JP2648508B2 - Transdermal absorption enhancer - Google Patents

Description

The present invention relates to a preparation having a transdermal absorption promoting action.

[Problems to be solved by conventional technology and invention]

Oral administration or injection is widely used as a drug administration method.However, oral administration has drawbacks such as insufficient absorption of medicinal components and side effects such as gastrointestinal disorders. doing. On the other hand, administration by injection causes a side effect such as shock or a burden on the patient.

In recent years, external preparations by transdermal administration of drugs have been studied in order to reduce side effects of pharmaceuticals. However, in many cases, administration with an external preparation does not provide sufficient transdermal absorbability.

 Topical formulations allow the drug to maximize its therapeutic effect
In order for the drug to be effective,
It is necessary to move to the affected area and reach the affected area. That
Drugs that are dispersed or dissolved in the base in external preparations
Various measures have been taken to increase the transdermal absorbability of products.
You. For example, after applying an external preparation to the affected area,
There is a law. However, seal therapy has given patients discomfort
Depending on the location, implementation may be difficult. In addition,
Dimethylacetamide, dimethyl
Sulfoxide, dimethylformamide, Azon (Azon
e) Known substances such as (N-methyl-2-pyrrolidone)
All of which have been reported,
Not always satisfactory in terms of safety and usability
No.

On the other hand, prednisolone, which is an anti-inflammatory steroid used in the experimental examples of the present invention, is known to have a physiological activity such as an anti-inflammatory effect and an immunosuppressive effect, and is widely used.
For example, in the treatment of rheumatoid arthritis and the like, it has been applied as an oral preparation or an injection and has been effective, but side effects such as shock have been reported. In addition, there is an example in which prednisolone is used as an ointment or a cream, but it does not penetrate into the skin even when applied to an affected area, does not reach the affected area, and cannot exert its effect sufficiently. .

[Means for solving the problem]

In view of the above problems, the present inventors have studied the transdermal absorption promoting action of various crude drugs. As a result, it was found that the extract of acetone extracted from ginger, ginger, rhubarb, and yellow oak listed in the Japanese Pharmacopoeia has a transdermal absorption promoting effect. Therefore, in the present invention, the active ingredients of ginger and ginger were further studied.

Show owl is a perennial plant, Elettaria cardomomum M
It is contained in the fruits and seeds of aton, and the main components are monoterpenoids such as d-α-terpinyl acetate, d-α-terpineol, 1,8-cineole (cineol), and limonen (limonen). It is known to contain much.

Separation and purification of the extract of Shozuku acetone by column chromatography, confirmation of the structure,
Transdermal absorbability was studied.

That is, a commercially available Japanese pharmacopoeia listed in the Japanese Pharmacopoeia was dried, pulverized, cold-immersed in 10 times the volume of acetone for 3 days, extracted three times, filtered, and concentrated under reduced pressure at 40 ° C. or lower to obtain a sample.
When thin layer chromatography of the extract was performed,
The chromatogram of FIG. 1 was obtained.

Next, the extracted extract was fractionated by column chromatography using silica gel as an adsorbent with a mixed solvent of n-hexane: ethyl acetate (20: 1 → 1: 1). Was isolated and purified, and the structure was identified using infrared absorption spectrum (IR) and nuclear magnetic resonance spectrum (NMR). Fraction 1 was terpinyl acetate, and fraction 2 was terpineol.

Similarly, the active ingredient of ginger was examined.

Ginger is contained in the ginger rhizome,
Zingiberene, bisalon
e), α-pinene, camphene
e) It is known that terpenoids such as 1,8-cineole, β-phellandrene, and myrcene are contained. (Varma
KK, Bhattacharyya SG, et.al., Tetrahedron, 18,9
79 (1962), Kami T., Hayashi S., et.al., photochemi
stry, 11,3372 (1972)).

Commercially available ginger in the Japanese Pharmacopoeia was dried, pulverized, cold-immersed in 10 times the volume of acetone for 3 days, extracted three times, filtered, and concentrated under reduced pressure at 40 ° C. or lower to obtain a sample. When the extract was subjected to α-thin layer chromatography, the chromatogram in FIG. 2 was obtained.

Next, the extracted extract was fractionated by column chromatography using silica gel as an adsorbent to isolate gingiberene from fraction 1 and gingiberol from fraction 2, and to perform thin layer chromatography (TLC), infrared absorption spectrum (I
R), nuclear magnetic resonance spectrum (NMR), mass spectrometer (M
The structure was identified using S).

Next, terpinyl acetate, terpineol, which was extracted and isolated from the crude drug components, show porcine,
Using gingiberene and gingiberol, the effect of promoting percutaneous absorption was examined by the following method.

 Ddy male mice weighing 15-25 g (Oriental Bio
Hair removal of the abdomen of Science) using a hair remover and release for 24 hours
After placement, peel off the skin from the depilated area to remove fat, etc.
Was. Remove the peeled skin with a Franz-type diffusion cell (C
(Round Glass Co., USA)
According to the method shown in 1, an aqueous ointment of prednisolone is prepared.
Percutaneous absorbability was studied using this method. Known dermal as control
Azone, an absorption enhancer (N-methyl-
2-pyrrolidone) was used.

As a result, they found that zingiberene, zingiberol, terpineol, and terpinyl acetate all have excellent transdermal absorbability, and have completed the present invention.

That is, the present invention provides a preparation for promoting percutaneous absorption characterized by containing any one of zingiberene, zingiberol, terpineol and terpinyl acetate.

In the present invention, terpinyl acetate, terpineol,
Zingiberen and Zingiberol are added as an auxiliary agent for promoting percutaneous absorption in a commonly used external preparation base, but the amount of these added in the preparation of the present invention is not particularly limited depending on the kind of the medicinal ingredient and the like. , 5 of the total amount of external preparation
% W / V or more is preferable.

In the present invention, terpinyl acetate, terpineol,
As gingiberene and zingiberol, a component isolated and purified from a crude drug component extract or a commercially available compound may be used.

The percutaneous absorption-promoting preparation of the present invention is absorbed by being applied to the skin or hair, etc., and many external preparations expected to have pharmacological effects, for example, liquid sprays, lotions, ointments, creams, gel sols・ Aerosol,
It can be advantageously used for poultices, tapes and the like.

Examples of those in which the use of the percutaneous absorption enhancing preparation of the present invention increases the efficacy are, in addition to prednisolone shown in the following experimental examples, steroidal anti-inflammatory agents such as dexamethasone, non-steroidal anti-inflammatory agents such as indomethacin, Antihistamines such as diphenhydramine, sulfa drugs such as sulfamethizole, antibiotics such as tetracycline, antifungals such as naphthiomate, antineoplastic agents such as actinomycin, analgesics such as aminopyrine, prostaglandin preparations, Ophthalmic agents, psychotropic drugs such as reserpine, antiparkinson agents such as levotoba, cardiotonic agents such as digoxin, antiarrhythmic agents such as propranol hydrochloride, hypertensive agents such as reserpine, but are not limited thereto. Absent.

〔The invention's effect〕

Hereinafter, the effects of the present invention will be described in detail with reference to experimental examples.

Experimental Example 1 (Percutaneous Absorption Test) A prescription of hydrophilic ointment listed in the Japanese Pharmacopoeia as a base was prepared by adding 200 mg each of terpinyl acetate, terpineol, gingiberene, and gingiberol to 10 mg of prednisolone, an anti-inflammatory steroid. , 100 mg of propylene glycol and 690 mg of isopropyl alcohol were added to make a total amount of 1 g, and a hydrophilic ointment suspension was prepared.

Separately, a hydrophilic ointment suspension containing 200 mg of Ringer's solution instead of the transdermal absorption enhancer was prepared and controlled.

 Also, a commercially available transdermal absorption enhancer Aison As well as 200m
g was blended to prepare a hydrophilic ointment suspension, which was used as a control sample.

In the experiment of transdermal absorption, the abdomen of a ddy male mouse weighing 15 to 25 g was depilated with a depilatory cream and wiped with 70% ethanol.
After leaving for 24 hours, only the skin of the depilated portion was peeled off, and after removing fat, the skin was fixed in a Franz type diffusion cell, and after leaving for 1 hour, the above-mentioned adjusted samples 1 to 4 and controls, 2 ml of each control sample was precisely weighed, 8 ml of physiological saline (0.9% NaCl) was added, and the mixture was stirred and mixed at 150 rpm and applied. The application area is 1.77 cm ² .

After applying each sample, 10 hours and 20 hours later, the skin was collected from the cell, the drug was extracted by a conventional method, and the remaining amount of the drug was measured by the following high-performance liquid chromatography conditions.
The skin absorption was measured.

<High-performance liquid chromatography conditions> Stationary phase: ODS-based reverse phase chromatography (silica gel) Mobile phase: 40% acetonitrile Flow rate: 0.1 ml / min Detection: 254 nm ultraviolet absorption The results are shown in FIG.

 FIG. 3 shows that the dermal absorption enhancer of the present invention, terpini acetate
Le, terpineol, gingiberene, gingiberol
All are control, commercially available transdermal absorption enhancer Aison
It showed a remarkable transdermal absorption promoting effect.

Experimental Example 2 The effect of promoting absorption by changing the concentration of terpinyl acetate and terpineol was examined.

That is, in Experimental Example 1, the addition amount of terpinyl acetate or terpineol was formulated so as to be 5% V / V, 10% V / V, 15% V / V, and 20% V / V. The effect of promoting percutaneous absorption was examined.

 FIG. 4 shows the results.

From this, terpinyl acetate and terpineol were 5%
V / V also shows a remarkable transdermal absorption promoting effect.
Terpineol also showed concentration dependence.

〔Example〕

Hereinafter, the present invention will be described in more detail by examples,
The present invention is not limited to these examples.

Example 1 200 mg of terpinyl acetate was added to 10 mg of prednisolone and mixed, and as a base, 100 mg of propylene glycol and 690 mg of isopropyl alcohol were added to make a total amount of 1 g, thereby preparing a suspension.

Example 2 Prednisolone (10 mg) was mixed with terpinyl acetate (200 mg) and dissolved, and as a base, white petrolatum (250 mg), a hydrophilic ointment listed in the Japanese Pharmacopoeia, and stearyl alcohol (200 m2)
g, 40 mg of polyoxyethylene hydrogenated castor oil and 10 mg of glycerin monostearate were dissolved by heating at 75 ° C. on a water bath and stirred.

To this, methyl paraoxybenzoate and propyl paraoxybenzoate and propylene glycol 120m
g was added and, if necessary, dissolved by heating, and an appropriate amount of purified water was added to make a total amount of 1 g. This was heated to about 75 ° C., and stirred to obtain an emulsion, and then cooled and stirred well until hardened to produce an O / W type ointment.

Example 3 In Example 2, 200 mg of "terpineol" was added instead of "terpinyl acetate", and O / W was performed in the same manner as in Example 2.
Ointment was prepared.

Example 4 In Example 2, 200 mg of "zingiberene" was added in place of "terpinyl acetate", and an O / W ointment was produced in the same manner as in Example 2 below.

Example 5 200 mg of "gingivalol" was added in place of "terpinyl acetate" in Example 2, and O / W was performed in the same manner as in Example 2.
A mold ointment was produced.

[Brief description of the drawings]

1 is a thin-layer chromatogram of an extract of acetone extracted from ginger, FIG. 2 is a thin-layer chromatogram of an extract of acetone extracted from ginger, FIG. 3 is a graph showing the results of Experimental Example 1, and FIG. It is a graph shown.

Claims (1)

(57) [Claims] (1) Zingiberene, Zingiberol, Terpineo
l) a dermal absorption promoting preparation, which comprises any one of terpinyl acetate.