JP2003026567A - Composition for administration to mucosa and containing coenzyme q as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for administration to the mucosa, capable of effectively supplying coenzyme Q to a patient to whom oral administration of the coenzyme Q is practically difficult or an old person who is difficult to swallow the coenzyme Q and capable of administering the coenzyme Q to topcal diseases, when the coenzyme Q highly useful for human health maintenance is supplied, and to provide a method for effectively supplying the coenzyme Q. SOLUTION: This composition for administration to the mucosa contains the oxidized coenzyme Q and/or reduced coenzyme Q as active ingredients, wherein the oxidized coenzyme Q and reduced coenzyme Q are contained in a ratio of 0.0001-99 wt.% based on the total amount of the composition. The composition is effective for increasing a concentration of the coenzyme Q in the blood and the concentration thereof in the local mucosa.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition for mucosal administration containing coenzyme Q as an active ingredient.

[0002]

2. Description of the Related Art Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals. Coenzyme Q plays a role as a transfer component in the electron transfer system by repeating oxidation and reduction in vivo, and it is known that reduced coenzyme Q is an antioxidant. In many animals including human beings, fish and birds, the main component is coenzyme Q ₁₀ which has 10 repeating structures in the side chain of coenzyme Q, and this coenzyme Q ₁₀ is usually found in vivo. It is known that about 40 to 90% exists in a reduced form. Coenzyme Q is not included in the classification of vitamins because it can be biosynthesized in the living body, but is considered to be substantially the same as vitamins. Moreover, since the ability of coenzyme Q ₁₀ biosynthesis in humans decreases with age and the content in vivo decreases, it has been advocated that there is some form of supplementation.

[0003] Of the coenzyme _{Q 10,} oxidized coenzyme _{Q 10}
Is used as a congestive heart failure drug for pharmaceutical applications,
Besides vitamins, it has been reported to be used in a wide range of fields such as the use of nutritional supplements and nutraceuticals as well as vitamins, effectiveness against allergic diseases, increase in exercise capacity, etc. Furthermore, since it has been reported to be effective in diseases related to the brain such as dementia, it can be expected that it will be highly useful for the elderly.

Thus, the usefulness of coenzyme Q ₁₀ is high,
In a safety test using animals, 1.2 g using rats
It is a compound that has been proved to be highly safe without any toxic findings even after continuous administration for 52 weeks at a high dose of / kg / day (J. Agric. Food Ch
em. 1999 Vol. 47p3756-376
3). However, in the administration routes other than oral administration, only a few dermatological agents are actually used, and it is true that it is administered to severely ill patients who are difficult to take orally, elderly people, infants, etc. It was difficult. Also,
For local areas such as the intestinal tract, nose, and ears, which are prone to suffer from allergic diseases, sufficient coenzyme Q concentration cannot be obtained by oral administration, and the reality is that coenzyme Q cannot be effectively used. Is.

[0005]

The present invention has coenzyme Q as an active ingredient and is effective for local use where it is easy to use for patients or the elderly who have difficulty in oral intake or where it is difficult to obtain a sufficient concentration. The present invention is intended for a preparation capable of supplying coenzyme Q to

[0006]

As a result of research to solve the above problems, the present inventors have found that coenzyme Q can be absorbed into a living body by utilizing mucosal absorption. Furthermore, in the coenzyme Q preparation, reduced coenzyme Q
Oxidized coenzyme Q by using a composition containing
It has been found that a significantly higher blood concentration can be obtained compared to a composition containing only. It was also found that coenzyme Q can be effectively delivered locally by utilizing mucosal absorption.

That is, the present invention provides the following formula (1)

[0008]

[Chemical 3]

Oxidized coenzyme Q represented by the formula (n represents an integer of 1 to 12) and / or the following formula (2)

[0010]

[Chemical 4]

A composition for mucosal administration containing a reduced coenzyme Q represented by the formula (wherein n represents an integer of 1 to 12) as an active ingredient, wherein the oxidized coenzyme is the total amount of the composition. A composition for mucosal administration, wherein the total proportion of Q and the reduced coenzyme Q is 0.0001 to 99% by weight. The composition may be for human application or for animal application. Examples of animals include pets such as dogs and cats, horses such as competitive horses, livestock such as cows, pigs, rabbits, rats, and mice, and birds.

In the present invention, the "composition for mucosal administration" refers to a composition having a form so as to be absorbed into the body through the mucous membrane. In the present invention, "mucosa" refers to intestine, nasal mucosa, oral mucosa, ear mucosa, vaginal mucosa and the like.

Further, the present invention is characterized in that the composition for mucosal administration is applied to human or animal mucous membranes, and coenzyme Q is used.
It is also a method of delivering to the living body. As for the conditions for application, generally known conditions can be used depending on the form of the composition. For example, in the case of a suppository, a suppository containing coenzyme Q is used once a day. Is preferred. The content of coenzyme Q at this time is preferably 30 mg or more and 100 mg or less, and more preferably 50 mg or more and 100 mg.
It is the following. In the case of eye drops or nasal drops, it is preferable to use eye drops or nasal drops containing coenzyme Q 2 to 3 times a day. At this time, the concentration of coenzyme Q is
The content is preferably 0.01% by weight or more and 10% by weight or less, and more preferably 0.1% by weight or more and 3% by weight or less.
The present invention is described in detail below.

The compound represented by the above formula (1) is oxidized coenzyme Q, and the compound represented by the above formula (2) is reduced coenzyme Q. Oxidized coenzyme Q and reduced coenzyme Q
The method of obtaining coenzyme Q is not particularly limited, and, for example, a method of obtaining coenzyme Q by a conventionally known method such as synthesis, fermentation, extraction from a natural product, and the like, and then concentrating each section in the effluent by chromatography Can be adopted. In this case, when it is desired to obtain reduced coenzyme Q, a general reducing agent such as sodium borohydride or sodium dithionite (sodium hydrosulfite) is added to the above coenzyme Q, if necessary. May be added, and the oxidized coenzyme Q contained in the above-mentioned coenzyme Q is reduced by a conventional method to obtain reduced coenzyme Q, followed by concentration by chromatography. It can also be obtained by a method of reacting the existing oxidized coenzyme Q with the above reducing agent.

The oxidized coenzyme Q and the reduced coenzyme Q which can be used in the present invention have a side chain repeating unit (n in the formula) of 1 as represented by the above formulas (1) and (2). Among these, those having a side chain repeating unit of 10, that is, oxidized coenzyme Q ₁₀ and reduced coenzyme Q ₁₀ can be particularly preferably used.

The content of coenzyme Q in the composition of the present invention is appropriately determined depending on its use, dosage form and the like.
The total proportion of oxidized coenzyme Q and reduced coenzyme Q in the total amount of the composition (when only oxidized coenzyme Q is contained, it is the proportion of oxidized coenzyme Q in the total amount of the composition, When only reduced coenzyme Q is contained, the lower limit of the ratio of reduced coenzyme Q to the total amount of the composition is 0.0001% by weight and the upper limit is 99% by weight.
A preferred lower limit is 0.005% by weight and a preferred upper limit is 50% by weight. A more preferable lower limit is 0.01% by weight, and a further preferable upper limit is 3%.
It is 0% by weight.

When the composition of the present invention contains both oxidized coenzyme Q and reduced coenzyme Q, the reduced coenzyme Q in the total amount of oxidized coenzyme Q and reduced coenzyme Q is reduced. It is preferred that the proportion of enzyme Q exceeds 20% by weight. More preferably, it is 40% by weight or more. The upper limit is 100% by weight or less, preferably less than 100% by weight, and more preferably 98% by weight or less.

The composition for mucosal administration of the present invention comprises a suppository, a vaginal suppository, a nasal drop, an ear drop, an oral mucous membrane patch, a toothpaste, a troche, a drop, a lozenge and an oral cavity according to the route of administration. It can be formulated into a form such as an internal dissolution agent. Each of these preparations can be produced by combining the preparation additives usually used in the respective preparations and preparing the preparations by a conventionally known method.

When the formulation is a suppository, the formulation additives are:
For example, isocacao (manufactured by Kao), Witepsol (manufactured by Huls), saposia (manufactured by Gatefosse), Pharmasol (manufactured by NOF Corporation), Massa Estanalim (manufactured by Hils), Novata (manufactured by Henkel), S
Semi-synthetic hydrogenated oils such as B base (manufactured by Taiyo Oil & Fats Co., Ltd.), cocoa butter, palm oil, palm kernel oil, coconut oil, fractionated coconut oil, natural oils and fats such as lard, waxes such as lanolin and reduced lanolin. , Vaseline, squalene, squalane, hydrocarbons such as liquid paraffin, lauryl alcohol,
Higher alcohols such as cetanol and stearyl alcohol, fatty acid esters such as butyl stearate and dilauryl malonate, glycerin medium and long chain carboxylic acid esters such as triolein and tristearin, glycerin substituted carboxylic acid esters such as glycerin acetoacetic acid ester Examples thereof include polyethylene glycol such as macrogol and cetomacrogol, and derivatives thereof.

When the formulation is a nasal drop, examples of the formulation additive include physiological saline, a lactate-based buffer as a buffer, an acetate-based buffer, a phosphate-based buffer, etc.
As a preservative, paraoxybenzoic acid ester, propylene glycol, benzethonium chloride, benzalkonium chloride, sorbic acid or its salt, chlorobutanol, etc.,
As a thickener, polyvinyl alcohol, polyvinylpyrrolidone, dextran, alginic acid metal salt, sucrose, gelatin, methyl cellulose, hyaluronic acid metal salt, etc., crystalline cellulose as a powder administration base, α-cellulose,
Examples thereof include crosslinked sodium carboxymethyl cellulose, hydroxypropyl cellulose, β-cyclodextrin, dimethyl-β-cyclodextrin and lactose.

Further, the composition of the present invention may contain an absorption enhancer suitable for each form and purpose.

The composition for mucosal administration of the present invention can be used as a medicine. Examples of diseases to be treated in this case include hemorrhoids, ulcerative colitis, Crohn's disease, heart disease,
Brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction,
Examples include allergic rhinitis, hay fever, conjunctivitis, gingivitis, and alveolar pyorrhea. In this case, a medicinal component other than coenzyme Q may be further contained.

The suppository according to the present invention is intended for the drugs commonly used for intestinal diseases such as hemorrhoids, ulcerative colitis, Crohn's disease, and the whole body such as antipyretic analgesics and nutritional supplements. It can contain substances.

The nasal drops according to the present invention may include agents usually used for allergic rhinitis or hay fever.

The toothpaste according to the present invention may contain components such as medicinal components commonly used for gingivitis or alveolar pyorrhea.

The composition for mucosal administration of the present invention can also be used for nutritional supplementation. In this case, a nutritional supplement component other than coenzyme Q may be further contained. Examples of the nutritional supplement components include vitamins, crude drug extracts, herb extracts, polyphenols, propolis and the like.

[0027]

The present invention will be described in more detail with reference to the following examples and formulation examples, but the present invention is not limited to these examples. Example 1 (1) Preparation of Specimen Sample 1 1 g of oxidized coenzyme Q ₁₀ was melted in a 50 ° C. water bath, and Macrogol 1000 (PEG1000) was added to make 10 ml. This is homogeneously melt mixed at 50 ° C.,
It was solidified at room temperature to obtain a column-shaped suppository having a diameter of about 5 mm.

(2) Preparation of Specimen Sample 2 1 g of reduced coenzyme Q ₁₀ (5% of oxidized coenzyme Q ₁₀
Was melted on a 50 ° C. water bath, and then PEG1000 similarly dissolved was added to make 10 ml. This was homogeneously melt mixed at 50 ° C. and solidified at room temperature to obtain a suppository. The ratio of reduced coenzyme Q _{10 in} the suppository is coenzyme Q ₁₀
It was 95% of the total amount, and no oxidation was observed during preparation.

(3) Transmucosal absorption test Specimen samples 1 and 2 were used as test samples. test
Is an overnight Wistar male Wistar rat (body weight 2
50-300 g). 1 in the rat rectum
Sample sample 1 or sample sample 2 at the rate of g / kg
I inserted each. After insertion, blood is collected over time and fermented in plasma
Elementary Q₁₀The amount was quantified. Coenzyme Q in plasma ₁₀Table 1
It was shown to. Each value is the average value ± standard deviation of n = 10.

[0030]

[Table 1]

As mentioned above, coenzyme Q₁₀As a suppository
Membrane administration of coenzyme Q in plasma ₁₀Can increase the quantity
I found out that This result is poorly soluble and taken orally
Coenzyme Q without a method₁₀, If ingestion is difficult
Even in the case of coenzyme Q, if administered transmucosally₁₀Supply
It shows that you can do it. Even more surprising is the reduction
Type coenzyme Q₁₀Coenzyme Q containing 95% of₁₀Sitting by
Agent is oxidized coenzyme Q₁₀Compared to those containing 100%
Then, coenzyme Q in plasma₁₀To increase the amount more
And coenzyme Q to the living body₁₀Better than supply
It was found that

(Example 2) Mucosal translocation test In the same manner as in Example 1, a suppository containing oxidized and reduced coenzyme Q ₁₀ was prepared. This suppository was used to evaluate the transferability of coenzyme Q ₁₀ to rat large intestinal mucosa. As the test method, as in Example 1, male Wistar rats were used, and the sample sample 1 or sample sample 2 was inserted into the rectum of the rat at a rate of 1 g / kg. The rectum of the rat was collected over time and thoroughly washed, and then the amount of coenzyme Q ₁₀ in the rectal tissue was measured with HPL.
It quantified in C. Table 2 shows the amount of coenzyme Q ₁₀ in the rectum. Each value is the average value ± standard deviation of n = 5.

[0033]

[Table 2]

As described above, it was found that the amount of coenzyme Q ₁₀ in the rectal mucosa can be increased by transmucosally administering coenzyme Q ₁₀ as a suppository. This result, mucous membranes, indicating that the coenzyme Q _{1 0} can be effectively supplied. Even more surprisingly, suppositories with coenzyme Q ₁₀ containing 95% reduced coenzyme Q ₁₀ contained ₁₀ % oxidized coenzyme Q ₁₀ .
The amount of coenzyme Q ₁₀ in the mucosa can be increased more than that of the one containing 0%, and coenzyme Q to the mucosa can be increased.
It turned out to be better for ₁₀ replenishments.

Preparation Example 1 Suppository Coenzyme Q ₁₀ 1.0 g Macrogol Total 100 g However, coenzyme Q ₁₀ has a reduced form: oxidized form ratio of 98: 2.
Is.

Preparation Example 2 Eye drop Coenzyme Q ₁₀ 0.1 g Glycerin 1.0 g Propylene glycol 1.0 g Polysorbate 80 1.5 g Sodium dihydrogen phosphate 0.1 g Benzalkonium chloride 0.005 g Distilled water Total amount 100 mL However, coenzyme Q ₁₀ had a reduced: oxidized ratio of 98: 2.
Is.

[0037]

EFFECT OF THE INVENTION Since the composition of the present invention has the above-mentioned composition, it is excellent in systemic supplementation of coenzyme Q other than oral administration and accumulation in local mucosa, and it can be used for health care of the elderly or severely ill patients and colon. It exerts excellent effects against diseases that occur in local mucosa such as diseases and allergic diseases.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 1/00 A61P 1/00 171 171 1/02 1/02 1/04 1/04 3/10 3 / 10 9/00 9/00 9/10 9/10 103 103 103 9/14 9/14 11/02 11/02 27/02 27/02 37/08 37/08 (72) Inventor Takayoshi Hidaka Kobe Hyogo Prefecture 2-21-8 F-term, Tarumi-ku, Ichi (reference) 4C076 AA01 AA12 BB22 BB24 BB25 BB26 BB30 CC29 EE23A FF68 4C206 AA01 AA02 CA19 CB27 KA01 MA02 MA37 MA48 MA76 MA77 MAZA ZA36 ZA ZA ZA ZA ZA ZA ZA ZA ZA ZA ZC35

Claims (17)

[Claims] 1. The following formula (1): (In the formula, n represents an integer of 1 to 12) Oxidized coenzyme Q and / or the following formula (2): A composition for mucosal administration containing a reduced coenzyme Q represented by the formula (wherein n represents an integer of 1 to 12) as an active ingredient,
A composition for mucosal administration, wherein the total proportion of the oxidized coenzyme Q and the reduced coenzyme Q is 0.0001 to 99% by weight based on the total amount of the composition. 2. The oxidized coenzyme Q represented by the formula (1) is an oxidized coenzyme Q ₁₀ and the reduced coenzyme Q represented by the formula (2) is a reduced coenzyme Q ₁₀ . The composition for mucosal administration according to claim 1. 3. A suppository, a nasal drop, an ear drop, an oral mucous membrane patch, a troche, a drop, a lozenge, an oral dissolving agent, a vaginal suppository, or a toothpaste. A composition for mucosal administration. 4. The composition for mucosal administration according to claim 1, which is used as a medicine. 5. The composition for mucosal administration according to claim 4, further comprising a medicinal component other than the oxidized coenzyme Q represented by the formula (1) and the reduced coenzyme Q represented by the formula (2). . 6. A method according to claim 4 for treating hemorrhoids or enteric diseases.
The composition for mucosal administration described. 7. The composition for mucosal administration according to claim 6, further comprising a therapeutic agent for hemorrhoids or intestinal diseases. 8. The composition for mucosal administration according to claim 6, wherein the intestinal disease is ulcerative colitis or Crohn's disease. 9. A method for treating heart disease, brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction, allergic rhinitis, hay fever, conjunctivitis, gingivitis, or alveolar pyorrhea. A composition for mucosal administration. 10. Heart disease, brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction, allergic rhinitis, hay fever,
The composition for mucosal administration according to claim 9, further comprising a therapeutic agent for conjunctivitis, gingivitis, or alveolar pyorrhea. 11. Claims 1 to 3 for use in nutritional supplementation.
The composition for mucosal administration according to any one of 1. 12. The composition for mucosal administration according to claim 11, which contains a nutritional supplement component other than the oxidized coenzyme Q represented by the formula (1) and the reduced coenzyme Q represented by the formula (2). . 13. A composition for mucosal administration according to any one of claims 1 to 12 for application to humans. 14. Claims 1 to 12 for application to animals.
The composition for mucosal administration according to any one of 1. 15. The composition for mucosal administration according to claim 14, which is applied to dogs and / or cats. 16. The composition for mucosal administration according to claim 14, which is applied to a racehorse. 17. A method for delivering coenzyme Q in vivo, which comprises applying the composition for mucosal administration according to any one of claims 1 to 15 to the mucosa of humans or animals.