JPS6042322A - Novel emulsified preparation - Google Patents

Abstract

PURPOSE:To provide an emulsified preparation composed of water, iodized oil, a water-soluble organic iodine compound, a surface active agent and a water-soluble active component, having high stability with time, and useful as a remedy for the diseases of the lymphatic system. CONSTITUTION:(A) 2.0-99pts.wt., preferably 87-33pts.wt. of an iodized oil (e.g. iodized olive oil, poppy oil, etc.) is mixed homogeneously with (B) 0.01-25pts.wt., preferably 0.1-15pts.wt. of a surface active agent (e.g. Tween 80). Separately, a water-soluble organic iodine compound (e.g. meglumine amidotrizoate) is dissolved in refined water to obtain an aqueous solution having a specific gravity of 1.2-1.5 and a concentration of 20-90w/w%. An active component (e.g. a carcinostatic agent such as actinomycin) is added and dissolved in the above solution at a concentration of 0.05-10w/w%, preferably 0.1-5w/w%. The iodized oil mixture is emulsified with the aqueous solution by a homogenizer for 10-60min to obtain the objective preparation. The volume ratio of the aqueous solution to the iodized oil is selected to 0.01-4.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an emulsified formulation consisting of water, an iodized oil, a water-soluble organic iodine compound, a surfactant and an active ingredient.

Since the formulation of the present invention can localize water-soluble active ingredients in the lymphatic system for a long time, it can be used for the prevention and treatment of various lymphatic system diseases.

Attempts have already been made to apply iodized oils in formulations. For example, Konno et al. discovered that when iodized poppy oil fatty acid ethyl ester, which is a type of iodized oil, was injected into the feeding blood vessels of ulcers, it selectively remained in the tumor for a long time.
It has also been reported that, utilizing this property, when an iodized poppy oil fatty acid ethyl ester solution of the lipophilic anticancer drug Sumansuk is administered into the hepatic artery, Sumansuk selectively reaches liver tumors (Cancer and Treatment, Vol. (Vol. 9, pp. 200-2015, 1982) In addition, Ime et al., one of the inventors of the present invention, conducted further research on iodized poppy oil fatty acid ethyl ester, and found that when this was injected into the inguinal lymph nodes of rats, lymph It was discovered that it did not disperse rapidly within the ducts and was localized in the lymphatic system even after 24 hours. This fact suggests that preparations in which lipophilic active ingredients are dissolved in iodized oil are effective against various diseases of the lymphatic system.

However, it is not possible to produce such formulations using water-soluble active ingredients, since many active ingredients are water-soluble and not soluble in iodized oils.

Therefore, the present inventors conducted various studies in order to manufacture the above-mentioned formulations using water-soluble active ingredients. Emulsified formulations consisting of ingredients have good stability over time,
It was also found to be effective for diseases of the lymphatic system.

The present invention has been completed based on the above findings.

Iodized oils used in the present invention include unsaturated fatty acids and their esters, as well as iodized products of plant and animal fats and oils containing these, and specifically include olive oil, peanut oil, castor oil, coconut oil, cottonseed oil, sesame oil,
Poppy oil, hydrogenated castor oil, rapeseed oil, cocoa butter, egg yolk fat,
Examples include iodized products such as beef tallow, pork fat, lanolin, and cod liver oil. The iodine content of these iodized oils is 15 to s o
W/W Li6, more preferably 30-45 W/W%
belongs to.

The content ratio of this to the formulation content is 99-2, O
W/W %, preferably about 87-55 W/W %0 As a water-soluble iodine compound, the solubility in water is usually 50%.
or more, preferably 40 inches or more, and the specific gravity of the aqueous solution is 1
- There is no particular restriction as long as it is about 2-L5, for example, meglumine iocalmate, azibioton meglumine, proviriodone iotroxate, metrizoic acid, sodium amitodorizoate 1), rum, meglumine amitodorizoate,
Examples include sodium metrizoate, iodamide meglumine, sodium iothalamate, meglumine iothalamate, and the like. The usage ratio of this product to the total amount of the preparation is 0.1~
75 W/W%, and the efficiency is about 4.5-55 W/W%.

There are no particular restrictions on the surfactant as long as it can produce a physically stable emulsion, but preferred surfactants include 1, 1, 7), 6, Tween B, and 3.

-68■■ 5pan85, sucrose fatty acid esters, lecithin, etc.

The usage ratio of this product to the total amount of the preparation is α01+ 25
W/W%, preferably tL<, is about (11-15 W/W%).

The water used in the present invention is preferably purified water for injection, and its usage ratio is a1 to 64 W/w based on the total amount of the preparation.
Preferably it is about 2 to 37 W/W.

The active ingredient is not particularly limited, but it is preferably water-based, such as anticancer agents, such as actinomycin D1, aclarpicin hydrochloride, daunorubicin hydrochloride,
Cytosine arabinoside, pleomycin hydrochloride, pepromycin sulfate, chromomycin A3, neocarzinostatin, mitomycin C, vinblastine sulfate, vincristine sulfate, mercaptopurine riboside, fluorouracil, pisipanil, ftrafur, cytarabine, cyclophosphamide, carbocone Ancitabine hydrochloride, cisplatin, L-asparaginase, methotrexate,
and chlormethine-N-oxide hydrochloride, etc.
Other examples include antibacterial substances such as cephalosporins such as evacephalothin and cefmetazole, antibiotics such as cephamycins and gentamicin, and local anesthetics such as lidocaine hydrochloride. The usage rate is [105~1Q W
/W ratio, preferably about α1-5Wβchi.

For example, the preparation of the present invention may be produced as follows. That is, first, 2.0 to 99 parts by weight of iodized oil, preferably 87 to 33 parts by weight, 0.0 to 25 parts by weight of surfactant,
Preferably, α1 to 15 parts by weight are added and mixed uniformly.

Separately, a water-soluble organic iodine compound is added and dissolved in purified water so that the specific gravity of the aqueous solution is 1.2 to 15, preferably 1.25 to 1.4. The concentration of the water-soluble organic iodine compound at this time is about 20 to 9. Q W/W %, preferably about 45 to 80 W/W %. Next, the active ingredient is added to this liquid and uniformly dissolved.

The ζ-iodized oil obtained as described above and an aqueous solution may be combined and emulsified using a homogenizer, shaker, etc. in a conventional manner. Emulsification is usually completed in 10 to 60 minutes. The ratio of aqueous solution to iodized oil is α0 by volume.
1 to 4, preferably about 01 to 2.

The emulsified preparation of the present invention is capable of selectively retaining active ingredients in the lymphatic system and tumor areas for a long period of time.
When Preparation A is directly administered, it exhibits an extremely efficient anticancer effect. Particularly in recent treatments for adenocarcinoma, it has become common practice to use multiple anticancer drugs in combination, but when using the preparation of the present invention, one or more lipophilic anticancer drugs are added to the iodized oil layer. It is possible to use multiple anticancer drugs in combination by adding them to an aqueous solution of a water-soluble organic iodine compound, and the anticancer effect can be further enhanced.

Next, the contents and effects of the present invention will be specifically explained in Examples and Experimental Examples.

Example 1 Iodinated poppy oil fatty acid ethyl ester (iodine content approximately 40 W/W%) 7.3@J% Tween ao [
124■me, 5pan 85n 47ml mixed solution,
Pleomycin hydrochloride 300 Misaki titer, 01M sodium phosphate buffer (pH 5.0) α36d1 aqueous solution of meglumine amitodrizoate (specific gravity 1.213) 1.5
2d and the mixed solution were thoroughly stirred and emulsified using a homogenizer to obtain 10 m of emulsified preparation.

Example 2 Iodized sesame oil (iodine content approximately 3 b W/W, %
) 7.5rd, polyoxyethylene hydrogenated castor oil derivative ■ HCO-600, 25p, 5pan ao 0.5m
(7) Mixed solution, 5-fluorouracil 100μ, and 65% aqueous solution of meglumine iothalamate (specific gravity 1..27)
) 1.65#l/mixed solution is sufficiently stirred with a homogenizer to emulsify and obtain emulsified preparation 10d.

Example 3 Iodized peanut oil fatty acid propyl ester (iodine content approx. 9v%) 7. Otrtl, Tw
A mixed solution of een 800.51ml11 egg yolk lecithin 0.5Of is thoroughly stirred and emulsified using a modinizer to obtain 10 sJ of an emulsified preparation.

Example 4 In Example 1, 0-i
Emulsifier 10d was obtained in the same manner as in Example 1, except that 0.6 mg%5pan85 was used vertically and gentamicin 150Wi was used in the pleomycin wash.

Experimental Example 1 Experiment to confirm the physical stability of the emulsified formulation of the present invention (1) Sample A-1: Emulsified formulation obtained in Example 1. Specific gravity 1.28゜A-
2 = 75% meglumine amitodorizoate in Example 1
An emulsion preparation prepared using a 75% sucrose aqueous solution (specific gravity 1.1a) instead of an aqueous solution.

A-3 = Amitodorizoate meglumine 7 in Example 1
An emulsion preparation prepared using a 20% sodium chloride aqueous solution (specific gravity 1.1S) instead of a 5% aqueous solution.

B-18 Emulsified formulation obtained in Example 2.

B-2: Meglumine iothalamate 65 in Example 2
An emulsified preparation prepared using a 65% sucrose aqueous solution (specific gravity 1.16) instead of a 65% aqueous solution.

B-3: Meglumine iothalamate 65 in Example 2
Emulsions and formulations prepared using a 20% aqueous sodium chloride solution (specific gravity 1.15) instead of an aqueous solution of sodium chloride.

(2) Experimental method: Inject 10 volumes of six types of emulsified preparations, Samples A-1 to B-5, into a 10 ml menu cylinder, and observe changes in appearance 50 minutes immediately after injection, 1, 2, 24, and 72 hours later. Observed with the naked eye. The evaluation is as follows.

++: Sufficiently emulsified.

+: Slight phase separation.

±: Hole with large phase separation.

- Complete phase separation.

(3) Results and Discussion As is clear from the observation results in the table below, the specific gravity of the water layer is 1.
The emulsified formulations A-1 and B-1 of the present invention having a molecular weight of 25 or more are:
Instead of water-soluble iodine compounds, the specific gravity of the water bath liquid is 1.2.
It can be seen that compared to the following formulations using sucrose and sodium chloride, the emulsification is stable over time without phase separation.

Experimental Example 2 Administration experiment on tumor-bearing rats (1) Experimental method AH-66 was administered to the right iliac lymph node of Don ryu rats.
was transplanted, and for 5 consecutive days starting from the next day, 1 m6 of the emulsified preparation o of Example 1 of the present invention (3 m6 as pleomycin hydrochloride) was added.
At this time, as a control, an aqueous solution containing 3 pleomycin hydrochloride was administered intravenously.

(2) Results and discussion The survival rate 60 days after administration is shown in the following table.

It can be seen that in-cylinder administration of the emulsified preparation of Example 1 has a superior effect to intravenous administration of an aqueous solution, which is a conventional method.

Patent applicant 2 Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) An emulsified preparation consisting of water, iodized oil, a water-soluble organic iodine compound, a surfactant, and an active ingredient.