after preparation of each emulsion was measured, and -20 to -3
After frozen storage at 0 ° C. overnight, freeze-drying was performed at room temperature to obtain dried products 3, 4, and 5, respectively. Each dried product was restored and redispersed with purified water, and its dispersion state and particle size were measured and compared. As shown in Table 2, MFGM-I also showed good redispersibility depending on the amount added. Redistribution is 3
This was performed by heating at 7 ° C. for 10 minutes and stirring with a vortex mixer for 2 minutes.

Example 3 Higher Protein Dairy Byproduct MFGM Containing MFGM
-I, dairy by-products MFGM-II, MFGM containing high lactose
-III was heated to 95 ml of purified water (50 ml each).
C) Disperse. On the other hand, DL-α-tocopherol 100
mg of Pharmasol B-105 (Nippon Oil & Fats Co., Ltd.)
5 g of an oil layer that has been heated (40 ° C.) and dissolved.

[Table 2] Re-dispersion state immediately after emulsification Average particle diameter after re-dispersion Average particle diameter MFGM Emulsion 3 (Dry 3) 739 nm Dispersion is good 2526 nm MFGM-I Emulsion 4 (Dry 4) 2267 nm Floating particles Yes MFGM-I emulsified liquid 5 (dry matter 5) 636 nm Dispersion good 4900 nm To each of the oil phases, the above MFGM-I, MFGM-II and MFGM-III dispersions were added, and the mixture was emulsified with a homogenizer. Sonic treatment (40 W, 3 min.) Was performed to sequentially obtain emulsions 6, 7, and 8. The particle size was measured immediately after the preparation of each emulsion, and then frozen and stored at -20 to -30 ° C overnight, and then lyophilized at room temperature to obtain dried products 6, 7, and 8, respectively.
When the comparisons shown in Table 3 were performed for each, all were dry powders exhibiting good redispersibility.

[Table 3] Immediately after emulsification Re-dispersion After re-dispersion After freeze-drying Average powder after freeze-drying Average particle size Particle size Properties MFGM-I Emulsion 6 (dry 6) 481 nm Dispersion good 419 nm dry MFGM-I Emulsion 7 (dry matter 7) 507 nm Good dispersion 1041 nm dry matter MFGM-I Emulsion liquid 8 (dry matter 8) 713 nm Good dispersion 712 nm dry matter [Example 4] Dairy by-product MFGM-III containing MFGM and containing higher lactose 20 g was heated to 225 ml of purified water (5
(0 ° C.) disperse. On the other hand, 1.125 g of phylloquinone (manufactured by Nippon Roche Co., Ltd .; vitamin K ₁ )
3.875 g heated (40 ° C) dissolved oil layer is prepared. The dispersion of MFGM-III was added to this oil layer and emulsified with a homogenizer. This operation was performed about 20 times to obtain about 5 l of the primary emulsion. This primary emulsion was subjected to a microfluidizer (manufactured by Microfluidics, USA) twice (about 1000 kg / cm ² ) to form a microemulsion to obtain an emulsion 9 having an average particle diameter of 346 nm. This emulsified liquid 9 was used as a stock solution and sprayed with a spray drier (spray dryer LT-8 manufactured by Okawara Kakoki Co., Ltd.) under the following conditions:
Dry powdered.

[0020] 154.8 g and 23.6 g of the dried product 9 thus obtained were obtained under the spray dryer and in the cyclone, respectively.
As shown in Table 4, all of these powders had good powder properties and a good charge recovery (92%) of phylloquinone (vitamin K ₁ ) in the powder.

[Table 4] Evaluation data of dried product 9 Filoquinone Recovered amount Particles Particle size Dryness Color mg / g Powder (recovery rate including the shape%) 154.8 g under the body Spherical 30-40μ Good Good Light yellow 23 mg / g (92%) 23.6 g in cyclone Spherical 30-40μ Good Pale yellow-When MFGM was used as an emulsifier to prepare an emulsion, the feature that the viscosity was not increased was favorable in spray drying operation. In addition, even with a low melting point oil component such as soybean oil used as a dissolving oil agent for filoquinone, a uniform dry powder could be obtained without an outflow from the emulsifying system and the powder system in the operation process of the encapsulated filoquinone. . Further, a method such as a microfluidizer capable of producing a microemulsion of a submicron order while having a high-speed processing ability was useful for the purpose of the present invention.

[Example 5] Dairy by-product M containing MFGM
10 g of FGM-I was warmed to 237.5 ml of purified water (50 g).
C) Disperse. On the other hand, Menaquinone-4 (Nisshin Flour Milling Co., Ltd.)
Preparation: An oil layer is prepared by dissolving 0.5625 g of vitamin K _{2 in} 11.0375 g of Pharmasol B-105 at 50 ° C. in advance. The MFGM-
The dispersion of I was added and emulsified with a homogenizer. This operation was performed about 20 times to obtain 5 l of a primary emulsion. The primary emulsion is treated twice with a microfluidizer (about 1000 kg /
under the condition of cm ² ) and microemulsified to obtain an emulsion 10 having an average particle diameter of 306 nm. The emulsion 10 was used as a stock solution, and the following operating conditions I and II were used by a spray dryer.
To dry powder.

Operating conditions I Operating conditions II (stock solution conditions) Solid content concentration 9% 9% Specific gravity 1.02 1.02 Apparent viscosity 7 cps 7 cps Used liquid amount 1.14 kg 1.60 kg (Operating conditions) Stock solution processed amount 2 kg / hr 2kg / hr Disk type MC-50 MC-50 Number of revolutions 25000rpm 10000rpm Inlet temperature 150 ° C 130 ° C Outlet temperature 80 ° C 70 ° C Cyclone differential pressure 75mmAq 92mmAq Operating time Approx.40min. Approx.50min. Conditions I) and 11 (operating conditions II) showed good powder properties as shown in Table 5, and also a good charge recovery of menaquinone-4 (vitamin K ₂ ) in the powder.

[Table 5]

[0025]

[0026]

EFFECT OF THE INVENTION O for oral administration obtained by the method of the present invention
The dry powder of the / W emulsion has excellent homogeneity of the powder particles, good redispersibility at the time of emulsion restoration, and a high drug collection recovery rate.

Continuation of the front page (51) Int.Cl. ⁷ identification code FI A61K 47/46 A61K 9/14 (58) Investigated field (Int.Cl. ⁷ , DB name) A61K 31/12 A61K 9/107 A61K 9 / 14 A61K 31/07 A61K 31/355 A61K 47/46 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (1)

(57) [Claims] A lipid capable of orally administering a fat-soluble vitamin,
An oil phase dissolved in fats or oils or a mixture thereof is emulsified using a milk fat globule membrane component to produce an O / W emulsion,
A method for producing a dry powder of an O / W emulsion for oral administration, which is freeze-dried or spray-dried.