JPS5933219A - Lipometabolism improving agent - Google Patents

Abstract

PURPOSE:To provide a lipometabolism improving agent containing oxyethophylline as an active component, having the activity to increase the high density lipoprotein cholesterol in blood serum, and effective to the prevention and remedy of arteriosclerotic cardiopathy and cerebropathy. CONSTITUTION:Oxyethophylline is used as an active component of the titled agent. Preferably, the lipometabolism improving agent contains an arbitrary amount, e.g. 0.1-99.5%, especially 0.5-90% of the active component impregnated in a pharmacologically permissible non-toxic or inert carrier. The carrier is composed of one or more inert and pharmacologically permissible solid, semi- solid or liquid dilutent, filler and adjuvant for drug preparation. Dose: usually 50-2,500mg, preferably 200-600mg of the active component daily. It is administered by oral or parenteral administration, local application, or rectal infusion.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides high voltage riboproteins in serum.
nsiLy1ipoproLein 1' 11 D
LJ) and very low density riboprotein (Very low density 1pop).
rotein (hereinafter referred to as r V I-L') L J)
and low density 1i
decreases proprotein (hereinafter referred to as rLDLJ)
Close it.

(V L D L 0 L D l,)/I [Relating to a lipid metabolism improving agent having the effect of reducing the value of DL.

Many factors are involved in the development of arteriosclerosis.

Hyperlipidemia, hypertension, smoking, and obesity were cited as four risk factors.

A characteristic of arteriosclerosis, especially atherosclerosis, is the accumulation of cholesterol in the arterial walls, and most of this cholesterol is absorbed by serum L.
Because it is derived from DL cholesterol.

High serum LDL levels are thought to be a contributing factor to arteriosclerosis.

Conventionally, attempts have been made to prevent the progression of arteriosclerosis by improving high levels of serum LDL, and serum Li
) ■ Many drugs have been developed that have the effect of reducing .

However, in recent years, it has been reported that there is a negative correlation between IIDL and ischemic heart disease (American
Journal of Medicine No. 628.7o7 True.

1-11) for the prevention or treatment of arteriosclerotic heart disease and brain disease (1977), and the development of a drug that can be called an L-enhancing drug has come to be expected.

In view of the clinical importance of II D L as described above, the present inventors conducted intensive studies and published two documents (Dtsch
, Med.

Oxyetophylline (7-(2- 11ydroxyethyl
) Lt+eophylline), but surprisingly HI)
The present invention was completed by discovering that it has a strong effect of raising and lowering L-cholesterol.

The pharmaceutical composition of the present invention can be used in large amounts to small amounts, such as O1I9.
The composition contains from 6 to 99.5%, preferably from 0.5% to 90%, of the biological material in a pharmaceutically acceptable, non-toxic and inert carrier.

The carrier is a non-toxic, inert and pharmaceutically acceptable solid;
Consisting of one or more semi-solid or liquid diluents, fillers and formulation adjuvants.

Such pharmaceutical compositions are preferably in dosage unit form. The dosage alone is 1. 2.3
．． 4 or more times the dose or vice versa
．． It can contain an amount of 1/3 or even 1/4.

A small dose is one or more doses corresponding to a predetermined amount, such as the whole, half, 1/3 or ]/4 amount of the daily dose when administered 1.2.3 or 4 times. The above dosage units should contain a sufficient amount to produce the desired therapeutic effect upon administration. Other therapeutic agents are also possible.

Setting the dose requires careful adjustment in each case. For example, the dose should be determined by seeking professional judgment or taking into account the patient's age, body weight, other patient conditions, method of administration, nature and severity of the disease, etc. 50 to 2500 mg per person, preferably 200 to 6 (10n
A range of +g is desirable. In some cases, J1 below this
A sufficient therapeutic effect may be achieved in 11 doses, and in other cases, a higher dose may be required.

The composition according to the present invention can be administered orally, parenterally, topically, or enterally. These 4J-known methods can be used to formulate the drug into a form suitable for the administration method. For example, tablets and capsules are particularly preferred.

For oral administration, use solid or lt' dosage units, such as powders.

+lk agent 1 tablet, sugar coating, capsule, granule, suspension.

Liquid, syrup, l? +:+ knob agent, tongue agent]・Can be performed using other dosage forms.

Powders are prepared by comminuting the active substance to a suitable fineness. Powders form the active substance to a suitable fineness and then a similarly finely divided pharmaceutical carrier, such as starch.

It is produced by mixing with other edible carbohydrates such as mannitol. Flavoring agents and preservatives as required.

You can also mix medicines and other things into the mouth.

Capsules are manufactured by first filling powdered powders or powders as described above into capsule shells such as gelatin capsules. Lubricants such as colloidal silica, talc, stearic acid, solid polyethylene glycol, etc. are mixed into the powdered material. , it is also possible to carry out the filling operation accordingly. Addition of disintegrants and solubilizers, such as agar, calcium carbonate, monolium carbonate, etc., can improve the effectiveness of the drug when the capsule is taken ME.

In addition, a fine powder of the active substance is suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant.

ζ This can also be wrapped in a gelatin sheet to form a soft capsule.

For tablets, make a powder mixture and granulate or slug it.
It is then manufactured by adding a disintegrant or a wetting agent and then tableting. Powder mixtures are prepared by mixing a suitably powdered substance with the diluents and bases mentioned above, and adding a binder (if necessary).
For example, carpoximenal cellulose, alginate,
gelatin, polyhinylvirolitone, etc.).

A solubility retardant (for example, paraphyllin), a resorption promoter (for example, quaternary salt) and/or an absorbent (for example, hentonite, kaolin, calcium phosphate, etc.) may also be used in combination.

The powder mixture is first prepared with a binder such as syrup, starch paste,
It can be made into granules by moistening it with gum arabic, a cellulose solution or a polymeric substance solution and then forcing it through a sieve. Instead of granulating the powder like this.

It is also possible to crush the resulting imperfectly formed slag into granules after passing it through a tablet machine.

The granules made in this way are made fluid by adding stearic acid, stearate, talc, mineral oil, etc. to prevent them from sticking to each other, without going through a moistening or slagging process. A transparent or translucent protective coating consisting of an occlusive coating of 41° shellac which may be directly compressed into tablets after mixing with an inert carrier.

It is also possible to use overlays of sugar or polymer + Al, and overlays of wax. Pigments may also be incorporated into these coatings for purposes such as distinguishing between different contents.

Other oral dosage forms, such as solutions, syrups, elixirs, etc., can also be made into dosage units, a fixed amount of which contains a fixed amount of the drug.

Syrups are prepared by dissolving the compound in a suitable flavored aqueous solution, and elixirs are dissolved using a non-toxic alcoholic medium. Suspensions are formulated by dispensing the compound in a non-toxic carrier.

Ia-improving agents, emulsifiers (eg, ethoxylated isostearyl alcohol, polyethoxyethylene sorbitol ester), preservatives, flavoring agents (eg, Pebamintoura, Zanocalin), and others may also be added as necessary.

If desired, dosage unit formulations for oral administration may be microencapsulated. The formulation may also be coated or
By embedding it in polymers, wax, etc., it is possible to prolong the action time and achieve sustained release.

Parenteral administration may be carried out using liquid dosage unit forms, such as solutions or suspensions, for intramuscular or intravenous injection. These can be used to deliver a fixed amount of a compound into a non-toxic liquid carrier suitable for the purpose of injection, for example in an aqueous or oily medium! ! Cloudy or dissolved, then the jl
It is manufactured by sterilizing a liquid or solution.

Alternatively, place an aliquot of the compound in a vial, then sterilize and seal the vial and its contents. Prepare a spare vial or body for mixing just before administration. Furthermore, stabilizers, preservatives, emulsifiers, and the like may also be used in combination.

For rectal administration, the compound may be mixed with low-melting water-soluble or insoluble solids such as polyethylene glycol, cocoa butter, higher ester acids (e.g., myristyl balmitate), and mixtures thereof. done by.

Next, examples of formulations will be given, but the following examples are merely for illustrative purposes and are not intended to limit the present invention.

Example - Per tablet (formulation) Oxy'-Tofillin 100 Ing Corn 11:J Starch 50 mg Lactose
110 mgL-II P C20
mg PVA 8 mg Magnesium Stearate 3 mg Cutal
9m size 00 mg (Production method) Micronized oxyethophylline and starch.

Mix lactose and L-HPC, add VC aqueous solution and knead. 1) Prepare granules for tabletting using a conventional method. Add magnesium stearate and talc and form into tablets of appropriate size.

The pharmaceutical effects of oxyetophylline according to the present invention will be explained in detail using the following test examples.

Test Example 1 Groups of 8 male Wistar rats (manufactured by Shizuoka Experimental Animal Cooperative) weighing around 50 g were fed a high-cholesterol diet (619.1 g of sea sugar, 220 g of casein, 50 g of Avicel, 50 g of coconut oil, (10g of coal, 2.5g of cole acid/thorium, 5.0g of hitamine mixture,
Mano Calano - 0g, chloride XI phosphorus 2.4g.

Mixed feed containing 1g of cod liver oil) to 1 (IITI free (H)
U, oxy: 1-tophylline 200 mg/kg,
400 mg/kg was orally administered 1-1 times for 10 days, and after the final administration (after fasting for 18 hours, blood was collected and serum lipids were measured).

Measurement of serum lipids includes total cholesterol (TC),
I-liglycerite, phospholipid enzymatic method, 111)
HI L-cholesterol (II D L-C)
) Digitran sulfate for the L fraction - Magnesium precipitation method 7 An enzyme was used for cholesterol 1.1-1 measurement.

111 ■ Total cholesterol minus IIDL-C (V L D L + L I') L )
:lReste I:I-ru toshi.

(VLDI, +L D l,) Cholesterol/l ID
1. -C was taken as the arteriosclerosis index.

As shown in Table 1, by taking a high-cholesterol diet for 1 hour,
C.

TG, PL, arteriosclerosis index increased, il I)
l -C was low 1ζ. These changes were alleviated by oxyetophylline injection, resulting in T C, T G, P L,
The arteriosclerosis index was 2 (at 10 mg/kgt3) compared to the cholesterol 1 group (cholesterol negative group);
Low 1-L, II D L-C is 400mg/
kg danyo no 1f'c jiJ'in' - shi! 1 Shinoko.

Test Example 2 After weighing 3 kg1ii+/Jll sex New Zealand White 1-1 group of 6 rabbits (11-electrolytic erosion) IY is 4
Feathers) Chicken 50.5% cholesterol diet < + + /-
1: 1LI + 0.5% in experimental animal feed NRT-Is”
1100g of mixed feed supplemented with J.
Gave.

Oxyetophylline was mixed in the feed at a ratio of 0.3% and 1%, and blood was collected on the 29th day of administration for 21if'1 to measure serum lipids.

The method for measuring lipids was as described in Test Example 1.

As shown in Table 2, by taking cholesterol in the diet, T
C, tlDL-C, arteriosclerosis index increased. Oxyetophylline administration suppressed TC, PL, and arteriosclerosis index by 1%, and HDL-C decreased by -1 compared to the control group.
1- rose.

In particular, HD L, −
C was significantly increased, and TC and arteriosclerosis index were significantly decreased.

- Experimental (column 3) Acute toxicity value of [oxy]fillin in t, n, +1F mice 1. I) 50 (mg/kg) I
The dose was 999 mg/kg for the I-L1 injection, and 612 mg/kg for the intraperitoneal dose.

Below-1-, II (according to an experimental example), the oxygen I-phyllin according to the present invention is
It has become clear that it is a substance that lowers the arteriosclerotic index and has a weak toxicity.

Applicant: Kuchimoto Shinyaku Co., Ltd. (1 other person) Agent: Patent Attorney Hiroshi Katama

Claims (1)

[Claims] Lipid metabolism improving agent containing oxyethophylline as the main component and having the effect of increasing high-density riboprotein in serum