JPH0517205B2 - - Google Patents

Description

Detailed Description of the Invention The present invention is an invention of a medicinal base material for external use, which is made by adding a specific polyethylene glycol to polyacrylic acid and does not contain water. This is an invention of a non-aqueous external medicinal base material that can quickly reach a desired level and maintain that level for a long period of time.

The base material for external medicine must be able to stably hold the drug at the desired high content over a long period of time, and when applied to the body surface, it can quickly transfer a large amount of the drug into the living body to achieve the desired blood concentration. At first glance, contradictory performance is required, such as the ability to reach the desired blood concentration level and the ability to maintain the desired blood concentration level for a long period of time.

From this point of view, we have been investigating the applicability of various substances as base materials for external medicinal use, and have found that combining a specific polyethylene glycol with polyacrylic acid to create a non-aqueous base material is suitable as a base material for external medicinal use. This discovery led to the present invention.

The polyethylene glycol used in the present invention has a molecular weight of 200 or more. By selecting this molecular weight, the biotransportability of the drug can be set to a desired value.

That is, by changing the molecular weight of the polyethylene glycol to be blended, the time required for the blood concentration to reach its maximum value can be freely controlled. In other words, it has become possible to increase the blood concentration of these drugs in a short period of time and maintain that concentration.

In addition, differences in the concentration of drugs in the blood due to differences in the molecular weight of these polyethylene glycols indicate differences in the permeability of drugs into the intradermal or subcutaneous tissue, and this allows for the following drug differences. It is something to do. In other words, for various types of drug delivery such as intradermal tissue only, subcutaneous tissue only, or systemic administration, changing the base material of the gel ointment will change the transdermal absorption rate or intradermal absorption rate of the drug. It can be applied to any shape or purpose.

If this value is less than 200, which is a low degree of polymerization, the polymer itself tends to be easily absorbed by the living body and is not suitable for the purpose of the present invention.

In addition, if the degree of polymerization is extremely high, it becomes difficult to handle and is not suitable as a medicinal base material for external use.

As the polyacrylic acid used in the present invention, an anhydride is used. Polyacrylic acid dissolves in polyethylene glycol, but in order to speed up the dissolution process, first dissolve the acrylic acid in a low boiling point solvent such as alcohol, mix it with polyethylene glycol, and then remove the alcohol if necessary. Bye. The alcohol used in this case may be monovalent or polyvalent, and glycerol such as methyl alcohol, ethyl alcohol, and propyl alcohol can also be used.
Note that hydroxypropylcellulose can also be used in almost the same way as polyacrylic acid.

All of the substances described above are listed in the Japanese Pharmacopoeia, and do not have irritating properties, so there are no particular problems when using them as medicinal base materials for external use.

The external medicinal base material of the present invention can have a viscosity of 1,000 to 8,000 centipoise at room temperature depending on the selection of materials, and maintains a generally stable viscosity range from a low temperature of about 10°C to a relatively high temperature of slightly over 40°C. show. Even after 6 months at 40°C, almost no change in properties was observed, and it remained in the form of a transparent, glossy gel.

The base material for external use of the present invention has very little interaction with common drugs, so it can be used in combination with various drugs to form external drugs.

That is, topical anti-inflammatory, analgesic, and antipruritic agents containing active ingredients such as menthol, camphor, oxybutazone, and indomethacin, as well as bleomycin, 5
- Topical anti-skin cancer and malignant melanoma agents containing active ingredients such as FU, mitomycin, and hydroxyurea; topical anti-skin infection agents containing meclizine hydrochloride as an active ingredient; and nitroglycerin as an active ingredient. It can also be used as a topical vasodilator or a cosmetic product containing vitamin C, vitamin E, etc. as an active ingredient.

In order to explain the present invention in more detail, the following examples are shown, but the present invention is not limited thereto.

Example 1 (i) Method for preparing oxyphenbutazone ointment First, oxyphenbutazone is dissolved in 20 g of polyethylene glycol having a molecular weight of 200 at an arbitrary concentration.

Next, 20 g of a 2.5% (wt/vol) polyacrylic acid ethanol solution is heated while stirring to evaporate as much of the ethanol as possible. The previously prepared polyethylene glycol solution of oxyphenbutazone is added to this, and the ethanol is completely evaporated to form a gel ointment.

In this case, when it is necessary to adjust the viscosity of the ointment, it is effective to add glycerin.

(ii) Experimental method for percutaneous absorption of gel ointment Using a gel ointment containing 50% (wt/vol) oxyphenbutazone, the concentration of oxyphenbutazone absorbed through the skin in the blood was determined by the following experimental method.

That is, 20-day-old male rats were used;
The rat's abdomen was shaved and cleaned.

Three grams of 5.0% oxyphenbutazone ointment was applied to an 18 cm ² abdominal skin area of the rat.

After that, blood from the thigh of the rat is collected every predetermined time.
ml was collected, and the oxyphenbutazone contained therein was recovered from the plasma by chloroform extraction. Its concentration was determined by high performance liquid chromatography.

(iii) Results of transdermal absorption experiment of gel ointment Figure 1 shows the change in blood oxyphenbutazone concentration over time after application of the gel ointment.

As shown in FIG. 1, the concentration of oxyphenbutazone in the blood reaches its maximum 4 hours after application of the gel ointment, and the value at that time of 1.5 μg/ml is very close to the blood concentration in other oral administrations.

Example 2 In the same manner as in Example 1, 5% (wt/wt/
vol) Oxyphenbutazone ointment was prepared.

Using the ointment, a transdermal absorption experiment of oxyphenbutazone was conducted in rats using the same procedure as in Example 1. The results are shown in Figure 2.

As shown in Figure 2, the concentration of oxyphenbutazone in the blood reached its maximum 6 hours after application of the gel ointment, and the value was the same as that of polyethylene glycol with a molecular weight of 200.

From Examples 1 and 2, it can be seen that the gel ointment base material of the present invention is an excellent base material for controlling the blood concentration of oxyphenbutazone.

Example 3 A gel ointment containing indomethacin as a medicinal ingredient was prepared in the same manner as in Example 1. The base material has a molecular weight
200 polyethylene glycol was used to make a 5% indomethacin ointment. A transdermal absorption experiment was conducted in rats using 3 g of this ointment in the same manner as in Example 1. The results are shown in FIG.

Comparative Example 1 In addition, a commercially available water-containing indomethacin ointment was used in a transdermal absorption experiment in rats, and the results are shown in FIG. When compared with FIG. 3, it is clear that the blood concentration of the drug increases extremely slowly.

Comparative Example 2 Polyethylene glycols containing 5% indomethacin and having a molecular weight of 200 and a molecular weight of 600 were prepared, respectively. A transdermal absorption experiment in rats was conducted in the same manner as in Example 1 using 3 g of the polyethylene glycol. The results are shown in Figure 5. As a result, in cartilage based only on polyethylene glycol, the time required for the blood concentration of indomethacin to reach its maximum is not much different between cases where the molecular weight of polyethylene glycol is 200 and 600, and the blood concentration of indomethacin is It can be seen that the time required to reach the maximum value cannot be controlled by the molecular weight of polyethylene glycol. Comparing FIG. 5 with FIGS. 3 and 4, it can be seen that the blood concentration of the drug increases more slowly, indicating that polyethylene glycol alone does not sufficiently absorb the drug through the skin.

Example 4 A 5% nitroglycerin ointment was prepared in the same manner as in Example 1 using polyethylene glycol (molecular weight 600) as the base material.

This ointment 3 was applied to rats in the same manner as in Example 1.
When a transdermal absorption experiment was conducted after applying G, the blood concentration of nitroglycerin reached its maximum level of 1.1μ 6 hours later.
g/ml.

On the other hand, polyethylene glycol (molecular weight 200)
The 5% nitroglycerin ointment based on polyethylene glycol (molecular weight 600) was thoroughly mixed with the previously prepared nitroglycerin ointment based on polyethylene glycol (molecular weight 600), and a transdermal absorption experiment using rats was conducted in the same manner as in Example 1. After 3 hours, the blood concentration of nitroglycerin reached its maximum level of 1.2 μg/ml.
It was possible to maintain almost the same concentration for 7 hours.

Example 5 In the same manner as in Example 1, polyethylene glycol with a molecular weight of 400 and polyacrylic acid (Carbopol, Gutudoritsu) were used as base materials, and vitamin C was added.
An ointment containing vitamin E as a medicinal ingredient was prepared.

According to the results of transdermal absorption experiments in rats, the blood concentration of vitamin C reached its highest level 3 hours after application.
It showed 0.8 μg/ml, and 1.4 μg/ml for vitamin E.

Example 6 In the same manner as in Example 1, an ointment containing 5-FU as a medicinal ingredient was prepared using hydroxypropyl cellulose as a base material.

In a transdermal absorption experiment using rats, the blood concentration reached its maximum value of 0.9 μg/ml 5 hours after application.

[Brief explanation of the drawing]

FIGS. 1, 2, and 3 are diagrams showing changes over time in blood concentration of drugs in Examples 1 to 3, respectively, and FIGS. 4 and 5 are diagrams showing comparative examples 1 and 2, respectively. FIG. In FIG. 5, molecular weight 200 and molecular weight 600 both indicate the molecular weight of polyethylene glycol.

Claims (1)

[Claims] 1. A medicinal base material for external use, which contains polyacrylic acid and polyethylene glycol with a molecular weight of 200 or more, and is substantially free of water.