JPH02243626A - Medical patch - Google Patents

Abstract

PURPOSE:To obtain a medical patch effective for treating sequelae of cerebrovascular disorder and cerebrovascular demensia, having improved percutaneous absorption, maintaining stability of drug, containing ifenprodil or an organic acid salt thereof in a pressure-sensitive adhesive layer under a specific condition. CONSTITUTION:A medical patch containing ifenprodil and/or or an organic acid salt thereof. The medical patch is obtained by adding an acidic substance (e.g. citric acid or succinic acid) and/or a basic substance (e.g. KOH or NaOH) to a pressure-sensitive adhesive layer [e.g. polybutyl (meth)acrylate] containing the active ingredient, adjusting the exposed surface of the pressure-sensitive adhesive layer to pH 7-9 and laminating the pressure-sensitive adhesive layer to a substrate.

Description

Detailed Description of the Invention Ca) Industrial Application Field The present invention relates to a medical patch containing iaenprosol and/or its organic acid salt, which has excellent percutaneous absorption and excellent storage stability. be.

(b) Prior Art Ifenprodil, a piperidi/alcamer derivative, has a blood circulation improving effect, has relatively low side effects, and is highly evaluated for its usefulness. For this reason, in Japan, it is widely used as a cerebral vasodilator and brain λ activation agent to treat various symptoms associated with the sequelae of cerebrovascular disorders, cerebrovascular dementia, and the like.

Ifenprodil and/or its organic acid salts are disclosed in, for example, Japanese Patent Publication No. 47-15348 and Japanese Patent Publication No. 58-24434.
Publication No. 1988, Special Publication No. 24435, Special Publication No. 1983-
It can be manufactured by the method disclosed in Japanese Patent No. 51940.

However, at present, the only approved formulation is a tablet for oral administration, which contains iaenpronol tartrate as the active ingredient. However, when iaenpronol tartrate is administered orally, it is absorbed in the gastrointestinal tract and then enters the liver via the portal vein, and a considerable amount of it becomes a glucuronide conjugate due to the so-called first-pass effect. Tablets are not an effective dosage form due to their low utilization rate.

Therefore, transdermal administration is considered as one of the administration routes to avoid this first-pass effect. As transdermal preparations, liquid preparations, ointments, poultices, and various other external patches are conventionally known.For example, preparations in which ifenprodil is prescribed are disclosed in JP-A-61-186311 for ointments. , an external patch is disclosed in Japanese Patent Application Laid-Open No. 61-18G31G. In either case, iaenpronol tartrate in the salt form is blended, and a water-soluble base is used to sufficiently dissolve it.

(c) Problem to be solved by the invention The stratum corneum of the human body is mainly composed of keratin, and contains large amounts of fat-soluble components such as fat, wax, and cholesterol. Because it has 8!1 ability to control the release of ingredients, the so-called "barrier 8! ability," it is difficult to easily absorb drugs through the skin.
A strong barrier against drugs in the salt form such as iaenpronol tartrate 8! ! Demonstrate one's abilities. Particularly, as mentioned above, when ifenprodil tartrate is dissolved and maintained in a water-soluble base, distribution of the drug from the base to the skin is considered to be extremely low.

On the other hand, rubber-based or acrylic-based polymeric substances with relatively high lipophilicity are used as base materials for tape preparations, but these generally have poor drug solubility, and salt forms such as ifenprodil tartrate. It is extremely difficult to maintain a uniform 'L'8 solution of the drug, and even if it is prepared in a conformal state, the drug contained therein may crystallize during storage, which may impede the transdermal absorption of the drug. there were.

The present invention provides ifenpronol and/or its organic acid salt by laminating a pressure-sensitive adhesive layer containing a surface pa+ regulating substance on a flexible support. The present invention provides a medical patch with improved skin absorption and storage stability.

(d) Means for Solving the Problems The present inventors solved the above-mentioned problems and improved the transdermal absorption of iaenpronol and/or its organic acid salt, as well as the storage stability of the formulation, to treat diseases. As a result of extensive research into patches that are effective for treatment, we have developed a pressure-sensitive adhesive that contains ifenprodil and/or its organic acid salt in combination with an acidic substance and/or a basic substance. When the pl+ of the exposed surface of the hot water layer is adjusted to a range of 7 to 9, the drug transfer of ifenprodil and/or its organic acid salt to the skin surface during removal of the patch becomes easy, and the barrier /,
The present invention was completed based on the discovery that it can easily pass through the stratum corneum as L and has good storage stability.

That is, the present invention is a patch comprising a pressure-sensitive adhesive layer containing iaenpronol and/or its organic acid salt as a medicinal ingredient, laminated on a support, and containing an acidic substance and/or a basic substance. The pressure-sensitive adhesive 11 coexists in the pressure-sensitive adhesive 1 layer, and the pl+ of the exposed surface of the pressure-sensitive adhesive q layer is in the range of 7 to 9.
It is a Shino that is characterized by the following.

The present invention will be explained in detail below.

The pressure-sensitive adhesive layer used in the present invention contains ifenprodil as a medicinal ingredient and/or its organic Il! A layer that contains and retains strange acidic and/or basic substances in order to improve the transdermal absorption of the salt and its storage stability, and is made of an adhesive that adheres closely to the skin surface. Although there are no particular limitations, acrylic pressure-sensitive adhesives such as those listed below are preferred from the viewpoint of adhesion to the skin and stability.

In addition, among these pressure-sensitive adhesives, adhesives with low skin irritation and good drug solubility properties, especially (meth)acrylic acid alkyl esters and adhesives with ether bonds in the molecule (
A pressure-sensitive adhesive comprising a copolymer of a meth)acrylic acid alkyl ester and a copolymerizable fumer other than these is preferably used.

Examples of the acrylic pressure-sensitive adhesives mentioned above include butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, hephthyl (meth)acrylate, and (meth)acrylic acid. Octyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic small R decyl ester, (meth)
A polymer of one or more alkyl (meth)acrylates, such as undecyl acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate, or a copolymer with one or more of these esters. Possible examples include copolymers with monomers.

Examples of copolymerizable monomers include carboxyl group-containing monomers such as (meth)acrylic acid, itafonic acid, crotonic acid, maleic acid, maleic anhydride, and hexamaric acid, styrene sulfonic acid, allyl sulfonic acid, Sulfoxyl group-containing monomers such as sulfopropyl 7-acrylate, (meth)acryloyloxynaphthalenesulfonic acid, acrylamide methylpropanesulfonic acid, acryloyloxybenzenesulfonic acid, (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxypropanesulfonic acid Hydroxyl group-containing monomers such as pull ester, (meth)acrylamide, trimethyl (meth)acrylamide, N-
Amide group-containing acrylic monomers such as butylacrylamide, tetramethylbutylacrylamide, N-methylol (meth)acrylamide, (meth)acrylic acid amide/ethyl ester, (meth)acrylic acid dimethylaminoethyl ester, (meth)acrylic acid alkylaminoalkyl group-containing acrylic monomers such as acid diethylaminoethyl ester, (meth)acrylic acid LerL-butyl ester, (meth)acrylic acid methoxyethyl ester,
(meth)acrylic acid ethoxyethyl ester, (meth)
Butoxyethyl acrylate, (meth)acrylic acid tetrahydrofurfuryl ester, (meth)acrylic acid methoxydiethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester, (meth)acrylic acid methoxypolypropylene glycol ester! 'Acrylic acid alkyl esters having one ether bond in the molecule, vinyl-based monomers such as N-(meth)acryloylamide 782, urethane of acrylic acid,
Functional Qtffi bodies such as fluorophores, acrylic monomers such as incyanate esters, and (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylbiveranone, vinylbiperatone, vinylpyrimidine, vinylpyrrole, vinyloxazole, vinylcaprolactam,
Examples include vinyl-based Jli ffi forms such as vinyl oxazole, vinylthiazole, vinylmorphorylene, and bis(N.N'-tumethylaminoethyl) maleate.

In the present invention, the above-mentioned (meth)acrylic acid alkyl ester and monomer capable of copolymerizing TrJ include various isomers in which the alkyl moiety is linear or branched, and various isomers and derivatives in which the position of the substituent group is different. It is inclusive.

Can be copolymerized with the above (meth)acrylic acid alkyl ester in acrylic pressure-sensitive adhesives! l'. The blending ratio of the fi form is preferably 50 to 99/1 to 50 by weight from the viewpoint of the balance of cohesive force for skin adhesion.

In addition, from the viewpoint of skin irritation, when using a (meth)acrylic acid alkyl ester having an ether bond in the molecule, a (meth)acrylic acid alkyl ester and a (meth)acrylic acid having an ether bond in the molecule are used. The blending ratio of the acid alkyl ester and other copolymerizable monomers is 40-8 015 9-1O/1-40 by weight.
It is desirable that it be 111.

Examples of pressure-sensitive adhesives include silicone rubber,
Polyisoprene rubber, polyisobutylene rubber, polybutadiene rubber, styrene-butanoene (or isoprene)
- Rubber materials such as styrene pro-7 copolymer rubber, acrylic rubber, and natural rubber, vinyl polymer materials such as polyvinyl alkyl ether, polyvinyl acetate, partially saponified polyvinyl acetate, polyvinyl alcohol, and polyvinylpyrrolidone. , cellulose derivatives such as methyl cellulose, carboquine methyl cellulose, and hydroxypropyl cellulose, polysaccharides such as pullulan, dextrin, and agar, polyurethane elastomers, and polyester elastomers can also be used.

In addition, when using the above pressure-sensitive adhesive, if there is a risk that the adhesive may remain on the skin after application due to insufficient cohesive force and cause contamination of the skin, please check the skin adhesion. Appropriate chemical cross-linking treatment (such as copolymerization of !A-linking monomers and addition of external cross-linking resistance) and physical cross-linking treatment (irradiation with ionizing radiation such as electron beams, ultraviolet cross-linking, etc.) to the extent that the properties are not impaired. ) is preferably applied to the composition.

Further, the pressure sensitive adhesive layer used in the present invention has a surface p
An acidic substance and/or a basic substance are coexisting in order to Arf6 the lI in the range of 7 to 9, thereby improving the transdermal absorption of iaenpronol and/or its organic acid salt, Furthermore, stability is also improved.

Although the reason for this is not clear, it is thought to be as follows.

When ifenprodil and an acidic substance and, if necessary, a basic substance are allowed to coexist in the pressure-sensitive adhesive layer, there is no interaction between iaenpronol, the acidic substance or basic substance, and the pressure-sensitive adhesive components. The intermolecular force of On the other hand, when the organic hydrochloric acid of iaenpronol and a basic substance, and if necessary, an acidic substance are allowed to coexist in the pressure-sensitive adhesive layer, the organic hydrochloric acid of iaenpronol is mixed with ifenprodil in the pressure-sensitive adhesive layer. , it becomes a quasi-free state, which is the process of changing into a so-called 7-unit, and while some intermolecular force remains between iaenpronol and the liberated organic acid, the same mutual intermolecular force as above acts. Presumed.

This intermolecular force is different from that in a solution in terms of the interaction mode or size of the molecules, and there are various forces such as forces that do not occur in a solution and forces that are weaker than in a solution. It is thought that it will have good stability like a tape formulation containing only salt and good transdermal absorption like a tape formulation containing only iaenpronol.

In this case, the surface pH is defined as the value when distilled water is dropped onto the surface of the pressure-sensitive adhesive layer and pl+ of the dropped water reaches equilibrium.

When the surface pl+ is less than 7, ifenprodil does not transfer sufficiently to the skin surface, while when the surface pH exceeds 9, skin irritation becomes noticeable. By the way, the base material does not contain water, and therefore the acidic substance contained in the pressure-sensitive adhesive pre-layer is not contained in the base material. The basic substance is different from the commonly referred to pl+ regulator. The stability of the patch prepared in this way is
The results were better when compared with a patch prepared by incorporating only ifenprodil into the base.

As such a basic substance, it is preferable to use a stronger base than iaenpronol, but from the viewpoint of safety, a basic substance within a pharmaceutically acceptable range is preferable, specifically, Examples include =+n compounds such as potassium hydroxide and F hydroxide, amines such as triethanolamine, jetanolamine, triisopropanolamine, and noisopropanolamine, and amino acids such as L-fulginine. From the viewpoint of skin irritation, triethanolamine is preferred.

In addition, the acidic substance is not particularly limited as long as it is within a pharmaceutically acceptable range from the viewpoint of safety, but organic acids are preferably used, and organic carboxylic acids are particularly preferred. Examples include organic carboxylic acids such as citric acid, succinic acid, tartaric acid, maleic acid, heptamalic acid, salicylic acid, and lactic acid.

The content of these acidic substances and/or basic substances is 0.1 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of iaenprocle and/or its acid salt. be.

Further, the content of ifenprodil and/or its organic acid salt as a medicinal ingredient used in the present invention is not particularly limited as long as it exhibits its pharmacological effect, but in the above pressure-sensitive adhesive material, it is 0.1 to 50%. % by weight, preferably 1-30% by weight
range of 20 to 3000 μs/c per unit area.
Theory 2, preferably 100 to 2000 μg/cra2.

Examples of the support for carrying the pressure-sensitive adhesive layer containing the above-mentioned iaenprocle and/or its organic acid salt and the above-mentioned acidic substance and/or basic substance include, for example, plastic film, nonwoven fabric, woven fabric, paper, etc. , metal foil, foamed film, or a combination thereof.

(e) Examples Hereinafter, the present invention will be explained in detail based on Examples, but the present invention is not limited to these in any way, and various modifications are possible. In addition, in the main text, the term "part" indicates the mfi part.

Example 1 55 parts of acrylic acid 2-ethylhexyl ester, 30 parts of acrylic acid methoxyethyl ester, 15 parts of vinyl acetate, and 0.3 parts of azobisisobutyronitrile were charged into four flasks and heated under an inert gas atmosphere for 60 parts. The polymerization reaction was started by raising the temperature to ~63°C, and the reaction was continued for 10 hours while controlling the reaction temperature while dropping 12 parts and 5 parts of ethyl acetate.
Further aging was performed at a temperature of 75 to 80°C for 2118 hours to obtain an acrylic copolymer solution (hereinafter, the copolymer solution obtained in this way will simply be referred to as copolymer solution (A)). .

Iaenprosyl tartrate and triethanolamine were added and mixed to the obtained copolymer solution (Δ) so that the content after drying was 5fflfi% and double plate%, respectively.
Drug-containing 9 on polyester release liner 200/
It was coated at a concentration of Ig/cm2 and dried to form a pressure-sensitive adhesive layer I7!5.

Next, the pressure-sensitive adhesive layer was transferred onto a support made of polyethylene film to obtain a medical patch of the present invention.

Example 2 Same as Example 1 except that iaenpronol tartrate and triethanolamine were added and mixed to the copolymer solution (A) so that the content after drying was 5% by weight and 1% by weight, respectively. A medical patch of the present invention was obtained.

Example 3 Same as Example 1 except that iaenpronol tartrate and triethanolamine were added and mixed to the copolymer solution (A) so that the content after drying was 5% by weight and 4% by weight, respectively. A medical patch of the present invention was obtained.

Example 4 Example except that iaenpronol tartrate and 1-trietamine were added and mixed to the copolymer solution (A) so that the contents after drying were 5% by weight and 1% by weight, respectively. A medical patch of the present invention was obtained in the same manner as in Example 1.

Example 5 Polymer solution! In (A), the contents of ifenprodil tartrate and potassium hydroxide after drying are 51% by weight and 1%, respectively.
A medical patch of the present invention was obtained in the same manner as in Example 1, except that the ingredients were added and mixed in such a manner as to achieve the same weight %.

Example 6 Ifenprodil and citric acid were added to the co-m combination solution (A) with a dry content of 5% by weight and 0°5I [(f
A medical patch of the present invention was obtained in the same manner as in Example 1, except that the ingredients were added and mixed in such a manner as to give i%.

Example 7 Same as Example 1 except that ifenprodil tartrate and triethanolamine were added and mixed to the copolymer solution (A) so that the content after drying was 20% by weight and 8% by weight, respectively. Example 8 95 parts of acrylic acid 2-ethylhexyl ester and 5 parts of acrylic acid were charged into four flasks, and further 4 parts of ethyl acetate were charged.
2.9 parts of azobisinbutyronitrile and 0.3 parts of azobisinbutyronitrile were respectively added, and the reaction was started by raising the temperature to 65"C under an inert gas atmosphere. The reaction was carried out while adding 107.1 parts of ethyl acetate in portions. Polymerize at a temperature of 65 to 67°C for 18 hours.Then, the temperature is raised and aged for 10 hours to form an acrylic copolymer solution (B
) (hereinafter referred to as copolymerization temperature fi(B)) was obtained.

The same procedure as in Example 1 was carried out, except that ifenprodil tartrate and triethanolamine were added and mixed to the obtained copolymer solution (B) so that the contents after drying were 20% and 1%, respectively. Thus, a medical patch of the present invention was obtained.

Comparative Example 1 This product was obtained in the same manner as in Example 1, except that only iaenpronol tartrate was added and mixed to the co-merged solution fi (A) so that the content after drying was 5% by weight. be.

Comparative Example 2 Example 1 except that ifenprodil tartrate and triethanolamine were added and mixed to the copolymer solution (A) so that the contents after drying were 5% by weight and 0.2% by weight, respectively. It was obtained in the same way.

Comparative Example 3 In the copolymer solution (A), the contents of iaenpronol tartrate and citric acid after drying were 5% by weight and 1% by weight, respectively.
This was obtained in the same manner as in Example 1, except that the ingredients were added and mixed so that the following results were obtained.

Surface pl+ measurement test Examples 1 to 8 and Comparative Examples 1 to 8 obtained as above
Cut out the adhesive patch No. 3 into a circular shape of 12IoIIlφ, peel off the liner, and apply 0 on the surface of the exposed pressure-sensitive adhesive layer.
．． Distilled water of IIIN was added dropwise, and the pH value of the dropped water was measured when the pH value reached almost equilibrium. The term "almost equilibrium" as used herein means that the value does not change for 30 seconds or more.

Skin-lit transfer test The patches of Examples 1 to G and Comparative Examples 1 to 3 cut out into 35 lml6X 4015111 were placed on the back of a human being.
After the patch was applied at 5 o'clock, it was peeled off, and the remaining iaenpronol tartrate or iaenpronol was extracted with methanol, and the amount transferred to the skin surface and the transfer rate were calculated from the initial content.

These test results are shown in the Pt51 table.

In addition, the surface pH is the average value of 4 samples for each example and each comparative example, and the skin transfer amount and skin transfer rate are the average value of 3 samples for each example and each comparative example. Each is shown.

In Examples 4 and 5, the skin surface was slightly reddened immediately after peeling off the patch, but it did not cause strong irritation. However, when the surface II exceeded 9, clear erythema or edema was observed.

(Leaving space below) Table 1 Human blood lobular concentration How can I cut out the patch obtained in Example 7 and Example 8 so that the medicinal ingredient content is 40a+H and stick it on the upper back of a human? 4 examiners, 2.8.24.36.48
Plasma concentrations after hours were measured by GC-MS. The detection limit for this method is 200 for plasma l111.
It is pg. Figure 1 shows the average values of the obtained results in a graph (Example 7 is indicated by a black circle in Figure 1, Example 8 is indicated by a black circle in Figure 1).
is shown as a triangle in Figure 1).

For comparison, the results of measuring the plasma concentration upon oral administration (20 mg) are also shown in FIG. 1 (white circles in FIG. 1).

Comparative Example 4 This was obtained in the same manner as in Example 1, except that ifenprodil free form was added and mixed to the copolymer solution (A) so that the content after drying was 5% by weight.

Stability of the patch The patches obtained in Example 1 and Comparative Example 4 were heated at a temperature of 50°C.
After storing it for 1 month, 2 months, and 3 months, it becomes large! !
A circle of 30IIIφ in diameter was cut out, and the remaining ifenprodil tartrate was extracted with methanol, and the residual ratio relative to the initial content was calculated. The results are shown in FIG.

From FIG. 1, it can be seen that Examples 7 and 8 have higher maximum blood concentrations than the orally administered comparative product, and are also stable over a long period of time.

Furthermore, from the tjrJ2 diagram, it is recognized that the residual amount of iaenpronol tartrate is higher in Example 1 than in Comparative Example 4, and the stability of this drug is improved.

(g) Effects of the Invention As described above, the medical patch of the present invention has 1) II on the exposed surface of the pressure-sensitive adhesive layer containing iaenpronol and/or its organic acid salt to an iI of 7 to 9. ¥! As the drug is adjusted to a suitable temperature, transdermal absorption is improved and the stability of the above drug is maintained, and as a result, it has effects such as being effective in treating sequelae of cerebrovascular disorders or cerebrovascular dementia. It is.

[Brief explanation of drawings]

Figure 1 shows the degree of meridian n in the blood of Examples 7 and 8 and a comparative product of J7 type J7. FIG. 2 is a characteristic diagram showing the changes over time, and FIG. 2 is a characteristic diagram showing the stability over time of Example] and Comparative Example 4. −<T> Moaning/Ho1°, \→Kuyakuya(su)

Claims (1)

[Claims] (1) A patch formed by laminating a pressure-sensitive adhesive layer containing ifenprodil and/or its organic acid salt as a medicinal ingredient on a support, in which an acidic substance and/or a basic substance is added to the pressure-sensitive adhesive layer. A medical patch comprising a pressure-sensitive adhesive layer coexisting in the layer, and the pH of the exposed surface of the pressure-sensitive adhesive layer being adjusted to a range of 7 to 9.