JPH01131115A - Clebopride percataneous poultice - Google Patents

Abstract

PURPOSE: To obtain a percutaneous patch preparation capable of stably performing a percutaneous absorption for a long time by containing clebopride or a salt thereof into a sticky gel base material consisting of a water soluble polymer, water and a water holding agent. CONSTITUTION: This percutaneous patch preparation is obtained by blending clebopride or a salt thereof with a sticky gel base material obtained by blending a water soluble polymer (e.g.; polyvinyl alcohol), water and a water holding agent (e.g.; glycerol) as indispensable components and as necessary an ultra high water absorbing polymer, an assistant for the absorption, a surfactant, an antioxidant, a preservative, etc., suitably, containing 0.5-60wt.% water soluble polymer, 20-80wt.% water and 5-60wt.% water holding agent based on the amount of the base material and preferably adjusting at pH4-7, and coating the blended material on a substrate (e.g.; a nonwoven fabric). The concentration of the clebopride car the salt thereof is 100-600μg/cm<2> .

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a transdermal patch containing clebopride.
More specifically, the present invention relates to a transdermal patch capable of stably transdermally absorbing the drug clebopride or a salt thereof for a long period of time.

Clebopride has the formula It is a well-known antiemetic.

Conventional technology and problems to be solved Clebopride exerts an antiemetic effect by acting on the trigger zone of the human body's chemoreceptors, and is used as an antiemetic to suppress nausea and vomiting after administration of anticancer drugs and L-dopa preparations, or after surgery. It is used. Clebopride has traditionally been administered orally and is usually available in the form of a salt, eg, clebopride malate.

By the way, although known antiemetic agents containing clevopride exhibit excellent antiemetic effects, they have the following drawbacks due to their oral administration, which poses practical problems.

■ Oral administration during vomiting is not easy, and even if the drug is initially administered orally, there is a high possibility that it will exit the body through vomiting.

■ Absorption from the gastrointestinal tract is highly susceptible to the effects of pH in the gastrointestinal tract, food and drink, etc., and therefore individual differences occur in the absorption level of drugs. Furthermore, if administered in a somewhat excessive amount, side effects such as drowsiness, irritability, and numbness may occur on the psychoneural system, constipation, dry mouth, diarrhea, etc. may occur on the digestive system, and other side effects such as skin eruptions and itching may occur.

■ Because the biological half-life of clebopride is as short as approximately 1.5 hours, it is difficult to achieve effective activity when administered once a day, and furthermore, blood levels must be suppressed below the level where side effects occur. It is difficult to do so.

Therefore, patients are required to take medicine three times a day.

It's being disrespected. With such frequent administration, it is difficult to achieve complete prevention or treatment because patients may forget to take the drug or become ill while sleeping.

In order to overcome the problems of oral administration, the present inventors investigated the possibility of administering clevopride locally in the form of an ointment, gel, or liquid, and found the following problems. Served.

i) These topical preparations have been administered by rubbing on the skin or by spraying, but it is difficult to administer a prescribed dose of clebopride in this way, and it is difficult to administer by hand,
It often stains fingers, clothes, etc. In order to prevent this, it is possible to prevent this staining by covering the application area with gauze or the like, but this is cumbersome.

i) Furthermore, as a result of the solvent in these preparations volatilizing, drug crystals precipitate, reducing the transdermal absorption of clevopride. In addition, if the application site is covered with an appropriate film to prevent this precipitation, it is expected that the moisture content of the epidermal stratum corneum of the skin will become excessive and skin allergic symptoms such as skin rashes and hives will appear. .

Therefore, as a result of further research on other administration methods, we found that by incorporating clevopride or its salt into a specific adhesive gel base consisting essentially of a water-soluble polymer, water, and a water-retaining agent, the adhesive gel base It has been discovered that the drug has a drug release control function, has a reliable adhesive effect on the skin despite its water-retaining properties, and hydrates the epidermal stratum corneum of the skin. Furthermore, these effects work together to improve the quantitative transdermal absorption of the drug, which substantially overcomes the above problems and maintains the lowest effective level of drug concentration in the blood for a long period of time. It was discovered that something could be done.

Structure and Effects of the Invention The present invention provides a drug-retaining layer on a support, comprising clevopride or a salt thereof in an adhesive gel base containing a water-soluble polymer, water, and a water-retaining agent as essential components. The present invention provides a transdermal patch containing clebopride.

Examples of water-soluble polymers used in the present invention include polyvinyl alcohol, gelatin, polyacrylic acid, sodium polyacrylate, methylcellulose, carboxymethylcellulose, lpyrrolidone, gums, dextrins, or appropriately crosslinking these to improve cohesive strength. Examples include things that caused
These can be used alone or in a mixture of two or more. These water-soluble polymers, together with other components of the adhesive gel base, contribute to the development of desired physical properties. The amount of polymer component used varies somewhat depending on the specific polymer used and the type and physical properties of other gel base components, but is usually 0.1 to 70% of the total amount of adhesive gel base (unless otherwise specified). % by weight, hereinafter the same), preferably 0.

It may be selected within the range of 5 to 60%. If it is less than 0.1%, the cohesive force of the adhesive gel base will be insufficient, resulting in unsatisfactory shape retention, and the base may remain on the skin when the patch is peeled off. Furthermore, as a result of the rapid drug release, an amount of drug that is higher than the permeability outside the skin accumulates in the skin, causing skin irritation. Moreover, if the concentration exceeds 70%, the base becomes hard due to the relationship with other ingredients, resulting in insufficient adhesive strength, resulting in poor compatibility with the skin and a decrease in transdermal absorption rate.

The adhesive gel base of the present invention contains water as a drug solvent or drug transfer medium, and the rate of drug release into the skin is greatly affected by the volatilization of water during storage or use of the patch. be done. Therefore, it is necessary to incorporate a water retention agent into the gel base. The amount of water retention agent used is 1%
If it is less than that, the desired water retention effect cannot be obtained.

Examples of the water retention agent used in the present invention include glycerin,
Examples include glycols and saccharides such as 1,3-butanediol, sorbitol, maltitol, and polyethylene glycol, and one type or a mixture of two or more of these can be used. The proportion of water retention agent in the gel base is usually selected in the range of 1 to 70%, preferably 5 to 60% of the adhesive gel base. Moreover, if it exceeds 70%, the gel strength may decrease due to the relationship with other components, and the amount of the drug to be blended may be restricted, which is not preferable. In addition, in order to further improve the water retention property, an ultra-high water-absorbent polymer can also be blended, and such ultra-high water-absorbent polymers include starch
Examples include acrylonitrile graft polymer, starch-acrylic acid graft polymer, starch-styrene sulfonic acid graft polymer, starch-vinyl sulfonic acid graft polymer, polyvinyl alcohol crosslinked product, acrylic acid-acetate a vinyl saponified product, polyethylene glycol diacrylate crosslinked product, etc. , such ultra-super absorbent polymer, in the adhesive gel base, 10% or less, preferably 0
．． It is used in a range of 0.01 to 10%.

The amount of water used in the adhesive patch of the present invention should be determined while taking into consideration the solubility of the drug in water and the shape retention and adhesive strength of the adhesive gel base.
It may be selected within the range of 0 to 90%, preferably 20 to 80%. If it is less than 10%, the blending amount of the drug and water-soluble polymer will be limited, making it difficult to prepare a base with an optimal concentration that exhibits medicinal efficacy, and the mobility of the drug in the base will decrease, resulting in long-term problems. The medicinal efficacy cannot be expected, and the balance between the adhesiveness and shape retention of the adhesive gel base itself is lost. Moreover, if it exceeds 90%, it becomes difficult to blend other ingredients, and the adhesiveness and shape retention of the gel base cannot be maintained.

The adhesive gel base used in the patch of the present invention contains at least one water-soluble polymer as described above, water and a water-retaining agent as essential components, and may optionally contain an absorption aid (stearic acid n- butyl, benzyl alcohol, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, diethyl sebacate, etc.) and a surfactant to emulsify the absorption aid in the water in the base, and to improve the stability of the base. Appropriate amounts of antioxidants and preservatives may be added to make the product last longer.

When adding antioxidants and preservatives, consideration should be given to the effect on drug release control function and skin irritation.

The pH of the adhesive gel base is preferably adjusted between pH 4 and 7 to minimize skin irritation and optimize drug stability.

The adhesive gel base contains clebopride or a pharmaceutically acceptable salt thereof. Experiments with clebopride and its salts have shown that it is advantageous to use the malate, citrate, hydrochloride, methanesulfonate or phosphate salts, and such salts can be used in the application of the present invention. It is preferable to incorporate it into a drug. The concentration of clebopride or its salt in the patch is not critical. This is because it is inevitable that a portion of the active substance always remains on the patch and is not clinically utilized. The concentration is also determined in part by the desired period of time that a patient wears a particular patch. Considering these,
The initial clebopride or salt concentration on the patch is 1100-6
ooI1/cm2, preferably about 300μg/c
m” is specified.

The transdermal patch containing clebopride according to the present invention is produced by blending a desired amount of clebopride or a salt thereof (for example, clebopride malate) as an active ingredient into the above-mentioned adhesive gel base, and then applying an appropriate support to the resulting gel base. It can be manufactured by coating the drug on the support to form a drug-retaining layer on the support. Furthermore, a liner made of a suitable material may be attached to the surface of the drug-retaining layer for the purpose of preventing moisture volatilization in the drug-retaining layer and protecting the core layer during storage.

The support is preferably made of a flexible material that can easily follow the movements of the human body to some extent, such as various nonwoven fabrics, woven fabrics,
Examples include spantex, flannel, or those laminated with polyethylene film, polyvinyl chloride film, ethylene-vinyl acetate film, polyurethane film, etc.

According to the transdermal patch of the present invention having the above configuration, a drug can be released quantitatively, and it is easy to use and can be applied for a long time.

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these examples.

Example 1 Revised W/W% polyvinyl alcohol (average degree of saponification at least 95%) ・・・・・・1O0
5 Glycerin 5.
0 Karayagam ・・・・・・ 1
．． 5 Clebopride malate ・・・・・・
1.5 Purified water ・・・・・・
81.5 A drug-loaded adhesive gel base is prepared using the above ingredients, and then a transdermal patch is manufactured. That is, after mixing and stirring the components other than clebopride malate while heating them to about 40° C., clebopride malate is added thereto and further stirred. Next, the drug-containing adhesive gel base (base pH
5,0) in an amount of 200 g/m" to form a drug-retaining layer. A liner made of silicone-treated polyethylene terephthalate film (PET film) was applied to the surface of the core layer, and cut into a desired size. A transdermal patch was obtained for use by patients.The drug content of the transdermal patch was 300 μg/am''.

Example 2 The same procedure as in Example 1 was carried out except for using the following components, drug content 300 μg/cm 2 and gel base pH 5.
, 0 transdermal patch was manufactured.

Ingredients W/W% polyvinyl alcohol (average degree of saponification at least 95%) 9.
0 Glycerin 15.
0 dextrin...
4.0 Clebopride malate ・・・・・・
1.5 Purified water・・・・・・
-70.5 Example 3 A transdermal patch with a drug content of 300 μg/cm" and a gel base having a pH of 6.0 was produced in the same manner as in Example 1, except for using the following components.

Ingredients W/W% polyvinyl alcohol (average degree of saponification at least 95%) 5.
0 Sodium polyacrylate 3
．． 0゜Carboxymethylcellulose ・・・・・・
3.0 Polyacrylic acid・・・・・・
・ 2.070% Sorbitol ・・・・
...30.0 Clebopride malate...
・・・ 1.5 Purified water ・・・
...55.5 Example 4 A transdermal patch having a drug content of 300 μg/am' and a gel base having a pH of 7.0 was produced in the same manner as in Example 1 except for using the following components.

Ward W/W%
Gelatin ・・・・・・ 3.
0 Polyvinylpyrrolidone ・・・・・・
1.0 Sodium polyacrylate ・・・・・・
3.0 Carboxymethyl cellulose...
・ 3.0 starch-acrylic acid graft polymer [manufactured by Sanyo Chemical Industries, Ltd., Sanu Sent IM-300] ...
0.10 glycerin...
・30.070% Sorbitol ・・・・
...15.0 Clebopride malate...
... 1.5-propyl paraoxybenzoate ...
...0.05 purified water
...43.35 Example 5 Ingredients W/W% Urethane prepolymer ...10.0 Propylene glycol ...10.01.
3-butanediol...8.0 Glycerin...20.0 Clebopride malate...1.
5 Purified water ・・・・・・50
．． 5. Mix the above components and the components other than the medium urethane prepolymer, and apply this together with the urethane prepolymer in an amount of 200 g/m'' on the same support as in Example 1 using a two-component type urethane spray device, PE after gelling of coating film
A T-film liner is applied to the surface of the gel layer and the entire system is cut to obtain a transdermal patch.

The transdermal patch of each Example was subjected to the following pharmacological tests.

Test 1 The amount of clebopride malate permeating through the abdominal skin of rats was quantified by HPLC using a 7-Lantz diffusion cell.

A circular piece with a diameter of 2 cm was punched out from each sample patch (containing 942 μg of clebopride malate) and applied onto the rat skin of a diffusion cell. pH 6 on the register side,
8 phosphate buffer was used (n=6). The results are shown in FIG. The results shown in FIG. 1 show that even if the patch is continued for 24 hours, the drug permeation through the skin continues continuously during that time, and the permeation rate is good.

Test 2 After removing hair from the abdomen of a peagle dog, apply each sample to the removed area in a 5cm x 5cm area (malic acid sauce poplidore, 5m
The paper was cut to a size of 100 g (including g) and pasted on it. Thereafter, blood was collected from the dog at regular intervals, each time at a volume of 5 ml/dog. The amount of clevopride free base in serum was measured by RIA (radioimmunoassay) method, and the results are shown in FIG. At the same time, apomorphine (20 μg/kg) was intravenously injected, and the number of vomitings was measured (n-3). The results are shown in Table 1 below.
Shown below.

Comparative Example 1 A similar experiment was conducted by orally administering a soft gelatin capsule containing 4 mg of clebopride malate.

Example 6 A transdermal patch having a drug content of 525 μg/cm'' and a gel base with a pH of 7.0 was obtained according to the method of Example 1, except that the following components were used.

In this example, the gel base was coated in an amount of 350 g/m''.

Ward Bon W/W%PVA
(Average degree of saponification: at least 95%) 15.0 Propylene glycol 1.0 Dextrin
0.5 clebopride malate 1
．． 5 Purified ice 82.03.5X
A patch having dimensions of 3.5 cm and actually containing 4.82 mg of clebopride as free base or 3.5X5. O
cm and actually clebopride free base 6.8
A patch having 8 mg was tested as described in Test 2 above.

The patch was removed from the heat after 24 hours. Table 2 shows the frequency of vomiting after apomorphine injection.

Table 3 shows the concentration of clebopride free base in the serum of test dogs measured at the indicated times in ng/mQ.

Main features and aspects of the invention may be as follows.

1. A drug-retaining layer comprising clevopride or a pharmaceutically acceptable salt thereof in an adhesive gel base containing a water-soluble polymer, water, and a water-retaining agent as two essential components is provided on a support. A skin patch characterized by:

2. Paste as described in 1 above, where the water-soluble polymer is polyvinyl alcohol, latin, polyacrylic acid, sodium polyacrylate, methylcellulose, carboxymethylserose, polyvinylpyrrolidone, gum, denistrin, or a crosslinking reaction product thereof. agent.

3. The adhesive patch according to 1 or 2 above, which contains 0.5-60% by weight of a water-soluble polymer based on the weight of the adhesive gel base.

4. The water retention agent is glycerin 1,3-butanediyl,
4. The adhesive patch according to any one of 1 to 3 above, which is sorbitol, maltitol, polyethine glycol, or sugar.

5. The patch according to any one of 1 to 4 above, wherein the water retention agent is present in an amount of 5 to 60% by weight of the adhesive gel base.

6. The patch according to any one of 1 to 5 above, wherein water is present in an amount of 20-80% by weight of the adhesive gel base.

7. The adhesive patch according to any one of 1 to 6 above, wherein the adhesive gel base has a pH of 4 to 7.

8. The concentration of clebopride or its salt is 100-600μ
g/cm".

9. The adhesive patch according to any one of 1 to 8 above, wherein the adhesive gel layer is protected with a liner sheet before use.

10. The adhesive patch according to any one of 1 to 9 above, wherein the support is a flexible nonwoven fabric or a flexible laminate.

11. Form a sticky gel base by mixing clebopride or a pharmaceutically acceptable salt thereof with water, a water retention agent, and a water-soluble polymer, and coat the resulting sticky gel base on a support. A method for producing a transdermal patch, characterized by:

12. The method according to 11 above, for producing the patch according to any one of 2 to 10 above.

[Brief explanation of the drawing]

The drawings show the results of pharmacological tests of the transdermal patches of the present invention obtained in Examples. FIG. 1 is a graph showing the relationship between drug permeation time and application time of the patch. FIG. 2 is a graph showing the relationship between the blood concentration of the patch and the application time. Patent Applicant Hortonal Société Anonymous ~・1.

Claims (1)

[Claims] 1. A drug-retaining layer comprising clevopride or a pharmaceutically acceptable salt thereof in an adhesive gel base containing a water-soluble polymer, water, and a water-retaining agent as essential components as a support. A transdermal patch characterized by being provided on the top. 2. Form a sticky gel base by mixing clebopride or a pharmaceutically acceptable salt thereof with water, a water retention agent, and a water-soluble polymer, and coat the resulting sticky gel base on a support. A method for producing a transdermal patch, characterized by: