JPH0455404B2 - - Google Patents

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 ₁₀ , exhibits a range of biological activities and is 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 VCand coll.-
Ann.Rev.Biochem.46−201−1977; Nakamura
T. et al. Chem Pharum. Bull. 27−1101−1979). 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 (Folkers K. et al. J.
Vit. Nutr. Res. 40−380−1970; Sugijama S.
Expperientia 36−1002−1980). When coenzyme Q ₁₀ is administered as a hexogen to these pathologies, significant recovery is observed and therapeutically important results are obtained (Yamasawa G.-
Biomedical and Clinical Aspects of Co−
enzyme Q-Elsevier-North Holland-Ed.Vol.
II, pp. 333-1980). However, coenzymes administered according to the usual regimen
The oral absorption of Q ₁₀ is extremely low, so special measures must be taken to increase absorption. In addition, for the above-mentioned pathologies, coenzyme Q ₁₀ 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 ₁₀ , 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. 58-113127 (JP 60-4280) describes aqueous ubidecarenone compositions containing varying amounts of hydrogenated lecithin as a stabilizer and solubilizer. ing. 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 composition according to the invention consists of 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 auxiliary agent. Particular preference is given to using the nonionic surfactants or emulsifiers sold by BASF under the trademark Cremophor EL. Also advantageously, glycols as polyhydroxylation solvents,
Glyceral, polyglycol, alcohol, glycofural, sorbitol, water, etc. are used. Suitable antioxidants in the present invention are vitamin E, pyrogallol, ascorbic acid and other known antioxidants. In the compositions of the invention, the nonionic emulsifier 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. The antioxidant is added in an amount of 0.5 to 2 mg per 100 mg of active ingredient, and dimethylacetamide, which serves to reduce the amount of cremophor EL and polyhydroxylation solvent, is present in an amount of 0.5 to 5 ml per 100 mg of active ingredient. In the compositions of the present invention, the amount of active ingredient, e.g. coenzyme _Q10 , is usually between 50 and
It is 500mg. Flavoring agents, if necessary and by known means.
Compositions of the present invention to which excipients such as bactericides and buffers can be added may be diluted with medicinal salts, glucosate, vitamin solutions at the time of use without causing 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 ₁₀ is dissolved in 800 mg of Cremophor EL at 60°C and 70% Solobitol 0.4 is preheated to 60°C while maintaining the temperature at 60°C.
ml under stirring, then 1.6 ml H ₂ O heated to 60 °C containing 0.2 ml acetamide and antioxidants (0.5 mg pyrogallol, 0.5 mg vitamin E, 1 mg vitamin C). was added. Similarly, the following compositions were prepared. Example 2 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 400 mg Dimethylacetamide 2.30ml Glycofurol 1.15ml Pyrogallol 11 mg Example 3 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 1000 mg Dimethylacetamide 0.5ml Glycofurol 1.0ml Pyrogallol 1 mg Example 4 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 780 mg Glycofurol 600 mg H ₂ O 220 mg Dimethylacetamide 0.5ml Example 5 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 500 mg Glycofurol 700 mg H ₂ O 200 mg Dimethylacetamide 0.5ml Example 6 Coenzyme Q ₁₀ 100 mg (Cremophor) EL 600 mg Polyglycol 200−400 400 mg H ₂ O 100 mg Dimethylacetamide 0.5ml Example 7 Coenzyme Q ₁₀ 100 mg (Cremophor) ) EL 600 mg Glycerin 400 mg H ₂ O 100 mg Dimethylacetamide 0.5ml Example 8 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 600 mg 70% Solobitol 400 mg H ₂ O 100 mg Dimethylacetamide 0.5ml Example 9 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 600 mg 95% ethanol 400 mg H ₂ O 100 mg Dimethylacetamide 0.5ml Example 10 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 500 mg Glycofurol 700 mg Dimethylacetamide 0.5ml Vitamin E 0.5 mg Vitamin C 1.0mg H ₂ O 100 mg Example 11 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 500 mg Glycofurol 500 mg Dimethylacetamide 0.5ml Vitamin E 0.5mg H ₂ O 100 mg Example 12 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 600 mg Polyglycol 200-400 400 mg Dimethylacetamide 0.5ml Vitamin E 0.5mg H ₂ O 100 mg Example 13 Coenzyme Q ₁₀ 100 mg (Cremofur) EL 1000 mg Dimethylacetamide 0.5ml Glycofurol 0.5ml Pyrogallol 0.1mg Vitamin E 0.1mg Toxicological testing Laboratory animals (rats, guinea pigs, rabbits)
Various toxicological tests carried out using Coenzyme Q10 have shown that the results obtained with the administration of coenzyme _Q10 in the solution according to the invention are consistent with the administration with other excipients showing the same properties of low toxicity and good tolerability. The results were shown to be comparable to those obtained with coenzyme Q ₁₀ . Pharmacological Tests Coenzyme Q ₁₀ prepared according to the invention was compared in therapeutic terms with the results obtained by oral and parenteral administration of coenzyme Q ₁₀ dissolved in other fatty acids and aqueous vehicles. As a result, its absorption and pharmacokinetic properties are much better. by intravenous route in the form of an aqueous composition prepared according to the invention () - Example 10 -, a glycofurol composition () or a soybean lecithin composition ();
or by the oral route in the form of a soybean oil composition.
A comparison of plasma, liver and heart concentrations of coenzyme Q ₁₀ when administered to Sprague-Dawley rats shows that the composition of the present invention has a higher absorption rate and tissue concentration, as shown in Table 1. I understand what is shown. Other solutions according to the invention, such as Example 1,
Similar results were obtained using 2, 5, 6, 7 and 12. High performance liquid chromatography (HPLC) was used to evaluate coenzyme Q ₁₀ in the blood and tissues of animals injected with various coenzyme Q ₁₀ compositions.
(lkenoya et al.−Chem.Pharm.Bull.29−158−
1981; Takada et al.−Method inenzimology
105−147−1984). 2 ml per 1 ml of blood serum obtained from test animals, rats.
of diluted H ₂ O, 4 ml ethanol and 10 ml n-
Hexane was added. The solution was placed in a test tube, vortexed and centrifuged at 2000g for 10 minutes. The n-hexane collected from the three extractions was combined and extracted with _N2
Evaporated under running water. The residual dry matter was dissolved in 100 mc of dioxane and 10 mc was processed by HPLC.
The same extraction procedure was performed using a tissue homogenate obtained by dissolving 100 mg of tissue in 2 ml of dilution water. The absorption rate of coenzyme Q ₁₀ obtained by intravenous administration of coenzyme Q ₁₀ prepared according to the present invention is high and long-lasting, and its liver and tissue concentration is about 100 times that of oral administration. It is less than that, and more than twice that of normal parenteral administration. This clearly shows the excellent therapeutic effect of coenzyme _Q10 in clinical use. Also, the oral administration of coenzyme Q ₁₀ with the composition of the present invention is far superior in absorption properties to that of conventional compositions. 【table】

Claims (1)

[Scope of Claims] 1. A liquid pharmaceutical composition for oral, parenteral, rectal and topical administration in the form of an aqueous or organic solvent solution containing a nonionic emulsifier and an antioxidant, which ubiquinone as a component, a nonionic emulsifier, a hydroxylated solvent, an antioxidant, and dimethylacetamide, the nonionic emulsifier being a polymer derived from the condensation of ethylene oxide and a nonhydrogenated fatty acid oil, and the antioxidant is selected from vitamin E, ascorbic acid, pyrogallol or mixtures thereof, and the nonionic emulsifier is present in an amount of 4 to 10 times the weight of the active ingredient;
A liquid ubiquinone pharmaceutical composition, characterized in that the hydroxylated solvent is present in an amount of 10 to 25 times the weight of the active ingredient and the antioxidant is present in an amount ranging from 0.5 to 2 mg per 100 mg of active ingredient. 2. The composition of claim 1, wherein the hydroxylation solvent is selected from alcohols, glycols, polyglycols, glycerin, glycofurols, water and mixtures thereof. 3. The composition according to claim 1 or 2, wherein the nonionic emulsifier is derived by condensation of ethylene oxide and castor oil. 4. The composition according to any one of claims 1 to 3, wherein the active ingredient is ubiquinone _Q10 .