JPS62158209A - Liquid ubiquinone drug composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to water-soluble pharmaceutical compositions containing ubiquinone as an active ingredient.

Ubiquinone, or coenzyme Q lo, exhibits a range of biological activities and is therefore used in a variety of treatments.

For example, coenzyme Q10 plays an important role in electron transfer and oxygen utilization in the mitochondrial level of cells (De Pierre V, Cand col
l, -^nn, Rev, Biochem, 46-
201-1977; Nakamura T, et
al., Chem Pharm, Bull.

27-11fH-1979).

Its activity is necessary for ATP production and the energy functions of various cells and tissues. This deficiency is seen in many pathologies such as myocardial insufficiency, hypertension, post-infarction sequelae and myasthenia (Folkerg K, et al, J, Vit.
, Nutr, Res, 40-380-1970;
Sugijama S, Expperientia
36-1002-1980).

When coenzyme QIo is administered as a hexogen to such pathologies, significant recovery is observed and important therapeutic results are obtained (Yamasawa G, - Biomedi
cal and C11nical Aspects
of Co-enzyme Q -Elsevier
-North 1roland -Ed.

Vol, If, pp, 333-1980).

However, coenzyme Q Io administered according to the usual regimen
The amount of oral absorption is extremely low, so special measures must be taken to increase absorption. In addition, for the above-mentioned disease states, coenzyme Q lo needs to be readily absorbed into tissues in high concentrations.

For the above reasons, there is a need for a method of administering coenzyme Q Io, either alone or in combination with other aqueous compositions, in solutions that are easily absorbed and allow for parenteral administration by intravenous, intramuscular or subcutaneous routes. If so, it would be extremely useful.

Japanese Patent Application No. 113127/1987 discloses that various amounts of hydrogenated lecithin are contained as stabilizers and solubilizers.
Aqueous ubidecarenone compositions are described.

The present inventors have now discovered that it is possible to obtain a ubiquinone composition that can be administered orally, parenterally, and topically, and is water-soluble and stable, that is, does not show precipitation of the active ingredient even when diluted with a large amount of water. I found it. The compositions according to the invention also have good bioavailability (in other words good absorption of the active ingredient), which means an increased therapeutic effect.

The ubiquinone compositions according to the invention contain a nonionic emulsifier obtainable by condensation of ethylene oxide with a non-hydrogenated fatty acid oil, a hydroxylated solvent, an antioxidant and, optionally, dimethylacetamide as an adjuvant. Cremophor EL (Cren+) from BASF
Particular preference is given to using nonionic surfactants or emulsifiers sold under the trademark ophor EL).

It is also advantageous to use glycols, glucose, polyglycols, alcohols, glycofural, sorbitol, water, etc. as polyhydroxylation solvents. Suitable antioxidants in the present invention include vitamin E, pyrogallol,
Ascorbic acid and other known antioxidants.

In the compositions of the invention, Cremophor EL is present in an amount of 4 to 10 times the weight of the active ingredient and the polyhydroxylated solvent is present in an amount of 10 to 25 times the weight of the active ingredient.

Antioxidant content is 0°5-2 per 100 mg of active ingredient.
Dimethylacetamide, added in an amount of 0.5 to 5 mg per 100 mg of active ingredient, also has the function of reducing the insecticidal properties of Talemofol EL and polyhydroquinated solvents.
Make it exist in m of m12. In the composition of the present invention,
Active ingredients, such as coenzyme Q. The usage m is usually 50-5
00 mg.

The composition of the present invention can be supplemented with excipients such as fragrances, disinfectants, buffers, etc., if necessary and by known means.
During use, it may be diluted with medicinal salts, glucosades, and vitamin solutions that do not cause precipitation or incompatibility problems.

EXAMPLES The present invention will be further explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 100 mg of coenzyme Q+O was heated to 60'C for 800 min.
After adding 0.4 mQ of 70% sorbitol dissolved in mg of Cremophor EL and preheated to 60°C while maintaining the temperature at 60°C, 0.2 mQ of acetamide and antioxidant ( 0,5 mg pyrogallol, 0
．． Contains 5mg of vitamin E, Img of vitamin C),
1.6 ml of Ht 2 O heated to 60° C. was added.

Similarly, the following compositions were prepared.

Example 2 Coenzyme Q+o 100 mg (
Cremophor) EL 400 mg
Tsumethylacetamide 2.30 ra (1
Glycofluor 1.15 to(1
Pyrogallol 11 +++g.

Example 3 Coenzyme Q. 100 mg (Cremophor) EL 1000 mg Dimethylacetamide 0.5 m (2 Glycofurol 1.0 mQ Pyrogallol
B・Example 4 Coenzyme QIo 100 mg (
Cremophor) EL 780 mg Glycofurol 600 mg 1120
220 mg dimethylacetamide 0.5 mQ.

Example 5 Coenzyme QIo 100 1g (Cremophor) EL 500 11g Glycofurol 700 111gII,
0 200 rtr g
Dimethylacetamide 0.5 tmQ.

Example 6 Coenzyme QIo 100 mg (
Cremophor) EL 600 mg
Polyglycol 200-400 400 mg
lltoloo mg dimethylacetamide 0.5 mQ.

Case 0 7 Coenzyme QIo 100 mg (
Cremophor) EL 600 m
g Glycerin 400mgll
20 100 x g dimethylacetamide 0.5 mQ Example 8 Coenzyme. ,. 100 B (Cremophor) EL 600 mg7
0X Sorbitol 400 mg+1J
100 mg dimethylacetamide 0.5 m (1° Example
9 Coenzyme QIo 100 mg
(Talemofol) EL 600 m
g95z ethanol 400 B+1
20
100 ra g dimethylacetamide
0.5 mQ.

Example] 0 Coenzyme Q. 100 B (Cremophor) EL 50 (l rag glycofurol 700 B dimethylacetamide 0.5 m12 Vitamin E
O, 5mg vitamin C1, O
mg 1120 100 mg
.

Example 11 Coenzyme Q. 100 1ng (Cremophor) EL 500 mg Glycofurol 500 mg Dimethylacetamide 0.5 mQ Vitamin E
O,5mg1120
100 mg.

Coenzyme Q. 100 mg (
Talemofol) EL 600 mg
Polyglycol 200-400 400 mg
Dimethylacetamide 0.5 mQ Vitamin E O, 5'mg11zO
100mg.

Example 13 Coenzyme QIo 100 mg
(Cremophor) EL 1000 m
g Dimethylacetamide 0.5 mQ Glycofurol 0.5 m (1 Pyrogallol 0.1 mg Vitamin E
O, 1 mg.

Toxicological Tests Various toxicological tests conducted using experimental animals (rats, guinea pigs, rabbits) have shown that the results obtained by administering the solution of coenzyme Q+O according to the present invention have low toxicity and excellent tolerability. The results were shown to be comparable to those obtained with coenzyme Q+o administered with other excipients exhibiting the same properties.

PHARMACOLOGICAL TESTS Coenzyme Q lo prepared according to the invention is useful from a therapeutic point of view compared to other fatty acids and coenzyme Q dissolved in an aqueous vehicle.
,. Compared to the results obtained by oral and parenteral administration, the absorption and pharmacokinetic properties are much better.

Aqueous composition prepared according to the invention <X) Example 10
- male Sprague-Da by intravenous route in the form of glycofurol composition (II) or soybean lenotin composition (III) or by oral route in the form of soybean oil composition.
Coenzyme Q, when administered to wley rats. As shown in Table 1, it can be seen from the comparison of the plasma concentration, liver concentration, and heart concentration that the composition of the present invention exhibits a higher absorption rate and tissue concentration. Similar results were obtained using other solutions according to the invention, such as Examples 1, 2.5.6.7 and I2.

Various coenzyme Ql. The method used for coenzyme Q+o evaluation in the plasma and tissues of animals injected with the composition was high performance liquid chromatography (IIPLc) (lkeno
Ya et al, -Chem, Pharm.

Bull, 29-158-1981; Takada e
tal, -Method 1nenzinlog
y 105-147-1984).

2 m in plasma Imf7 obtained from the test animal rat.
Dilution of 12 H, 0.4 mff ethanol and IOmQ
of n-hexane was added. The solution was placed in a test tube, vortexed and centrifuged at 2000g for lo minutes. The n-hexane collected from the three extractions was combined and evaporated under a stream of N. Dissolve the residual dry matter in 100 m cc of dioxane and add 10 m cc! 2 was processed by HPLC. 10
The same extraction method was performed using a tissue homogenate obtained by dissolving 0 mg of tissue in 2 m (2 m) diluted water.

The absorption rate of coenzyme Q 1o obtained by intravenous administration of coenzyme Q 1o prepared according to the present invention is high and the duration is long (and its liver and tissue concentration is about 10 times or more than that of oral administration). and more than twice that of normal parenteral administration.

This is coenzyme Q. It clearly shows excellent therapeutic effects in clinical applications. Also, the oral administration of coenzyme Qla using the composition of the present invention is far superior in absorption properties to that of conventional compositions.

Claims (5)

[Claims] (1) In a composition containing ubiquinone as an active ingredient, suitable for oral, parenteral, rectal and topical administration, a nonionic emulsifier, a polyhydroxylated solvent,
A liquid ubiquinone pharmaceutical composition characterized in that it consists of one or more antioxidants and, optionally, dimethylacetamide. (2) the nonionic surfactant is a polymer derived from the condensation of ethylene oxide and a nonhydrogenated fatty acid oil; the hydroxylating solvent is an alcohol, glycol, polyglycol, glycerin, glycofurol, sorbitol, water, and mixtures thereof; and Composition according to claim 1, characterized in that the antioxidants are vitamin E, ascorbic acid and pyrogallol. (3) The nonionic surfactant is Cremophor EL (C
The composition according to claim 2, characterized in that it is REMOPHOR EL). (4) nonionic emulsifier in an amount of 4 to 10 times the weight of active ingredient and hydroxylated solvent in an amount of 4 to 10 times the weight of active ingredient;
4. A composition according to any one of claims 1 to 3, characterized in that it is present in an amount of ~25 times. (5) The composition according to any one of claims 1 to 4, wherein the active ingredient is ubiquinone Q_1_0.