JPH0920658A - Improving agent for hyper-remnant blood disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an improving agent for hyper-remnant blood disease capable of remarkably inhibiting sthenia of the hyper-remnant blood disease but having improving activity and useful for preventing and curing arterial sclerosis by the participation of remnant-lipoprotein by bringing a specific highly unsaturated fatty acid as an effective ingredient. SOLUTION: This improving agent against hyper-remnant blood disease contains a highly unsaturated fatty acid of n-3 series, preferably eicosapentaenoic acid(EPA) and/or docosahexaenoic(DHA) acid as effective ingredients'. E.g. as an oil-containing fatty acid, an oil containing >=20% fatty acid based on the total fatty acid is preferable. Thus, it is preferable to use fish oil, etc., extracted from blueback fishes such as sardines, etc. It is preferable to administer about 100-5,000mg EPA or DHA per day.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug for improving hyperremnant blood pressure, which comprises, as an active ingredient, n-3 polyunsaturated fatty acids effective for the prevention and treatment of hyperremnant blood pressure.

[0002]

2. Description of the Related Art Remnant lipoprotein is an intermediate metabolite during the process in which lipoprotein produced in the small intestine and liver is secreted into the blood and then denatured by an enzyme. Chylomicron remnants originating from chylomicron, a triglyceride-rich lipoprotein, and VL originating from ultra-low-density lipoproteins
There are two types of DL remnant [= intermediate specific gravity lipoprotein (IDL)], and these remnants are known as lipoproteins rich in cholesterol among lipoproteins rich in triglycerides. This remnant lipoprotein usually disappears from the blood rapidly due to metabolism by an enzyme, etc., and is present only in a trace amount. Remnant lipoprotein (cholesterol)
Is 2.5mg / dl or less is a normal value, and when it is more than this is called hyperremnantemia. As the disease exhibiting this hyperremnantemia, in the primary disease, IIb type, III type,
Type IV, V hyperlipidemia, primary hepatic lipase deficiency, and familial hypercholesterolemia, which are secondary, include severe liver disorder, diabetes, obesity, renal disease, hypothyroidism,
Alternatively, steroid administration, high cholesterol diet intake, etc. are known. It has been previously reported that a large amount is present in the blood of patients with myocardial infarction, and it has been considered clinically involved in arteriosclerosis.

Recently, it has been clarified that remnant lipoprotein is taken up by macrophages and foams macrophages to form arteriosclerotic lesions, and has been attracting attention as a risk factor for arteriosclerosis.

It is known that n-3 polyunsaturated fatty acids, which are the active ingredients of the hyperremnantemia-improving drug of the present invention, have some useful physiological actions such as the action of inhibiting the arachidonic acid cascade. Has been. For example, a formulation for preventing and treating thrombotic symptoms (Japanese Patent Laid-Open Nos. 55-15444 and 57-3).
5512), a drug acting on the heart and cardiovascular system and a method for producing the same (JP-A-64-27), and a composition with selenium which acts on the thromboembolic state of the cardiovascular system (JP-A-2-22228).
No.), lipid metabolism improving agent (JP-A-3-24018), brain function improving agent (JP-A-3-58926) or angiogenesis inhibitor (JP-A-3-86819), functionality for improving brain function. There are foods (JP-A-2-49723) and the like.

Further, fish oil containing a large amount of icosapentaenoic acids and docosahexaenoic acids also suppresses the activity of macrophages [Dustin LB, et al., J. IMMUNOL. 14
4,488-4897 (1990)], LTB ₄ and LTC ₄ production inhibition [L
okesh BR, et al., BiochiBiophys. Acta, 958,99-1
07, (1988)], a report that suppresses the production of TNF [En
dres S., et al., N. Enl. J. Med., 320,265-271, (198
9)]

However, it is not known at all that n-3 polyunsaturated fatty acids have an action as a remedy for hyperremnantemia.

[0007]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a suitable improving drug for hyperremnantemia.

[0008]

[Means for Solving the Problems] The present inventors have found that administration of an effective amount of n-3 polyunsaturated fatty acids, particularly icosapentaenoic acids and / or docosahexaenoic acids, to patients with hyperremnantemia results in hyperremnantemia. The present invention has been completed based on the new finding that it is significantly improved.

That is, the present invention relates to a drug for improving hyperremnantemia, which comprises n-3 polyunsaturated fatty acids as an active ingredient.

Diseases that cause hyperremnantemia include
For primary, type III, type IV, type V hyperlipidemia (including type IIb), primary hepatic lipase deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, In the secondary, severe liver damage, diabetes, obesity, renal disease, hypothyroidism and indications other than disease include administration of steroids, intake of high cholesterol diet and the like.

The n-3 polyunsaturated fatty acids used in the present invention are preferably icosapentaenoic acid (EPA) and / or docosahexaenoic acid (DHA). These n-3 polyunsaturated fatty acids may be free acids, salts thereof, esters, glycerides and the like. Examples of the salt include sodium salt, potassium salt, calcium salt and the like, and examples of the ester include linear or branched alkyl esters having 1 to 6 carbon atoms, such as methyl ester, ethyl ester, propyl ester. ,
Examples thereof include i-propyl ester, butyl ester and hexyl ester. Glycerides are monoglycerides,
It may be either diglyceride or triglyceride. For example, monoglyceride of highly unsaturated higher fatty acid and its production method (JP-A-62-226947), glyceride of eicosapentaenoic acid, its production method and oil and fat products containing it (JP-A-62-26947). No. 153249), a method for producing a highly unsaturated fatty acid glyceride (JP-A-62-91188), a method for producing a glycerin ester of eicosapentaenoic acid (Japanese Patent Publication No. 5-82197) and the like.

As the oil containing the n-3 highly unsaturated fatty acids, the proportion of the n-3 highly unsaturated fatty acids (as a free acid) in the total fatty acids is 10% or more, more preferably 20% or more. Things are good. Examples of such products are sardines, mackerel, horse mackerel, salmon, fish oil extracted from blue-back fish such as saury, fish oil derived from orbital fat of large marine fish such as tuna and bonito, oil derived from microorganisms, krill oil, cod. And oils and fats derived from marine products extracted from squid liver and the like. Further, EPAs and DHAs that are highly purified to a purity of 90% or more are more preferable usage forms.

The dose of these EPAs or DHAs is
The amount of EPA is generally about 100 to 5000 mg per day, although it varies depending on the type of target disease, age, sex, weight, symptom of the patient, or administration form.
Taken once or in several divided doses. The amount of DHA is about 100 to 5000 mg per day, which may be taken once or in several divided doses.

The hyperremnantemia-improving drug of the present invention can be administered orally or parenterally. As the orally-administered agent, solid preparations such as powder, granules, capsules and tablets, or liquid preparations such as syrups and elixirs can be used. In addition, parenteral administration agents such as injections and suppositories can be used.

These preparations are manufactured according to a conventional method by adding pharmacologically and pharmaceutically acceptable manufacturing aids to the active ingredient. Further, it is also possible to prepare a sustained-release preparation by a known technique. When the production aid is used, the compounding amount of icosapentaenoic acid (as a free acid) of the hyperremnant blood pressure improving agent of the present invention is usually 1 to 90% by weight, preferably 10 to 50% by weight. The content of docosahexaenoic acid (as a free acid) is usually 1 to 90% by weight, preferably 10 to 50% by weight.

To prepare a solid preparation for oral administration, the active ingredient and excipients such as lactose, starch, crystalline cellulose, calcium lactose, magnesium aluminometasilicate, and silicic acid anhydride are mixed to prepare a powder. Alternatively, if necessary, a binder such as sucrose, hydroxypropylcellulose, polyvinylpyrrolidone, etc., a disintegrating agent such as carboxymethylcellulose, carboxymethylcellulose calcium, etc. are added to wet or dry granulate to obtain granules. To produce tablets, these powders and granules may be compressed as they are or by adding a lubricant such as magnesium stearate or talc. These granules or tablets are coated with an enteric base such as hydroxypropylmethylcellulose phthalate, methacrylic acid, methyl methacrylate copolymer and the like, and enteric-coated preparations, or coated with ethylcellulose, carnauba wax, hydrogenated oil, etc. You can also. To manufacture capsules, powders or granules should be filled in hard capsules, or the active ingredient should be dissolved as it is or in glycerin, polyethylene glycol, sesame oil, olive oil, etc. and then coated with a gelatin film to give soft capsules. You can

To prepare a liquid preparation for oral administration, an active ingredient and a sweetener such as sucrose, sorbitol and glycerin are dissolved in water to prepare a transparent syrup, and essential oil, ethanol and the like are added to form an elixir. Alternatively, gum arabic, tragacanth, polysorbate 80, sodium carboxymethyl cellulose, etc. may be added to prepare an emulsion or suspension. These liquid preparations may optionally contain a flavoring agent,
You may add a coloring agent, a preservative, etc.

In order to produce an injectable preparation, an active ingredient is optionally added with hydrochloric acid, sodium hydroxide, lactose, sodium lactate,
Dissolve in distilled water for injection together with a pH adjuster such as sodium monohydrogen phosphate and sodium dihydrogen phosphate, and an isotonic agent such as sodium chloride and glucose, and aseptically filter and fill into ampoules, or mannitol, dextrin , Cyclodextrin, gelatin and the like may be added and freeze-dried under vacuum to give a dissolvable injection before use. In addition, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to prepare an emulsion for injection.

To prepare a rectal preparation, is the active ingredient and a suppository base such as cocoa butter, tri-, di- and monoglycerides of fatty acids, polyethylene glycol, etc. moistened and melted and poured into a mold to cool? The active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then coated with a gelatin film.

To prepare an external preparation for skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to prepare an ointment, or rosin, an alkyl acrylate ester. After kneading with an adhesive such as a polymer, it is spread on a non-woven fabric such as polyethylene to obtain a tape.

The drug for improving hyperrenantemia of the present invention having the above-mentioned constitution can be produced by a known production method, for example, the method described in the general rules for preparations of the 10th edition of the Japanese Pharmacopoeia or a method with appropriate modifications.

The dose depends on the type of target disease, the age of the patient,
Depending on gender, weight, symptoms, or mode of administration,
Generally, the amount of the n-3 polyunsaturated fatty acid is about 0.1 to 5 g / person per day, and it may be used once or several times.

As a method for measuring blood remnant lipoprotein, cholesterol in remnant lipoprotein is usually
It can be measured using the monoclonal antibody method. Hereinafter, the present invention will be described in detail with reference to examples.

[0024]

【Example】

Test Example 1 Clinical Test Fish oil capsules were administered to 5 patients with hyperremnantemia. As shown in Table 1, the breakdown is 4 boys,
There was one girl. All were patients with hyperremnantemia with remnant lipoprotein cholesterol of 2.5 mg / dl or more. The fish oil capsules are tuna oils containing 6% EPA and 50% DHA, tocopherol added as an antioxidant, and wrapped in soft gelatin. The dose was 5400 mg per day, which was taken orally in 3 divided doses. Blood remnant lipoprotein was measured by collecting blood at the outpatient visit and measuring remnant lipoprotein cholesterol. Table 1 shows the results.

[0025]

[Table 1] * Remnant-like Particles Cholesterol

As described above, the results were effective in all 5 patients with hyperremnantemia.

[0027]

INDUSTRIAL APPLICABILITY The drug for improving hyperrennantemia containing the n-3 polyunsaturated fatty acid as an active ingredient of the present invention not only significantly suppresses the promotion of hyperrennantemia but also has a suitable improving action. Therefore, it is highly useful as an ameliorating drug for the prevention and treatment of arteriosclerosis in which the involvement of remnant lipoprotein is pointed out.

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Claims (2)

[Claims] 1. A drug for improving hyperrennantemia, which comprises n-3 polyunsaturated fatty acids as an active ingredient. 2. The drug for improving hyperrennanemia according to claim 1, wherein the n-3 polyunsaturated fatty acids are icosapentaenoic acids and / or docosahexaenoic acids.