JPH11209307A - Fat-soluble drug-containing preparation for injection - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a fat-soluble medicine-containing preparation for injection produced by using a surfactant which shows low toxicity and possesses high suitability to living bodies. SOLUTION: This preparation for injection includes a fat-soluble medicine, a nonionic surfactant [e.g. a poly(oxyethylene), a poly(oxypropylene) and/or a poly(oxyethylene)-poly(oxypropylene) copolymer] free from fatty acids, a phospholipid (e.g. egg yolk lecithin, soybean lecithin, phosphatidylcholine, phosphatidylserine or phosphatidic acid) and a saccharide As the fat-soluble medicine, vitamins, fat-soluble anticancer agents, vitamins A, D, E, K1, K2 and K3, vitamin C fatty acid esters, non-steroidal anti-inflammatory analgesics, steroids, immunosuppresants and antibiotics are illustrated.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a fat-soluble drug-containing injectable preparation produced by using a surfactant having low toxicity and high biocompatibility.

[0002]

2. Description of the Related Art Injectable preparations obtained by solubilizing a fat-soluble drug with a nonionic surfactant are widely used as general dosage forms.

[0003] For example, injection preparations in which vitamin Ks are solubilized using polyoxyethylene hydrogenated castor oil as a nonionic surfactant are commercially available (for example, "K2 injection Kaytwo: manufactured by Eisai Co., Ltd.). There are also examples of multivitamin injections in which fat-soluble vitamins are solubilized and compounded by similar nonionic surfactants.

However, injectable preparations containing polyoxyethylene hydrogenated castor oil may rarely cause hypersensitivity such as anaphylactic shock (for example, The I
nformed Prescriber Vol7 No1, 1-3, 1992). Thus, the use of non-ionic surfactants such as polyoxyethylene hydrogenated castor oil is problematic.

On the other hand, a nonionic surfactant containing no fatty acid has no toxicity, but when it is used to solubilize a lipophilic drug, an opaque and heterogeneous non-uniform surfactant such as an emulsion or a suspension can be obtained. The preparation is completed, and it is difficult to confirm the appearance change such as mixing of foreign substances and precipitation with time. Furthermore, in clinical settings, such opaque and heterogeneous preparations are avoided from being used due to physical changes such as the above-mentioned reasons and separation.

JP-A-3-279324 discloses an injectable preparation using a polyoxysorbitan fatty acid ester. Japanese Patent Publication No. 9-2627158 discloses injections, eye drops and the like using polyoxyethylene polyoxypropylene ether as a solubilizing agent. JP-A-2-167217 discloses a preparation for parenteral administration using a fat-soluble drug, lipid, glycerin, phospholipid and a nonionic surfactant. However, these preparations all have the above problems.

[0007] Therefore, there is a demand for the development of an injection in which a fat-soluble drug is transparently and uniformly solubilized with a safe surfactant.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have found that when solubilizing a fat-soluble drug with a nonionic surfactant containing no fatty acid, a transparent and uniform solution is obtained by coexisting a phospholipid and a sugar. They found that the preparation was completed and completed the present invention.

[0009]

That is, the present invention provides:
(1) a fat-soluble drug, a non-ionic surfactant containing no fatty acid, an injectable preparation containing a phospholipid and a sugar,
(2) fat-soluble drugs are vitamins, fat-soluble anticancer drugs, vitamin A, vitamin D, vitamin E, vitamin K1, vitamin K2, vitamin K3, vitamin C fatty acid ester, non-steroidal anti-inflammatory analgesic, steroid, immunosuppressant and Being selected from the group consisting of antibiotics,
(1) The injectable preparation according to (1), wherein (3) the nonionic surfactant containing no fatty acid is polyoxyethylene, polyoxypropylene and / or a polyoxyethylene-polyoxypropylene copolymer. Features,
(1) or the preparation for injection according to (2), (4) the phospholipid is egg yolk lecithin, soy lecithin, hydrogenated lecithin thereof, phosphatidylcholine, phosphatidylserine, phosphatidylic acid, phosphatidylinositol,
Injectable preparation according to any one of (1) to (3), which is phosphatidylethanolamine, sphingomyelin and / or lysophosphatidylcholine, and (5) the saccharide is a monosaccharide, a disaccharide, or a trisaccharide. Sugars and / or
Or, it relates to the preparation for injection according to any one of (1) to (4), which is a sugar alcohol.

The fat-soluble drugs used in the present invention include, for example, vitamin A, vitamin D, vitamin E and vitamin K.
1. Vitamin K2, Vitamin K3, Vitamin C fatty acid esters, and their preparations alone and derivatives thereof, and these vitamins widely used in multivitamin preparations; rhizoxin, rhizoxin palmitate, fturafur fatty acid ester, fluorouracil fatty acid ester, Fat-soluble anticancer agents such as mitomycin derivatives; non-steroidal anti-inflammatory analgesics such as indomethacin, ibuprofen, ketoprofen, piroxicam; steroids such as halcinonide, orgadron, triamcinolone acetonide, dexamethasone acetate; Antibiotics such as erythromycin and minocycline;

These drugs can be used alone, but if necessary, lipids that dissolve the drug, for example, vegetable oils such as soybean oil and sesame oil, semi-synthetic vegetable oils such as cyoctyl and decyl triglyceride, monodiglyceride caprate, lauric acid It can also be used after dissolving in a lower fatty acid mono- or diglyceride such as glyceride.

Polyoxyethylene, polyoxypropylene or polyoxyethylene-polyoxypropylene copolymer is a product called "Pluronic", which is obtained by changing the degree of polymerization between polyoxyethylene chains and polyoxypropylene chains. Have been created.

The type used in the present invention may be HLB10 or more. For example, Pluronic F68, F88, F77
(Product number).

In the present invention, the total amount of the nonionic surfactant containing no fatty acid to the fat-soluble drug and the phospholipid is preferably 10 to 1000% by weight.

The phospholipids are yolk lecithin, soy lecithin,
Examples thereof include hydrogenated lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylic acid, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine purified from natural or semi-synthesized products.

Phospholipids and Pluronics are used as a mixture, but the composition ratio is optimal depending on the solubilizing agent, and is in the range of 1: 100 to 100: 1.

The total concentration of the phospholipid and the pluronic used depends on the lipophilic drug to be solubilized and its concentration, but usually 100 to 1000% by weight of the drug is used. The saccharide used in the present invention is preferably a monosaccharide containing glucose, fructose, galactose and mannose, a disaccharide containing saccharose, maltose, lactose and trehalose, a trisaccharide containing melezitose and raffinose.

It is also possible to use sugar alcohols, such as sorbitol, xylit, inositol and the like.

These saccharides exhibit an effect at 20% by weight or more, and the preferred concentration is 30 to 60% by weight.

A buffer may be used in the preparation for injection of the present invention, if necessary. Examples of such a buffer include citric acid,
Organic acids such as tartaric acid, acetic acid, and maleic acid, and sodium salts and potassium salts thereof. In addition, inorganic salts such as inorganic salts such as phosphoric acid and boric acid, and sodium salts and potassium salts thereof are also used. Amino acids such as glycine are also used. The amount of the buffer is a commonly used amount,
A small amount of 1 to 200 mM, preferably 2 to 10 mM is incorporated.

[0021]

DETAILED DESCRIPTION OF THE INVENTION The injectable preparation of the present invention can be prepared by a method well known in the art.

For example, a fat-soluble drug, a phospholipid such as egg yolk lecithin, and a nonionic surfactant containing no fatty acid such as polyoxyethylene polyoxypropylene ether are heated and mixed. A saccharide solution dissolved at a high concentration is added to the mixture, and mixed and stirred with a suitable homogenizer. Further, a high-pressure homogenizer treatment is performed to obtain a transparent solution. The homogenizer uses a commonly used microfluidizer, Gaulin homogenizer, TSK homogenizer, or the like, and performs pressure treatment at 1 M pascal or more. The average particle size dispersed in this transparent solution is 10
１００100 nm.

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Embodiment 1 FIG. Vitamin A palmitate 5.0 g Vitamin E acetate 18.0 g Vitamin K2 3.0 g Egg yolk lecithin 70.0 g Pluronic F68 30.0 g The above components were mixed and dissolved while heating to 70 ° C. with stirring.

Saccharose 20.0 g Distilled water for injection 50.0 g After dissolving the above components, the two solutions were mixed and stirred with a Polytron at 7000 rpm for 5 minutes to obtain a uniform dispersion.

Furthermore, to give a clear solution is performed wherein the resulting solution pressure treatment of 500 Kg / cm ² at microfluidizer twice. Distilled water for injection was added to the solution obtained here to make a total volume of 1000 mL, which was divided into ampoules to prepare a preparation for injection.

The obtained preparation for injection was divided into vials and freeze-dried. The lyophilization condition is 4 after cooling to -40 ° C.
0 Torr. The temperature was raised to −10 ° C. in 3 hours, dried for 24 hours, and further dried at 30 ° C.

When the freeze-dried product was redissolved in distilled water, the transparency was maintained.

Embodiment 2 FIG. Vitamin K2 10.0 g Egg yolk lecithin 18.8 g Pluronic F68 18.7 g Purified soybean oil 10.0 g The above components were heated to 70 ° C. and mixed and dissolved.

Glucose 200.0 g Distilled water for injection 500.0 g After dissolving the above components, the two solutions were mixed and stirred and mixed with a TK homomixer at 5000 rpm for 10 minutes. The mixture was treated twice with a Gaulin homogenizer at 500 kg / cm ² to obtain a transparent solution. Distilled water for injection was added to the clear solution to make a total volume of 1000 mL to prepare a preparation for injection.

The injection solution subdivided into 1 mL brown ampules was kept transparent at room temperature for one year, and the stability of vitamin K2 was good.

Embodiment 3 FIG. Lysoxine palmitate 10.0 g Refined soybean oil 50.0 g Refined soybean lecithin 50.0 g Pluronic F68 30.0 g After solubilizing lysoxine palmitate in soybean oil, soybean lecithin and pluronic F68 were added and mixed.

Saccharose 20.0 g Distilled water for injection 40.0 g After dissolving saccharose in predetermined distilled water for injection, the two solutions were mixed.

The mixture was subjected to 7000 rpm and 5
The mixture was stirred for 1 minute to obtain a homogeneous mixture.

Further, 500 with a microfluidizer
Pressure treatment was performed three times at kg / cm ² to obtain a transparent liquid. Distilled water for injection was added to the same solution to make a total volume of 1000 mL to prepare a preparation for injection.

The preparation for injection was placed in a 2 mL or 15 mL vial and freeze-dried.

For freeze-drying, after cooling to -45 ° C, primary drying was performed at 0 ° C for 30 hours, and secondary drying was performed at 35 ° C for 10 hours.
The transparency of the obtained lyophilized product did not change even when it was redissolved in 2 mL of distilled water for injection.

Embodiment 4 FIG. Cyclosporin A 2.0 g Miglyol 812 5.0 g Egg yolk lecithin 20.0 g Pluronic F68 20.0 g Cyclosporin A was dissolved in Miglyol 812 by heating. Pluronic F68 and egg yolk lecithin were added, and a sugar solution having the following formulation was further mixed.

Trehalose 20.0 g Distilled water for injection 50.0 g The mixture was stirred with a TK homomixer at 5000 rpm for 10 minutes to obtain a homogeneous mixed solution. This mixture is treated with a Gaulin homogenizer.
Pressure treatment was performed three times at 500 kg / cm ² to obtain a transparent solution. Distilled water for injection was added to make a total volume of 1000 mL to prepare a preparation for injection.

Aliquot 5 mL of the clear solution into a 15 mL vial,
After freezing at 50 ° C, the primary drying was performed at -20 ° C for 50 hours and the secondary drying was performed at 30 ° C for 15 hours to obtain a freeze-dried preparation. When the obtained lyophilized preparation was redissolved in distilled water for injection, it became a reproducible transparent preparation for injection.

Embodiment 5 FIG. Triamcinolone acetonide 10.0 g Egg yolk lecithin 20.0 g Pluronic F68 60.0 g Triamcinolone acetonide was heated and dissolved at 70 ° C. together with Pluronic F68 and egg yolk lecithin.

Glucose 20.0 g Distilled water for injection 40.0 g Glucose was dissolved in distilled water for injection and mixed with the above triamcinolone acetonide solution.

This mixture was mixed with a TK homomixer at 5000
The mixture was stirred at rpm for 10 minutes to obtain a homogeneous mixed solution. The mixture was treated twice with a microfluidizer under a pressure of 1000 kg / cm ² to obtain a transparent solution. The total amount was made up to 1000 mL with distilled water for injection to prepare a preparation for injection.

Embodiment 6 FIG. Erythromycin 10.0 g Dioctyldecyl triglyceride 75.0 g Egg yolk lecithin 50.0 g Pluronic F68 50.0 g The above components were mixed and dissolved.

Galactose 150.0 g Distilled water for injection 165.0 g Galactose was dissolved in distilled water for injection and mixed with the above erythromycin mixture. This mixture was stirred with a polytron at 7000 rpm for 10 minutes to obtain a uniform mixture. This homogeneous mixed solution was treated three times with a microfluidizer at a pressure of 800 kg / cm ² to obtain a transparent solution, and distilled water for injection was added to make 1000 mL to obtain an injection solution.

Comparative Example 1a. Vitamin A palmitate 5.0 g Vitamin E acetate 18.7 g Vitamin K2 3.0 g Egg yolk lecithin 70.0 g Pluronic F68 30.0 g The above components were heated to 70 ° C. and mixed and dissolved. After adding 50.0 g of distilled water for injection to the obtained mixture, the mixture was stirred with a polytron at 7000 rpm for 5 minutes to obtain a uniform mixture. 500 kg / cm ^{2 of the} obtained homogeneous mixed solution was collected using a microfluidizer.
After treatment, distilled water for injection was added to make the total volume 1000 mL, but no clear preparation was obtained.

Comparative Example 1b. Vitamin A palmitate 5.0 g Vitamin E acetate 18.7 g Vitamin K2 3.0 g Egg yolk lecithin 100.0 g The above components were heated to 70 ° C. and mixed and dissolved.

Saccharose 20.0 g Distilled water for injection 50.0 g The above saccharose solution was mixed with the above mixed solution, and the mixture was stirred with a polytron at 7000 rpm for 5 minutes to obtain a uniform mixed solution. The obtained homogeneous mixed liquid is mixed with a microfluidizer for 50 minutes.
Although pressure treatment was performed at 0 kg / cm ² , a clear preparation was not obtained in the absence of Pluronic F68.

Comparative Example 2 Vitamin K2 10.0 g Egg yolk lecithin 18.8 g Pluronic F68 18.7 g Purified soybean oil 10.0 g The above components were heated and mixed at 70 ° C. Distilled water for injection 50
After adding 0.0 g and stirring with a TK homomixer for 10 minutes, the obtained mixture was added to a Gaulin homogenizer at 500 kg.
/ cm ² twice and add distilled water for injection to make the total amount 1
000 mL. However, a clear formulation was not obtained.

Comparative Example 3 Lysoxine palmitate 10.0 g Refined soybean oil 50.0 g Refined soybean lecithin 50.0 g Pluronic F68 30.0 g After solubilizing lysoxine palmitate in soybean oil, soybean lecithin and pluronic F68 were added and mixed.

Glycerin 20.0 g Distilled water for injection 40.0 g After glycerin was dissolved in the predetermined distilled water for injection, the two solutions were mixed.

The mixture was subjected to 7000 rpm and 5
The mixture was stirred for 1 minute to obtain a homogeneous mixture.

Further, 500 in a microfluidizer.
Pressure treatment was performed three times at kg / cm ² to obtain a transparent liquid. Distilled water for injection was added to the same solution to make a total volume of 1000 mL to prepare a preparation for injection.

The preparation for injection was placed in a 2 mL or 15 mL vial and freeze-dried.

For freeze-drying, after cooling to -45 ° C, primary drying was performed at 0 ° C for 30 hours, and secondary drying was performed at 35 ° C for 10 hours.
The resulting freeze-dried product had a candy-like cake, poor re-dissolvability, and the dissolved product was cloudy.

Test Example 1 In order to confirm the safety of the preparation for injection prepared in Example 2, the histamine releasing action as an index of anaphylactic shock was compared with a commercially available menatetrenone preparation (K2 injection Kaytwo: registered trademark, manufactured by Eisai Co., Ltd.).

The composition of K2 injection Kaytwo has the following composition.

Ingredients per 1 ml Menatetrenone 10 Polyoxyethylene hydrogenated castor oil 60 74 Propylene glycol 50 Glucose 50 Sesame oil 6 The experimental method was applied to Nippon Medical Shinpo No. 2810 (Showa 53.3.4), 3 male dogs and 3 female dogs. The histamine release value after administration of each preparation for injection was measured for each animal. The results are shown in Table 1 below.

[0059]

[Table 1] Change in blood histamine level due to administration of injection preparation (unit: nM) ^* ──────────────────────────────処方 Example 2 Prescription Formulation K2 injection Kaywo Before injection 10 minutes After injection Before injection 10 minutes 前オ ス Male 4.2 4.4 3.9 150 <12.0 7.2 4.1 150 <5.3 3.4 5.4 150 <Female 5.9 4.1 5.5 150 <3 4.4 4.1 4.2 150 <6.7 5.8 5.0 150 <───────────────────────────── * * Blood was collected 10 minutes after one shot.

The above results indicate that the preparation for injection of the present invention is safe.

[0061]

Industrial Applicability The preparation for injection of the present invention is transparent, uniform and can be used safely.

Claims (5)

[Claims] An injectable preparation containing a fat-soluble drug, a nonionic surfactant containing no fatty acid, a phospholipid and a sugar. 2. The fat-soluble drug is a vitamin, a fat-soluble anticancer drug,
Vitamin A, Vitamin D, Vitamin E, Vitamin K1,
The injectable preparation according to claim 1, wherein the preparation is selected from the group consisting of vitamin K2, vitamin K3, vitamin C fatty acid ester, non-steroidal anti-inflammatory analgesic, steroid, immunosuppressant and antibiotic. 3. The nonionic surfactant containing no fatty acid is polyoxyethylene, polyoxypropylene and / or a polyoxyethylene-polyoxypropylene copolymer. Or the preparation for injection according to 2. 4. The method according to claim 1, wherein the phospholipid is egg yolk lecithin, soy lecithin, hydrogenated lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylic acid, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and / or lysophosphatidylcholine. The preparation for injection according to any one of claims 1 to 3. 5. The saccharide according to claim 1, wherein the saccharide is a monosaccharide, a disaccharide, a trisaccharide and / or a sugar alcohol.
The preparation for injection according to any one of the above.