CA1216239A

CA1216239A - Percutaneous pharmaceutical preparations for external use

Info

Publication number: CA1216239A
Application number: CA000455119A
Authority: CA
Inventors: Yoshiaki Uda; Masayuki Yamada
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 1983-05-26
Filing date: 1984-05-25
Publication date: 1987-01-06
Also published as: ES532812A0; HUT35515A; EP0127468B1; ES8602774A1; DD223359A5; DK243084D0; EP0127468A3; HU191659B; DE3480262D1; US4731241A; EP0127468A2; DK243084A; NO842103L

Abstract

Abstract of the Disclosure A percutaneous pharmaceutical preparation for external use containing N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) and an absorption promoter selected from the group consisting of aliphatic monoalcohols of 10 to 22 carbon atoms, aliphatic monoamides of 7 to 17 carbon atoms and aliphatic monoamines of 10 to 16 carbon atoms gives a high blood concentration of molsidomine over a long time period when applied onto the human skin.

Description

Percutaneous pharmaceutical preparations Eor external use The present invention relates to a drug for percutaneous absorption which contains N-ethoxycarbonyl-3-morpholinosydno-nimine known as the generic name of "molsidomine", and the process for production thereof.
More particularly, the present invention relates to a percutaneous pharmaceutical preparation Eor external use which is adapted to permit absorption of molsidomine through the skin at an optional application site, without requiring oral administration or parenteral administration, and to thereby allo~ pharmacological effects of molsidomine to be sustained over a long time period, and the process for production thereof.
Molsidomine is a well-known compound having few side effects and excellent vasodilator activity, and has hereto-fore been used as a therapeutic agent for the coronary insuf-ficiency, hypertensive heart disease, myocardial infarction, angina pectoris, etc.
In the treatment of these dis~ases, it is desirable that molsidomine be administered in such a manner that it will be absorbed over a sustained time period and at a quanti-tative rate such that its blood concentration will consistently be higher than its effective concentration and lower than the critical concentration conducive to the onset of side effect. To meet these requirements, it has, for instance, been proposed and practiced to provide the drug Eor oral administration in the form of specially coated granules or beads, but this and other ~easures have not proved fully satisfactory, especially in terms of duration of effect.

Under the circumstances the present inventors explored the possibility to let molsidomine be absorbed thro~gh the skin to thereby allow its pharmacological effects to be sustained over a long time period and at the same time, either prevent or mitigate its possible adverse reactions.
By nature, some drugs are readily absorbed through the skin, while others are substantially not absorbed through the skin. Administered alone by the percutaneous route, molsidomine is not well absorbed and, there~ore, it cannot attain an effe~tive concentration in the blood by this route.
Therefore, some ingenuity is required for promoting the percutaneous absorption of molsidomine. Researches have been done towards solving this problem but no eEfective percutaneous absorption promoters have been discovered as yet.
In the percutaneous absorption of drugs generally, the horny layer of the skin acts as a barrier to the pene-tration of drugs, and in the case of a drug which would hardly be absorbed through the skin, it is important to find a means by which the permeability of the horny layer to the drug may be enhanced. For this purpose, there may be contemplated to find an absorption promoter which may be an agent that will soften and make permeable the h~rny layer r an agent that will expand the hair follicles, or an agent that will change the surface condition of the skin.
However, even if the properties of the horny layer be improved, it does never mean that all kinds of drugs are percutaneously absorbed. The percutaneous absorbability of drugs depends on, and varies considerably with, their physico-chemical 30 properties and the kinds of bases usedfor pharmaceutical preparations. It is, thus, acknowledged that there exists no absorption promoter agent that would assure percutaneous absorption o~ all kinds of drugs [Iyakuhin Kaihatsu Kiso Koza IX, Seizai Sekkei Ho (Lectures on Fundamentals of Dru~
35 Development IX, Drug Design) (1) p. 95-107, published by Chi~in Shokan in Japan]. That is to say, we have to search z~

for an individualized absorption promoter for each kind of drug.
For the vasodilator drug molsidomine, the present inventors attempted to promote its percutaneous absorption by adding a variety of compounds which are known to moisturize the horny layer, e.g. sorbitol, glycerin, propylene glycol, etc., and many compounds which are known to soften the horny layer, e.g. salicylic acid, methyl salicylate etc., but none of them proved meaningfully effective. Then, the present inventors attempted at a systematic classi~ication of compounds which could contribute to the percutaneous absorption of molsidomine and performed a series of experiments. As a result, certain aliphatic compounds were found to cause a marked promotion of percutaneous absorption of molsidomine and enable the drug to remain in the blood at a sufficient concentration for the development of its pharmacological effects over a sustained time period. The finding was followed by further investigations, which have resulted in the develop-meni of tne present invention.
Thus, the pres~nt invention relates to a percutaneous pharmaceutical preparation ~or external use which contains N-ethoxycarbonyl-3-morpholinosydnonimine and at least an absorption promoter selected from the group consisting of aliphatic monocarboxylic acids of 5 to 30 carbon atoms, aliphatic monohydric alcohols of 10 to 22 carbon atoms, aliphatic monoamides o~ ~ to 1~ carbon atoms and aliphatic monoamines of 10 to 16 carbon atoms, and the process for production thereof.
The aliphatic monocarboxylic acids of 5 to 30 carbon atoms include saturated, unsaturated, straight and branched fatty acids. The saturated fatt~ acids include those having 5 to 30 carbon atoms such as valeric acid, isovaleric acid, carproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, hehenic acid, lignoceric acid, cerotic acid, montanic acid, melissic 3$

acid, etc. Preferred are caprylic acid which contains 8 carbon atoms through behenic acid which contains 22 carbon atoms. Said unsaturated fatty acids include such olefinic acid as octenoic acid which contains 8 carbon atoms through arachidonic acid which contains 20 carbon atoms. Preferred are lauroleic acid which contains 12 carbon atoms through arachidonic acid which contains 20 carbon atoms. The aliphatic monohydric alcohols of 10 to 22 carbon atoms may be saturated or unsaturated. The saturated alcohols include capryl alcohol which has 10 carbon atoms through behenyl alcohol which has 22 carbon atoms. Preferred are lauryl alcohol which has 12 carbon atoms through stearyl alcohol which contains 18 carbon atoms. The unsaturated alcohols include such olefinic monohydric alcohols as decenol which has 10 carbon atoms through docosenyl alcohol which has 22 carbon atoms, preferably those having 12 to 18 carbons. The aliphatic monoamides of 8 to 18 carbon atoms may be saturated or unsaturated.
The saturated amides include octylamide which has 8 carbon atoms through stearylamide which has 18 carbon atoms. Prererred are laurylamide which contains 12 carbon atoms through myristyl-amide which contains 14 car~on atoms. The unsaturated amides include such olefinic monoamides as octenoic amide which has 8 carbon atoms through oleic amide which has 1~ carbon atoms f preferably those having 12 to 14 carbon atoms. The aliphatic monoamines of 10 to 16 carbon atoms may be saturated or unsaturated. The saturated amines include decylamine which has 10 carbon atoms through hexadecylamine which has 16 carbon atoms, and preferably are decylamine having 10 carbon atoms through dodecylamine which contains 12 carbon atoms.
The unsaturated amines include such olefinic amines as decenyl amine which has 10 carbon atoms through hexadecenyl amine which has 16 carbon atoms, preferably those having 10 to 12 carbon atoms~
The aforementioned absorption promoters may be used either alone or in combination, In the present invention, such absorption promoter or promoters can be effectively `2~

used in a proportion of at least 1/100 weight part to 1 weight par~ of molsidomine and preferably used in a proportion of at least 1/10 weight part. While the proportion of such absorption promoters in the entire pharmaceutical preparation cannot be specified in general terms, it is preEerably not less than 0.1~ by weight, more preferably 1 to ~0~ by weight.
The proportion of molsidomine in the pharmaceutical prepa-ration according to this invention is generally 0.1 to 40%
by weight, preferably 1 to 30% by weight, and 5 to 100 mg per dose unit.
The percutaneous pharmaceutical preparation can be produced by compounding or mixing with a absorption promoter.
In addition to said absorption promoter, the pharma-ceutical preparation according to this invention can be compounded with a base component, any of alcohols such as benzylalcohol, propylene glycol, sorbitol solution, glycerin, polyethylene glycol, etc., vegetable oils and fats such as olive oil, safflower oil, cottonseed oil, etc., animal oils and fats such as squalene, squalane, lanolin, etc., paraffins such as liquid paraffin, vaseline, etc.~ higher fatty acid esters such as isopropyl myristate, isopropyl palmitate, diethyl sebacate, glycerin ester such as monoacetin, diacetin, capryltriglyceride, caprintriglyceride, etc., C c/~O~O~v 2 ~ ~`~ f ~ e ~) or/and ethyl ~9~ methyl ~h~64}Y4, etc. in suitable proportions, although the preferred proportion of such base component is generally 10 to 95% by weight.
In addition to the absorption promoter and base component mentioned above, the pharmaceutical preparation for percutane-ous absorption according to this invention may contain a component for controlling the percutaneous absorption of molsidomine to thereby ensure a sustained blood concentration, such as solid paraffin, bee's wax, carnauba wa~, hydrogenated castor oil, lanolin, polyethylene glycol (eOg. P~G 400, 1500, 4000), sperm wax, glyceryl monostearate~ cholesterol, ~'a~"~ pO/ Lr~
35 ~b~æb~, carboxymethylcellulose, carboxyethylcellulose, silicone resin, etc., in suitable proportions, although

2~

the preferred proportion of such controlling co~ponent is generally 10 to 95% by weight.
In accordance with this invention, a pharmaceutical composition ~or percutaneous absorption containing the aEore-mentioned components can be applied to the human body surface,either as it is or as formulated into any of the hydrophilic, oleagenous and emulsion forms mentioned in the ~apanese Pharmacopeia. Or the pharmaceutical composition can be absorbed or deposited on a suitable support material and applied to the skin in such application forms as adhesive tape, sheet, patch or the like.
The support material mentioned just above is exemplified by high polymer film such as polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, polytetra-fluoro-ethylene cellulose acetate, cellulose nitrate, poly-acrylonitrile, ethylene-venylalcohol copolymer and poly-dimethylsiloxane, woven fabric, non-woven fabric made of, for example, nylone, polyester, polypropylene and polyethylene, paper and so forth. When the composition is made available in the form of an adhesive tape, sheet or pàtch, the adhesive agent may be selected from among materials of polyalkyl-vinylether, polyalkyl acrylate, polyisobutylene, natural rubber, synthetic rubber and other type. Further, for the purpose of imparting suitable degrees of plasticity and adhesivity, it is possible to add animal or vegetable oil, vaselin, lanolin or the like, or/and, as an antieruption component, an antihistaminic agent such as diphenhydramine, etc.
As stated in detail hereinbefore, the pharmaceutical preparation for percutaneous absorption according to this invention is characterized in that after mere application to tl~e human skin, its pharmacological effects are sustained for a prolonged time with the side e~fects being mitigated.
The invention will be described in further detail b~ way of examples which, however, should no means be construed as limiting the scope of the invention.

~2~ 3~

ExamPle 1 ~

The components indicated in ~able 1 were mixed and dissolved to prepare coating samples A through D.
Five male SD-JCL rats with a mean body weight of 250 g were anesthetized with pentobarbital and the abdominal hairs were clipped with an electric clipper (20 cm2: 5x4 cm).
Each of coating samples A though D was then coated on the clipped areaO At 1, 2, 4 and 6 hours after application (till 8 hours for evaluation of sustained effect), 0.5 ml of venous blood was collected from the tail vain of each rat and the plasma concentration of molsidomine was determined by the ~ollowing procedure.
Determination of plasma concentration of mclsidomine The venous blood sample was centrifuged and the plasma was separated. A 0.2 ml portion of the plasma was extracted with 1 ml of water and 5 ml of chloroform, and from 4 ml of the chloroform layer, the chloroform was evaporated.
The residue was dissolved in 0.2 ml of a mi~ture of 0.05 M sodium acetate, ace~onitrile and tetrahydrofuran (70:30:0.2, v/v) J and 50 ~ of the solu~ion was subjected to li~uid chromatography. The column used was ~-Bondapak C18.
Evaluation of percutaneous absorption The percutaneous absorption characteristic of molsidomine was evaluated in terms of AUCo, the area under the plasma concentration-time curve up to ~ hours after administration.
The sustained effect of molsidomine was evaluated by investi-gating the number of hours during which the concentration of molsidomine in the rat plasma remained at a level not less than 1 ~Ig/ml. The results are set forth in Table 1.

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Table 1 ~ 5~ code I ~ Molsidomine 10 10 ¦ 10 ~ Oleic acid ¦ 20 ~ _ _ o Isopropyl myristate 40 Isopropyl palmitate 40 Propylene glycol 170 190150 150 .
o ~ AUCo value (~g.hr/ml)40.3 2.5 0

3-~ ~ Period for which plasma ~ ~r~ concentration is maintained 4 0 0 0 o o ~ not low~r than 1 ~g/ml ~hr.) _ _ 3~

g It is apparent from Table l that the AUCo value of 40.3 ~g hr/ml for sample A of this invention was 15.9 times as large as the AUCo value of 2.5 ~9 hr/ml for sample B
which contained no absorption promoter. In the duration of effective plasma concentration, also, sample A was by far superior to sample B.
In the case of samples C and D, in which isopropyl myristate and isopropyl palmitate were respectively used in lieu of the oleic acid in Sample A, molsidomine was not detected in the rat plasma. It was thus found that even higher fatty acids did not promote the percutaneous absorption of molsidomine when they were used in the form of esters~
Reference Example l In a mixture of 20 mg of lauric acid, which is a per-cutaneous absorption promotor according to this invention, - and 177 mg of propylene glycol was dissolved 3 mg of clonidine to prepare a coating sample. Using this sample, a percutaneous absorption test was conducted in the same manner as Example l. The plasma concentration of clonidine was determined by the following procedure.
The venous blood was centrifuged and the plasma was separated. ~ 0.~ ml of the plasma was extracted with l ml of 0.01 N NaOH and 5 ml of chloroform, and from 4 ml of the chloroform layer, the chloroform was evaporated.
The residue was dissolved in 0.2 ml oE a mixture of 0.05 M sodium acetate, acetonitrile and tetrahydrofuran (70:3~:0.2, v/v), and 50 ~l of this solution was subjected to liquid chromatography to determine the clonidine concentration.
A column of ~-Bondapak Cl8 was employed. The evaluation of percutaneous absorption was carried out in the same manner as described in ~xample l. It was found that clonidine was not detected in the blood, indicating that lauric acid which is a percutaneous absorption promoter used in this invention is not effective in the case of clonidine. Similar tests were conducted usin~ oleic acid, lauryl alcohol, oleinamide Z~

and laurylamine as well but all of -them were ineffective for clonidine as was lauric acid.
Example 2 In a mixture of 30 mg of lauric acid, which is a per-cutaneous absorption promoter according to this invention,and 160 mg of propylene glycol 160 was dissolved 10 mg of molsidomine to prepare a coating sample. The percutaneous absorption test in rats, determination of the blood concen-tration of molsidomine, and the evaluation of pefcutaneous absorption characteristics were all conducted in the same manner as E~ample 1. The AUCo value of the above sample was 35.0 ~g hr/ml, which was 14 times as large as the AUCo value of sample B in Example 1, indicating that the sample according to this example offers a remarkably enhanced per-cutaneous absorption. Moreover, the percutaneous absorptioneffect of the abo~e composition lasted for 5 hours.
- Example 3 In a mixture of 20 mg of lauryl alcohol, which is a percutaneous absorption promoter according to this invention, and 170 mg o~ polyethylene glycol 400 was dissolved 10 mg of molsidomine to prepare a coating sample. The percutaneous absorption test in rats, determination of the blood concen~
tration of molsidomine, and the evaluation of percutaneous absorption characteristics were all conducted in the same manner as Example 1. The ACUo value of 31.3 ~g hr/ml for this preparation was 12.5 times as large as the AUCo value for sample ~ of Example 1, indicating a remarkably enhanced percutaneous absorption. The percutaneous absorption effect of this preparation lasted for 5 hours.
Example 4 20 mg of molsiæomine was dissolved in a mixture of 40 mg of oleic acid, which is a percutaneous absorption promoter according to this invention, and 340 mg of lanolin under warmin~ (60C) and the solution was gradually cooled to give a coating sample. The percutaneous absorption test in rats, determination of the blood concentration of molsidomine 2~3~

and the evaluation of percutaneous absorption characteristics were all conducted in the same manner as Example 1. The AUCo value oE 20.0 g hr/ml for the above preparation was 8 times as large as the AUCo value for sample B of Example 1, indicating a remarkably enhanced absorption. Moreover, the percutaneous absorption efEect of the preparation lasted for more than 8 hours.
Example 5 20 mg o~ molsidomine was dissolved in a mixture of ~0 mg of oleic acid, which is a percutaneous absorption promoter according to this invention, and 340 m~ of poly-ethylene glycol 1500 under warming, and the solution was gradually cooled to give a coating sample. The percutaneous absorption test in rats~ determination of the blood concen-tration of molsidomine, and the evaluation of percutaneousabsorption characteristics were all conducted in the same manner as Example 1. The AUCo value of 22.8 ug hr/ml for this preparation was 9.1 times as large as the ~UCO value of sample B, indicating a remarkably enhanced absorption~
Moreover, the percutaneous absorption effect of the prepa~
ration lasted for more than 8 hours.
Exam~le 6 The components indicated below in Table 2 were mixed and dissolved to prepare coating samples E through U. For each of samples E through U, the blood concentration and sustained effect were evaluated in accordance with the methods described in Example 1. The results are set forth in Table 2.

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. ~ o ~ o~ 0 ~ r ~ 'D ~ -~ D U C .C ~
~ ~_ U~ Sl~ 'U ~11 (~ U l U UO O 'O~ ":~S ~ ~ ~: ~: ~ ~1 ~1 ~: a) ~a~
~n o . . o o o o 1~ ~ ~ Q ~ U .,~ ~i U ~ S 3 E ~ ~
,~ a~ o ~ ~I ~ O ~ a~ v u ~ Ql ~, U ~ .,~ ~ ~ O ~: ~ ~ .1 O r~ ~ ~1 ~1) Q~ r~ Q~ r~ ~1 a) ,~ U ~1 ~J ~J ~ ~ O O h ~ ~ ~
a ~ ~n O u ~ ~ ~ _ o u ~ o o ~ ~ ~ ~ ~ v ~ ~ }, ~ v V

V U: O O 0 V ~ U
U 5~ ~ _ s _ ~ U
~ ~.~
' O _ _ ~S

Example 7 Preparation of Patch Flfty mg of molsidomine was added to a mixture solution of 20 mg of oleic acid and 1930 mg oE propylene glycol and dissolved thoroughly to give a percutaneous absorption phar-maceutical composition.
A container having a size of 5cm x 6cm and having an opening at one side was prepared by heat-sealing a polyethylene-laminated aluminum foil as a backing and a high-density polyethylene film (Highpore~ 2200, Asahi Chemical Industry Co., Ltd.) as a rate controlling membrane for molsidomine in the composition.
A sheet of non-woven fabric made from polypropylene having a 2mm thickness and 5cm x 4cm size was inserted into the container into which was poured 2 g of the above-mentioned composition.
The container was heat-sealed at the opening part and trimmed, and this trimmed part was coated with an acryl-type adhesive agent for a pressure sensitive contact adhesive, followed by ~oining the coated part with a protective peel strip to prepare a patch.
By applying the thus-prepared patch onto a site of breast, abdomen or back of a patientr a given amount of molsidomine can be absorbed through the skin to allow its 25 pharmacological effects to be sustained for a long time period.
Example 8 PreParation of TaPe To a mixture solution of 100 mg of lauric acid, 1000 mg of polyethylene glycol 400 and 800 mg of propylene glycol was added 100 mg of molsidomine. The whole mixture was stirred at room temperature to become a complete composition for a percutaneous absorption pharmaceutical composition.
In 10 m~ chloroform was dissolved 6 g of ethylene-vinyl-acetate copolymer, the content of the latter being 28 weight :32~

~, to which was added ~ g of the solu-tion containing 100 mg oE molsidomine. The mixture was spread on a polyethylene film to allow its thickness after drying to become 100 ~m.
After drying, the surface was covered with a protective peel strip and cut it into a desired size to prepare a tape.
By applying the thus-prepared tape onto a site of breast, abdomen or back of a patient, a given amount of molsidomine is absorbed through the skin to allow its pharmacological effects to be sustained for a long time period.
Example 9 Preparation_of _atch To a mixture of 200 mg of oleic acid, 600 mg of propylene glycol, 500 mg of polyethylene glycol 1500 and 600 mg of lS monoacetin was added 100 mg of molsidomene. The whole mixture was heated to give a solution.
A container having a size of Scm x 6xm was prepared by heat-sealing a polypropylene-laminated aluminium ~oil as a ~ac~ing and a polypropylene film (DURAGARD 2400, Polyplastic Co. Ltd.). To this container was poured 2 g of the above-mentioned solution. The container was heat-sealed at opening part to give a patch preparation according to a manner similar to that of Example 7. On to thus patch preparation was spread an acryl-type adhesive agent with a thic~ness of about 10 ~Im, which was covered with a protective peel strip ~S to prepare an object composition.
By applying the thus-prepared patch onto a site of breast, abdomen or back of a patient, a given amount of molsidomine is absorbed through the skin to allow its pharma-cological e~fects to be sustained for a long time period.
Example 10 Preparation of Patch A mixture of 50 mg o~ lauric acid, 200 mg of propylene glycol, 700 mg of polyethylene glycol ~00 and 850 mg of 35 polyethylene glycol 4000 was melted by heating at 90C, to which was dissolved 200 mg of molsidomine.

Onto a non-woven fabric of 5cm x ~cm in size rnad oE
polypropylene was spread evenly 2 g of the above-mentioned solution, which was fixed on a backing.
The thus-prepared composition was trimmed, and this trimmed part was coated with an acryl-type adhesive agent, for a contact adhesive followed by joining the coated part with a protective peel strip to prepare a patch.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A percutaneous pharmaceutical preparation for external use which comprises N-ethoxycarbonyl-3-morpholinosydnonimine and at least one absorption promoter selected from the group con-sisting of aliphatic monocarboxylic acids of 5 to 30 carbon atoms, aliphatic monoalcohols of 10 to 22 carbon atoms, aliphatic mono-amides of 8 to 18 carbon atoms and aliphatic monoamines of 10 to 16 carbon atoms.

2. A percutaneous pharmaceutical preparation claimed in Claim 1. which further comprises 10 to 95% by weight based on the preparation of at least one base component.

3. A percutaneous pharmaceutical preparation claimed in Claim 2, wherein the proportion of the absorption promoter is at least 0.01 weight part relative to N-ethoxycarbonyl-3-morpholino-sydnonimine.

4. A percutaneous pharmaceutical preparation claimed in Claim 2, wherein the proportion of N-ethoxycarbonyl-3-morpholino-sydnonimine and the absorption promoter to the whole preparation are 0.1 to 40% by weight and more than 0.1% by weight, respectively.

5. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, wherein the absorption promoter is a saturated fatty acid of g to 22 carbon atoms.

6. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, wherein the absorption promoter is an unsaturated fatty acid of 12 to 20 carbon atoms.

7. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, wherein the absorption promoter is a saturated aliphatic monoalcohol of 12 to 18 carbon atoms.

8. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, which is absorbed or deposited on a support material suitable for the application of the preparation to the human body skin.

9. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, which is deposited in a container mounted on a patch and adapted for the application of the preparation to the human body skin.

10. A percutaneous pharmaceutical preparation claimed in Claim 2, 3 or 4, which is absorbed or deposited on an adhesive sheet, tape or patch suitable for the application of the prepara-tion to the human body skin.

11. A process for the production of a percutaneous pharma-ceutical preparation for external use, which process comprises compounding or mixing N-ethoxycarbonyl-3-morpholinosydnonimine and at least one absorption promoter selected from the group con-sisting of aliphatic monocarboxylic acids of 5 to 30 carbon atoms, aliphatic monoalcohols of 10 to 22 carbon atoms, aliphatic mono-amides of 8 to 18 carbon atoms and aliphatic monoamines of 10 to 16 carbon atoms.

12. A process claimed in claim 11, wherein at least one base component in an amount of 10 to 95% by weight based on the prepa-ration is also compounded or mixed.

13. A process claimed in claim 12, wherein the proportion of N-ethoxycarbonyl-3-morpholinosydnonimine and the absorption promoter to the whole preparation are 0.1 to 40% by weight and more than 0.1% by weight, respectively.

14. A process claimed in claim 12 or 13, which further comprises absorbing or depositing the thus obtained mixture on a support material suitable for the application of the preparation to the human body skin.