JPH01113315A - Fat emulsion containing vitamin k2 - Google Patents

Abstract

PURPOSE:To provide a fat emulsion for intravenous injection, containing vitamin K2 as an essential component, having an average particle diameter falling within a specific range, having excellent stability and free from side effects such as shock. CONSTITUTION:The objective fat emulsion is composed of (A) 0.01-50%(W/V), especially 1-3% of vitamin K2, (B) 5-50%, especially 5-20% of a fat emulsion base selected from a vegetable oil, triglyceride of a 8-12C medium-chain fatty acid (e.g. caprylic acid) and mono- or di-glyceride of a 6-18C fatty acid (e.g. caproic acid or stearic acid), (C) 0.05-25%, especially 0.6-2.4% of an emulsifier selected from phospholipids (preferably having an HLB of 10-14) and (D) water and has a particle diameter of <=1mum, preferably <=0.3mum. The emulsion is further compounded, as necessary, with 0.1-0.5mol/l of an isotonic agent (e.g. glycerol), <=0.4% of an emulsification assistant (e.g. 10-20C fatty acid), <=1.2% of a stabilizer (e.g. cholesterol), etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a vitamin-2-containing fat emulsion, and more particularly to a vitamin-2-containing fat emulsion for intravenous injection that reduces side effects such as shock upon administration.

(Conventional technology and problems) Vitamin 2 is a type of fat-soluble vitamin, commonly called menatetrenone, which is involved in the activation process of several blood coagulation factors and activates the hemostasis mechanism of the living body. It is a substance that physiologically exerts a hemostatic effect.Medicinally, it has already been used in actual treatment as a drug that improves hypoprothrombinemia and activates the hemostasis mechanism, either by oral or intravenous administration or as an intramuscular injection. It is a substance that exists.

By the way, as mentioned above, vitamin 2 is a type of fat-soluble vitamin, so in order to make it water-soluble as an injection preparation, a nonionic surfactant such as HCO-60 is used.
(manufactured by Nikko Chemical Co., Ltd.) is used. However, the desired injectable formulation requires large amounts of HCo-so, and as a result, when administered to humans, HCo-so
HCO-60 can lead to the release of histamine-like substances, which can sometimes cause undesirable side effects such as shock, and recent administrative guidance suggests measures to avoid the use of HCO-60, which is used in injectable preparations. It is taken.

Although it is hoped that a new formulation without side effects will be put into practical use as an alternative to conventional injectable formulations containing water-soluble vitamin 2 using HCO-6'O, the desired formulation has not yet been developed. This is the current situation.

By the way, the present inventors have previously developed a method of administering certain fat-soluble drugs by dissolving them in lipid particles of a lipid emulsion.
We have provided a fat emulsion containing a biphenylylacetic acid compound in fat particles, and have confirmed that such a fat emulsion can serve as a new preparation to replace the injection preparations seen so far. This preparation takes advantage of the property of fat particles being taken up into the reticuloendothelial system, similar to liposomes. When a fat-soluble drug is dissolved in these fat particles and administered, the fat particles become drug carriers and the drug is identified. It selectively migrates to the body parts of the body, where it exerts its medicinal effects intensively, and is attracting attention from various quarters as a powerful drug administration method.

The present inventors also focused on this specific fat emulsion, and found that vitamin K
If 2 is administered in the form of a fat emulsion, the drug will be efficiently taken up into the reticuloendothelial system, exhibiting the desired medicinal effect, and HCO
The present inventors have newly discovered that it is possible to create a formulation that does not have any side effects such as shock, which are sometimes seen when using -60, and have completed the present invention.

(Structure of the Invention) That is, the present invention relates to a fat emulsion that contains vitamin 2 as an essential component and has an average particle diameter of 1.0 microns or less.

The fat emulsion of the present invention is prepared by introducing the above vitamin 2 into the fat particles of a conventional fat emulsion. For example, the vitamin 2 is dissolved in a fat emulsion base and dispersed in water using an emulsifier. It can be easily produced by forming it into an oil emulsion.

Therefore, the fat emulsion base that can be used in the preparation of the fat emulsion of the present invention includes any pharmaceutically acceptable fats and oils that have been conventionally used in the preparation of so-called fat emulsions. Specifically, vegetable oils such as soybean oil, cottonseed oil, rapeseed oil, and safflower oil; medium-chain fatty acids with 8 to 12 carbon atoms, usually abbreviated as MCT (e.g.
Triglycerides of 6 to 18 carbon atoms (e.g., caproic acid, capric acid, mili, stinic acid, palmitic acid, linoleic acid, stearic acid, etc.) -glyceride, etc., and these can be used alone or in combination of two or more types. Among these, soybean oil and Panacet 810 (manufactured by Bhon Yushi Co., Ltd., a mixture of MCT) are particularly preferably used. The amount of these fat emulsion bases to be used is not strictly limited and can vary widely depending on the type and amount of medicinal compounds and/or other ingredients, but generally 1.=50
% (W/v), preferably in the range of 3 to 30% (w/v), more preferably 5 to 20% (w/v).

In addition, in this specification, unless otherwise specified, the percentage "% (W/V)" used for the content or usage amount of components in a fat emulsion is 1 part by weight per 100 parts by volume of the final fat emulsion product. means.

Further, as an emulsifier for stably dispersing the above-mentioned fat emulsion base in water, at least one emulsifier selected from physiologically acceptable vine phospholipids is used. Physiologically acceptable phospholipids include, for example, egg yolk phospholipid, soybean phospholipid phosphatidylcholine, etc., and these emulsifiers can be used alone or in combination of two or more. The emulsifier used in the present invention generally has a molecular weight of 6 to 15, preferably 10 to 1
It is preferable to have an HLB within the range of 4.

These emulsifiers are used in amounts necessary to maintain stable dispersion of fat emulsion base particles containing vitamin 2 in water, and the amount generally ranges from 0.05 to 25 depending on the type of emulsifier.
% (w/v), preferably 0.2 to 6% (w/v), more preferably 0.6 to 2.4% (w/, v), and the fat emulsion group The appropriate amount is 6 to 15 parts by weight per 100 parts by weight of the base.

Further, as water serving as a dispersion solvent in the fat emulsion of the present invention, an appropriate amount of distilled water or ion-exchanged water can be used, and a small amount of a water-miscible organic solvent such as ethanol may be mixed in depending on the case.

The fat emulsion of the present invention may further contain additives such as isotonicity agents, emulsification aids, stabilizers, pH adjusters, etc., if necessary, as is commonly practiced. Examples of tonicity agents include glycerin: sugar alcohols such as sorbitol and xylitol; monosaccharides such as glucose and fructose; trisaccharides such as maltose; amino acids such as L-alanine, L-valine, and glycine. Among these, one or more types are appropriately selected and used. These tonicity agents are added to adjust the osmotic pressure of the fat emulsion to be approximately equal to the osmotic pressure of body fluids, and the amount thereof is such that the final concentration in the fat emulsion is generally 0.1 to 0.
5 mol/It, preferably 0.25-0.35 mol/1
The range is as follows.

In addition, examples of emulsifying aids that may be appropriately incorporated include fatty acids having 10 to 20 carbon atoms (e.g., stearic acid, palmitic acid, linoleic acid, lylunic acid, etc.) and salts thereof (e.g., sodium salt, potassium salt, etc.). , phosphatidylethanolamine, phosphatidylserine, stearylamine, etc., and these are generally 0.4% (W
/V), preferably 0.01-0.2% (w
/v), in particular, the above fatty acids or their salts can be used in the range of 0.01 to 0.1% (W/V), and phosphatidylethanolamine, phosphatidylserine, stearylamine is 0.05-0.3% (
(w/v), in particular in the range from 0.1 to 0.2% (w/v).

Furthermore, cholesterol or tocopherols can be used as stabilizers. Cholesterol is generally 1
．． up to 2% (W/V), preferably 0.2-0.4% (
It is convenient to use it in the range W/V).

Further, as the stabilizer, albumin or its fatty acid amide derivative, polysaccharide or its fatty acid ester derivative, etc. can also be used. In order to prepare human preparations, albumin of human origin is preferable from the viewpoint of antigenicity, and as its fatty acid amide derivative, 5 to 40% of the total amino groups present in albumin should be 1
Examples include those amidated with eight fatty acids (eg, palmitic acid, stearic acid, etc.). On the other hand, polysaccharides include dextran, pullulan, hydroxyethyl starch, etc., and fatty acid ester derivatives of these include fatty acids with 14 to 18 carbon atoms (e.g. Examples include those esterified with palmitic acid, stearic acid, etc.). These stabilizers are generally 0.02-5% (w/v
), preferably in the range of 0.2 to 2.5% (W/V).

The fat emulsion of the present invention is particularly intended as a preparation for intravenous injection, and therefore, a pH adjuster can be added as appropriate to adjust the pH of the fat emulsion itself to a level suitable for intravenous injection. Examples of such pH adjusting agents include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, and the desired pH can be adjusted as appropriate.
It can be added in an amount that makes it in the H region.

The fat emulsion of the present invention can be produced using a known emulsification method. In this case, an ordinary homogenizer can be used as an emulsifying machine, but in order to prepare a stable and fine fat emulsion, it is convenient to use two types of homogenizers together. Specifically, for example, 2 is dissolved and mixed in a predetermined amount of vitamins in the above-mentioned fat emulsion base, such as soybean oil, with appropriate heating, and a predetermined amount of an emulsifier, such as purified soybean phospholipid, is added to this and if necessary. Other additives, such as emulsifiers, stabilizers, isotonic agents, etc., are added and stirred to make them homogeneous. Next, water is added and treated with a homogenizer to prepare an oil-in-water crude emulsion. The fat emulsion of the present invention can then be obtained by homogenizing this with a pressure homogenizer, for example, a Manton-Gallin type homogenizer. Note that stabilizers and tonicity agents may be added to the purified fat emulsion.

In the above emulsification operation, the average particle size of dispersed fat particles in the resulting fat emulsion is generally 1 μ or less, preferably 0.3 μm or less.
It is desirable to progress to less than μ. In addition, vitamin 2, which is a medicinal ingredient, generally has a content of 0.01 to 50% (W/v).
, preferably in the range of 0.01 to 10% (w/v), more preferably 1 to 3% (w/v).

It was confirmed that the fat emulsion of the present invention produced as described above has excellent stability, has no side effects, and is a particularly excellent preparation.

The stability test results of the formulation are shown below.

Eyu 11 A 4-month stability test was conducted on the vitamin-2-containing fat emulsion provided by the present invention. The content was measured using high performance liquid chromatography (equipment 3: Hitachi 655-1).
5), and the particle diameter was measured using a light transmission particle size distribution analyzer (CAP A-500 manufactured by Yuyu Seisakusho). The results are shown in the table below. 40. Stability tests at 50 and 60°C for 4 months showed no decrease in content, change in appearance, or particle size (
No change in the average) was observed, and therefore, it can be said that the vitamin-2-fat emulsion of the present invention is extremely stable pharmaceutically.

Next, the present invention will be explained in more detail with reference to Examples, but it should be understood that the present invention is not limited to the scope of these Examples.

Example 1 Daily cycle of 10g of soybean oil and vitamins 21. Add Og,
Heat to dissolve. 1.2 g of purified soybean phospholipid and 2.5 g of glycerin are added to this and dissolved by stirring vigorously while heating, and then an appropriate amount of distilled water is added and stirred with a Polytron homogenizer to prepare a rough emulsion.

This rough emulsion was further high-pressure emulsified using a Manton-Gallarin type homogenizer, and then distilled water was added and 100 m
1, a fat emulsion containing 2 in extremely fine vitamins was obtained. The average particle size of the dispersed fat was 0.2μ, and no particles larger than 1μ were included.

Example 2 21 g of vitamin K is added to 10 g of diurnal soybean oil and dissolved by heating. 1.2 g of purified soybean phospholipid and 2.5 g of glycerin were added to this, stirred vigorously while heating, and after dissolving, added sodium bicarbonate to adjust the pH to 7.5.
Further, an appropriate amount of distilled water is added and stirred with a Polytron homogenizer to prepare a rough emulsion. This crude emulsion was further high-pressure emulsified using a Manton-Gallalin type homogenizer, and then distilled water was added to make 100 ml to obtain a fat emulsion containing vitamin 2. The average particle diameter of the dispersed fat particles in this fat emulsion was 0.22μ, and no particles larger than 1μ were included.

Patent applicant Nippon Redary Co., Ltd.

Claims (1)

[Scope of Claims] 1) A fat emulsion containing vitamin K_2 as an essential component and having an average particle diameter of 1.0 microns or less. 2) (a) Vitamin K_2: 0.01-50% (w/v
), (b) At least one fat emulsion base selected from vegetable oil, triglycerides of medium-chain fatty acids having 8 to 12 carbon atoms, and di- and monoglycerides of fatty acids having 6 to 18 carbon atoms: 5 to 50% ( 2. The fat emulsion according to claim 1, comprising (w/v), (c) an emulsifier which is a phospholipid: 0.05 to 25% (w/v), and (d) water. 3) The fat emulsion according to claim 2, further comprising at least one tonicity agent selected from glycerin, sugar alcohols, monosaccharides, disaccharides, and amino acids. 4) Claim 2 or 4 further contains at least one emulsifying agent selected from fatty acids having 10 to 20 carbon atoms and their salts, phosphatidylethanolamine, phosphatidylserine, and stearylamine. Fat emulsion according to item 3. 5) The fat emulsion according to any one of claims 2 to 4, further containing a stabilizer selected from cholesterol and tocopherol. 6) Claims 2 to 6 further containing a pH adjuster
Fat emulsion according to any one of Item 5.