JPH10310522A - Probucol-containing formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation capable of quickly approaching to an effective blood concentration of probucol and sustainable of the concentration in a single administration of a conventional dose, capable of quickly manifesting the pharmacodynamic action of probucol by containing probucol, oil component, an emulsifier and an appropriate amount of water. SOLUTION: This preparation is obtained by mixing (A) 1-50 mg/ml of probucol based on whole fat emulsion, (B) 5-30%(w/v) of the oil component such as purified soy bean oil, etc., (C) 0.1-5%(w/v) of the emulsifier such as purified phosholipid, etc., and appropriate amount of water, heating if required, emulsifying by a homogenizer. A stabilizer and an isotonizing agent, etc., may be added if required. For example, as the direction of usage and dosage, 10-1000 mg of probucol is administered once a day, by a parenteral administration such as intravenous injection, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a probucol-containing preparation, and more particularly to a probucol-containing preparation capable of rapidly reaching and maintaining an effective blood concentration of probucol.

[0002]

2. Description of the Related Art Probucol has the chemical structure name 4,4'-
(Isopropylidenedithio) bis [2,6-di-ter
t-butylphenol] and is clinically useful as a therapeutic agent for hyperlipidemia for indications such as hyperlipidemia, familial hypercholesterolemia, xanthomas, and arteriosclerosis. Probucol is highly lipophilic, hardly soluble in water, and conventionally only oral preparations (granules, tablets) are commercially available.
The dose is 500-1000 mg daily. In vivo pharmacokinetics, when 250 mg was orally administered to a healthy adult once a meal, the maximum value reached 5 μg / ml 18 hours after administration.
When 750 mg / day is administered continuously for 10 days, the maximum value reaches 12 μg / ml at 192 hours after the start of administration (according to Japan Pharmaceutical Collection). That is, the conventional probucol-containing preparation required a relatively long time to reach a certain blood concentration, and required continuous administration.

[0003] As described above, probucol is difficult to formulate into a homogeneous injection or the like due to its high lipophilicity and insolubility, and a practical product has not been obtained.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a probucol-containing preparation capable of quickly reaching and maintaining an effective blood concentration of probucol even with a single administration of a normal dose. It is another object of the present invention to provide a probucol-containing preparation capable of exhibiting the pharmacological action of probucol at an early stage.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and as a result, by converting probucol into a fat emulsion, even when a single dose of normal dose is administered, probucol is rapidly obtained. The present inventors have found that a sufficient effective blood concentration can be obtained by improving the blood concentration of, and that it can be more suitably administered intravenously, thereby completing the present invention.

That is, the present invention is as follows. (1) A probucol-containing preparation capable of reaching an effective blood concentration promptly after administration when a single normal dose is administered. (2) The probucol-containing preparation according to the above (1), which can maintain an effective blood concentration for a certain period of time after administration. (3) The probucol-containing preparation according to the above (1) or (2), which is in the form of a fat emulsion.

[0007] The "ordinary dose" means a dose at which the pharmacological effects of probucol can be expected to be sufficiently exhibited in view of conventional knowledge, and in which side effects such as toxicity do not substantially occur. Specifically, the daily dose per patient is about 10 to 1000 mg, in terms of kg body weight,
An example is about 0.1 to 20 mg / kg body weight.

[0008] The term "immediately after administration" means that the conventional probucol preparation requires at least a few weeks, generally a few months, to reach an effective blood concentration by administration of a normal dose. It means that the time is sufficiently shorter than these times. Specifically, the time is within 1 hour, preferably within 10 minutes after administration.

"Effective blood concentration" means the blood concentration required for probucol to exert its pharmacological action, based on the conventional knowledge. Specifically, at least 10 μg / m
About l is exemplified.

[0010] The "constant time after administration" is a time necessary for probucol to exhibit a pharmacological effect and a sufficient healing effect can be expected, and a sufficiently long time in view of conventional preparations. It means there is. Specifically, at least about one hour is exemplified.

[0011] The fat emulsion of the present invention contains probucol, an oil component, an emulsifier and an appropriate amount of water. As the oil component used in the present invention, generally, vegetable oil, fish oil, chemically synthesized triglyceride and the like can be mentioned. Vegetable oils include soybean oil, olive oil, sunflower oil, corn oil, sesame oil, cottonseed oil, peanut oil, castor oil,
Sesame oil and perilla oil are exemplified, and soybean oil is preferably used. As the soybean oil, refined soybean oil is preferable, and more preferably, refined soybean oil is further purified by, for example, a steam distillation method to obtain highly purified refined soybean oil (the purity is exemplified by 99% or more as triglyceride). It is.
Examples of chemically synthesized triglycerides include lipophilic bases such as medium chain fatty acid triglyceride (MCT), structured triglyceride, long chain fatty acid triglyceride (tripalmitin, trimyristin, etc.), and hard fat. The addition amount of these oil components is preferably 1 to 50% (w / v), more preferably 5 to 30% (w / v) in the fat emulsion of the present invention.

The emulsifier used in the present invention is not particularly limited as long as it can be added to pharmaceuticals, and includes known phospholipids such as egg yolk phospholipid, soybean phospholipid, and hydrogenated products thereof. Preferably, a purified phospholipid is used. The purified phospholipid is mainly composed of phosphatidylcholine, phosphatidylethanolamine, and other phospholipids such as phosphatidylinositol,
It also contains phosphatidylserine, sphingomyelin and the like. When a naturally occurring phospholipid is used, a purified product obtained by removing phosphatidylethanolamine from the purified product may be used.This is performed using a phospholipid such as egg yolk or soybean, and the organic solvent is fractionated by a conventional method. After that, it is obtained by purification with an inorganic adsorbent such as silica gel or alumina. The phospholipid thus obtained is mainly composed of phosphatidylcholine (Japanese Patent Application Laid-Open No. 60-1985).
149524). Further, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, sphingomyelin itself can be used. These phospholipids may be used alone or in combination of two or more. The constituent fatty acids of the phospholipids may be either saturated or unsaturated. The amount of the phospholipid to be added is 1 to 50 parts by weight, preferably 5 to 30 parts by weight based on 100 parts by weight of the oil component. With respect to the whole fat emulsion, preferably 0.01 to 10% (w /
v), more preferably 0.1 to 5% (w / v).

Further, as the emulsifier, a nonionic surfactant can be used in addition to the above phospholipid. Nonionic surfactants as emulsifiers include polyalkylene glycols (for example, having an average molecular weight of 1,000 to 10,000).
0, preferably 4,000 to 6,000 polyethylene glycol), polyoxyalkylene copolymer (for example, polyoxyethylene-poly having an average molecular weight of 1,000 to 20,000, preferably 2,000 to 10,000) Oxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivatives (eg, hydrogenated castor oil polyoxyethylene- (20) -ether,-(40) -ether,-(100) -ether, etc.), castor oil Polyoxyalkylene derivatives [for example, castor oil polyoxyethylene- (20) -ether,-(40) -ether,
-(100) -ether etc.]. The amount of the nonionic surfactant added in the fat emulsion is preferably 5% (w / v) or less, more preferably 1% (w / v).
It is as follows.

As described above, the phospholipid and the nonionic surfactant can each be used alone as an emulsifier in the fat emulsion of the present invention, but a phospholipid is preferably used. Further, both can be used in combination, but in this case, the added amount thereof can be appropriately changed so as not to exceed the above-mentioned range and to be suitable for preparing the preparation of the present invention.

It is also possible to add other emulsifying auxiliaries known in the art. Examples thereof include linear or branched aliphatic amines having 2 to 22 carbon atoms, such as primary amines and secondary amines, and pharmacologically acceptable salts thereof. Specifically, ethanolamine, propylamine, octylamine, stearylamine, oleylamine, linoleylamine and the like are exemplified as preferable ones. Also, as these pharmacologically acceptable salts,
For example, mineral salts (hydrochloride, hydrobromide, sulfate, sulfite, nitrate, phosphate, etc.), organic acid salts (acetate, lactate, succinate, maleate, fumarate, Malate, tartrate, citrate, methanesulfonate, etc.). The addition amount of this aliphatic amine is
In the fat emulsion, it is preferably at most 1.0% (w / v), more preferably at most 0.5% (w / v).

Further, for example, a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or a pharmaceutically acceptable salt thereof can be added. This fatty acid is not particularly limited as long as it can be added to pharmaceuticals, and may be linear or branched.Specifically, linear stearic acid, oleic acid, linoleic acid, palmitic acid, It is preferable to use linolenic acid, myristic acid and the like. Examples of these salts include pharmacologically acceptable salts such as alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.). The addition amount of these fatty acids is preferably 1.0% (w / v) or less, more preferably 0.5% (w / v) or less in the fat emulsion.

Further, in the present invention, a stabilizer, a polymer substance, a tonicity agent and the like can be added as required.

Examples of the stabilizer include cholesterols, glycerin or its fatty acid monoester (eg, monopalmitin, monostearin, monoolein, monolinolein, etc.), monosaccharides (eg, glucose, fructose, etc.) and disaccharides (eg, Examples thereof include sugars such as maltose and sucrose, sugar alcohols (eg, sorbitol and xylitol), and antioxidants (eg, tocopherols). Cholesterols and the like are not particularly limited as long as they can be used for medicine. The addition amount of these stabilizers is preferably 5% (w / v) or less, more preferably 1% (w / v) or less, in the fat emulsion.

Examples of the polymer substance include albumin,
Examples thereof include vinyl polymers (for example, polyvinylpyrrolidone, polyvinyl alcohol and the like), gelatin and the like. Here, as the albumin, a human-derived one is preferable due to the problem of antigenicity. The amount of these high molecular substances to be added is preferably 5% (w / v) or less, more preferably 1% (w / v) or less in the fat emulsion.

Examples of the tonicity agent include glycerin, monosaccharides (eg, glucose, fructose, etc.) and disaccharides (eg,
Examples thereof include maltose, sucrose, etc.), sugar alcohols (eg, sorbitol, xylitol, etc.), and electrolytes (eg, sodium chloride, etc.), as long as the minimum amount required for isotonicity is added. Moreover, you may add a pH adjuster as needed. Examples of the pH adjuster include sodium hydroxide, hydrochloric acid, various organic acids (eg, acetic acid, citric acid, phosphoric acid, lactic acid, etc.), various amines (eg, Tris, histidine, etc.), various buffer solutions (eg, acetic acid type, phosphate type) And the like).

Probucol used in the present invention is a known substance, and its production method is also described in US Pat.
62332 and the like. The content of probucol in the fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion. Specifically, 1 to 50 mg / m
About l is exemplified.

The fat emulsion according to the present invention can be produced by a known production method. For example, it is manufactured by the following method. That is, a predetermined amount of an oil component (for example, soybean oil), a phospholipid as an emulsifier, probucol, and other additives as required are mixed, and if necessary, heated, and a conventional homogenizer (for example, high-pressure injection) is added. Homogenizer, ultrasonic homogenizer, microfluidizer, etc.) to prepare a water-in-oil dispersion, and then add a necessary amount of water to the dispersion, homogenize again with the homogenizer, and perform water homogenization. It can be produced by converting into an oil type emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the preparation of the fat emulsion (JP-A-56-167161 and JP-A-58-22214). Alternatively, a fat emulsion can also be prepared by mixing all the components simultaneously and emulsifying at one time. The fat emulsion of the present invention thus produced is extremely fine, and the average particle diameter of the fat particles is about 0.0
5 to 0.5 μm.

The preparation containing probucol according to the present invention comprises:
It is preferably administered parenterally by injection, continuous infusion, etc.
It is administered intravenously, intraarterially, subcutaneously, intradermally, intramuscularly,
In particular, the present invention in the form of a fat emulsion is preferably administered intravenously taking advantage of its advantages. 1 dose / day for use / dose
The dose is about 10 to 1000 mg as probucol. The dose can be increased or decreased as needed depending on the administration route, symptoms, gender, age and the like.

[0024]

EXAMPLES The present invention will be described in detail below with reference to examples and experimental examples, but the present invention is not limited to these examples.

Example 1 100 g of purified soybean oil as an oil component, 2.5 g of probucol as a drug, 12 g of egg yolk phospholipid as an emulsifier and an appropriate amount of distilled water for injection were used, and the total amount was made 1000 ml, and coarse emulsification was carried out using a homomixer. Followed by Menton-
Using a Gaulin type homogenizer, a total pressure of 550 kg /
The emulsion was emulsified under a pressure of cm ² for 10 minutes. This gave a homogenized fat emulsion containing very fine probucol. The average particle size of the emulsion was 0.1 to 0.3 μm.

Example 2 A fat emulsion was obtained in the same manner as in Example 1 except that the amount of probucol was changed to 5 g.

Example 3 A fat emulsion was obtained in the same manner as in Example 1 except that the amount of probucol was changed to 10 g.

Experimental Example 1 Measurement of Probucol Concentration in Blood The probucol-containing fat emulsion prepared in Example 3 was intravenously administered to Wistar rats (male, body weight 200 g, 5 rats per group) at a dose of 10 mg / kg body weight. After administration, the blood concentration of probucol was measured over time. The results are shown in FIG.
Immediately after administration, the blood concentration reaches the effective level,
It was confirmed that a blood concentration of g / ml or more could be maintained for about one hour.

[0029]

According to the present invention, it is possible to obtain a sufficiently effective blood concentration in a short period of time even with a single administration of a normal dose, and to achieve an earlier onset of drug efficacy, as compared with conventional preparations. Such a probucol-containing formulation can be provided. It is also expected that this formulation may provide a new clinical application method of probucol. In addition, the present formulation has good storage stability, and can be stored at room temperature. Furthermore, it has good heat stability and can be subjected to high-temperature sterilization.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the time-dependent measurement of probucol concentration in blood when a single dose (10 mg / kg body weight, intravenous injection) of a probucol-containing fat emulsion of the present invention was administered to rats. The vertical axis represents the blood concentration of probucol, and the horizontal axis represents the elapsed time after administration.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Koji Michichika 2-25-1 Invitation Otani, Hirakata City, Osaka Prefecture Inside the Green Cross Research Institute, Inc. (72) Inventor Yasuo Ueda 2-25- Invitation Otani, Hirakata City, Osaka Prefecture 1. Inside the Green Cross Central Research Institute, Inc.

Claims (3)

[Claims] 1. A probucol-containing preparation capable of reaching an effective blood concentration promptly after administration when a single normal dose is administered. 2. The probucol-containing preparation according to claim 1, which can maintain an effective blood concentration for a certain period of time after administration. 3. The probucol-containing preparation according to claim 1, which is in the form of a fat emulsion.