RU2776063C2 - Rupatadine-containing patch - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to patch for external use, containing rupatadine, in which acrylic adhesive is used as an adhesive base, wherein the specified patch for external use additionally includes 3-20 wt.% of solubilizer, 5-25 wt.% of plasticizer, and 3-10 wt.% of surfactant.

EFFECT: implementation of the invention allows for the creation of patch for external use with improved rupatadine solubility in the patch base, excellent medicinal efficiency and physical properties, namely the implementation of this invention provides suitable adhesive, when applied to the skin, due to corresponding physical properties of patch, as well as good transdermal rupatadine absorption.

6 cl, 7 tbl, 12 ex

Description

The field of technology to which the invention belongs

The present invention relates to a topical patch containing rupatadine.

State of the art

Rupatadine (generic name), whose chemical name is 8-chloro-11-[1-[(5-methyl-3-pyridinyl)methyl]piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6 ]cyclohepta[1,2-b]pyridine is an N-alkylpyridine derivative that is a platelet activating factor (PAF) antagonist and has an antihistamine effect (Patent Document 1).

This compound has anti-allergic and anti-inflammatory effects. Its effectiveness lies in the relief of allergic rhinitis, including hay fever and itching associated with hives and skin diseases (eczema, dermatitis and itchy skin). As a second generation antihistamine, a tablet containing rupatadine fumarate, which is a pharmaceutically acceptable salt of rupatadine, as an active ingredient, has been approved for medical use and sold in 50 or more countries.

In Japan, tablets containing rupatadine fumarate (rupatadine) have not been approved for medical use and clinical trials have been conducted to obtain approval.

Since many second-generation antihistamines used to treat allergic diseases have at least a sedative effect, there are problems in which side effects such as drowsiness occur during administration.

For this reason, a precautionary measure is provided to "warn patients receiving second-generation antihistamines about the risky work with machines, such as driving cars."

Rupatadine is classified as a second generation antihistamine, has less sedative effect, and its side effects such as drowsiness are greatly improved. However, when taken orally, it is absorbed from the mucosal lining of the gastrointestinal tract and thereafter a first-pass effect occurs through the liver, so there is concern that its bioavailability will decrease. In this regard, the use of the patch, since the drug absorbed from the skin circulates systemically through the bloodstream, avoids the first pass effect through the liver and improves bioavailability. In addition, in the case of a patch, it is possible to ensure stable drug administration over a long period of time compared to oral administration. For these reasons, it is desirable to develop a patch that can exhibit the drug effect of rupatadine with less absorption into the body and that can stably administer the drug for a long period of time.

The development of this topical patch enhances the use of a drug containing rupatadine and is extremely beneficial in terms of patient compliance. However, the preparation of topical rupatadine patches has not yet been investigated.

List of cited patent literature

Patent Document 1: JP No. 2730612

Brief summary of the invention

Technical task

The aim of the present invention is to provide hitherto unexplored topical patches containing rupatadine.

Solution of the task

In order to solve the problem, the present inventors have carried out various studies. The inventors studied the adhesive base for the development of a rupatadine-containing patch, and as a result, for the first time, found that for a rupatadine-containing patch, an acrylic adhesive base is the most preferred among various adhesive bases.

Thus, the present invention was made.

More specifically, the main aspect of the present invention is:

(1) A topical patch containing rupatadine, characterized by using an acrylic adhesive as the adhesive base.

One particular aspect of the present invention is:

(2) an external patch according to (1) above, further containing any of a solubilizer, a plasticizer, and a surfactant.

Other specific aspects of the present invention are:

(3) patch for external use according to the above paragraph (1) or (2), which contains rupatadine in an amount of 3-20 wt. % relative to the mass of the patch;

(4) patch for external use in accordance with the above paragraph (2), in which the solubilizer is added in the amount of 3-20 wt. % relative to the mass of the patch;

(5) patch for external use in accordance with the above paragraph (2), in which the plasticizer is added in the amount of 5-25 wt. % relative to the mass of the patch;

(6) patch for external use in accordance with the above paragraph (2), in which the surfactant is added in the amount of 3-10 wt. % relative to the mass of the patch;

(7) the external patch according to (2) above, in which a C2-C7 organic acid is added as a solubilizer;

(8) the external patch according to (7) above, wherein the organic acid is an acid selected from the group consisting of acetic acid, lactic acid, propionic acid, valeric acid, levulinic acid, and hexanoic acid;

(9) the external patch according to (2) above, wherein a fatty acid ester is added as a plasticizer;

(10) the external patch according to (9) above, wherein the fatty acid ester is one, two or more kinds of fatty acid esters selected from the group consisting of oleyl oleate, isopropyl myristate, butyl stearate, isopropyl palmitate, дибутилфталата, диэтилфталата, диизооктилфталата, диизобутилфталата, дикаприлфталата, динонилфталата, диметилциклогексилфталата, диэтилгексилафталата, дибутилсебацината, диэтилсебацината, диэтилгексилсебацината, динонилсебацината, диизооктилсебацината, полипропиленсебацината, диметокси-циклогексилсебацината, дибутиладипината, диэтилгексиладипината, динониладипината, полипропиленадипината, диметилциклогексиладипината и дибутоксиэтиладипината; and

(11) The external patch according to (2) above, wherein one or a combination of two or more esters selected from the group consisting of glycerol fatty acid ester, sorbitol fatty acid ester, ester polyoxyethylene and fatty acid, polyoxyethylene alkyl ether and polyoxyethylene hydrogenated castor oil.

The most preferred aspect of the present invention is:

(12) an external patch containing rupatadine, characterized by using an acrylic adhesive as an adhesive base and further containing an organic acid having 2-7 carbon atoms as a solubilizer, a fatty acid ester as a plasticizer, and a surfactant; and in particular,

(13) The external patch according to (12), wherein either of lactic acid and levulinic acid are added as an organic acid, and oleyl oleate and isopropyl myristate are added as a plasticizer.

Positive Effects Achieved by the Present Invention

The present invention provides a topical patch that has suitable adhesion when applied to the skin due to the appropriate physical properties of the patch, as well as suitable transdermal absorption of rupatadine as an active ingredient.

In the current environment where a topical patch containing rupatadine for transdermal absorption has not been developed, the present invention particularly provides a more suitable transdermal absorption by using an acrylic adhesive as an adhesive base as opposed to another adhesive base. As a consequence, the present invention has a significant clinical effect.

Description of Embodiments

As described above, the main aspect of the present invention is a topical patch containing rupatadine and characterized by the use of an acrylic adhesive as an adhesive base.

Usually, rupatadine contained in the external patch of the present invention as an active ingredient is in the form of rupatadine free base, and its fumarate salt is contained in such a tablet, which has a dosage form for oral administration. However, the topical patch of the present invention preferably contains rupatadine free base.

The amount of rupatadine contained in the patch is not particularly limited, provided that the amount is sufficient to provide the desired beneficial effect through transdermal absorption. Its content can be 3-20 wt. % and preferably 5-17 wt. % relative to the mass of the patch.

The present invention is a topical patch in which rupatadine as such an active ingredient is contained in an adhesive base as a patch ingredient. The results of studies carried out by the inventors have shown that it is preferable to use an acrylic adhesive as the adhesive base.

As the adhesive ingredient of the external patch, a rubber-based adhesive base such as styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS), isoprene, polyisobutylene (hereinafter abbreviated as PIB), styrene block copolymer -butadiene-styrene (hereinafter abbreviated as SBS) and styrene-butadiene rubber (hereinafter abbreviated as SBR), and an adhesive silicone base such as polyorganosiloxane. When the active ingredient of the present invention is rupatadine, an acrylic adhesive has been found to be the most preferred in terms of skin penetration and adhesion.

Such an acrylic adhesive is not particularly limited as long as it is a copolymer containing at least one (meth)acrylic acid derivative represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate, etc.

Specific examples thereof may include the adhesives described in Iyakuhin TenkabUtu Jiten 2013 [Japanese Pharmaceutical Excipients Directory (Japanese Pharmaceutical Excipients Council) 2013] (edited by International Pharmaceutical Excipients Council Japan) (edited by International Pharmaceutical Excipients Council Japan) such as an acrylic copolymer acid and acrylic acid octyl ester, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer solution, acrylic acid-vinyl acetate copolymer, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion and alkanolamine solution of acrylic polymer contained in acrylic resin, and commercially available products such as the DURO-TAK acrylic adhesive series (supplied by Henkel) and the EUDRAGIT 20 series (supplied by Evonik Rohm Gmbh).

In addition, it has been found that, in addition to the acrylic adhesive, the topical patch of the present invention preferably further contains a solubilizer, a plasticizer and/or a surfactant.

The solubility of rupatadine in the acrylic adhesive is maintained at a certain level. However, the inventors' study has shown that it is better to make the solubility in the base more uniform by using a dissolving agent to ensure sufficient permeability from the base through the skin.

Examples of such a solubilizer may include, in particular, an organic acid having 2-7 carbon atoms. In the case of using an organic acid having 8 or more carbon atoms, it is difficult to ensure sufficient solubility of rupatadine in the patch ingredient. As a result, penetration of rupatadine from the patch through the skin may be reduced.

Examples of the organic acid having 2-7 carbon atoms may include acetic acid, lactic acid, propionic acid, valeric acid, levulinic acid (4-oxopentanoic acid), and hexanoic acid. In the case of levulinic acid and lactic acid (DL-lactic acid), suitable results were obtained.

The amount of such added solubilizer is not particularly limited in any way, provided that this amount is sufficient to provide the desired beneficial effect through transdermal absorption. This amount can be 3-20 wt. % and preferably 5-15 wt. % relative to the mass of the patch.

If the amount of added solubilizer is less than 3 wt. %, the solubility of the drug in the preparation may be reduced, and such an undesirable effect as precipitation of crystals may occur. If this amount is more than 20 wt. %, this may affect the physical properties of the drug.

Preferably, a plasticizer is also added to the topical patch of the present invention as an ingredient in the patch.

With the use of a fatty acid ester as such a plasticizer, particularly good results have been obtained compared to various other plasticizers.

Примеры таких пластификаторов могут включать сложные эфиры жирных кислот, выбранные из группы, состоящей из олеилолеата, изопропилмиристата, бутилстеарата, изопропилпальмитата, дибутилфталата, диэтилфталата, диизооктилфталата, диизобутилфталата, дикаприлфталата, динонилфталата, диметилциклогексилфталата, диэтилгексилафталата, дибутилсебацината, диэтилсебацината, диэтилгексилсебацината, динонилсебацината, диизооктилсебацината, polypropylene sebacate, dimethoxy-cyclohexyl sebacate, dibutyl adipate, diethylhexyl adipate, dinonyl adipate, polypropylene adipate, dimethylcyclohexyl adipate and dibutoxyethyl adipate. Preferably, one type of fatty acid ester may be used, or two or more types of such esters may be used in combination.

It is particularly preferred to add a combination of oleyl oleate and isopropyl myristate to the topical patch of the present invention. The amount of the combination to be added is not particularly limited, as long as the amount is sufficient to provide the desired benefit through transdermal absorption. This amount can be 5-25 wt. % and preferably 10-22 wt. % relative to the mass of the patch.

When the amount of plasticizer is less than 5 wt. %, it may turn out that the desired permeability value is not achieved. When it is more than 25 wt. %, the plasticizer may separate from the patch, degrading the physical properties of the patch.

In addition, it has been found that the external patch of the present invention preferably contains a surfactant as an ingredient of the patch.

In the present invention, this surfactant is added to improve transdermal absorption because the surfactant is amphipathic. Specific examples of surfactants may include glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ester, and polyoxyethylene hydrogenated castor oil. One type of surfactant may be used, or two or more types may be used in combination.

The amount of surfactant added is not limited in any way, provided that it is sufficient to provide the desired beneficial effect during transdermal absorption. This amount can be 3-10 wt. % and preferably 4-8 wt. % relative to the mass of the patch.

In addition, various base ingredients used for conventional topical patches can also be used in the topical patch of the present invention, provided that they do not interfere with the beneficial effects achieved.

Such main ingredients are not particularly limited in any way, and examples thereof may include water-soluble polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and polyacrylic acid; cellulose derivatives such as ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; silicon compounds such as silicon dioxide and undensified colloidal silicon dioxide; and inorganic fillers such as zinc oxide, alumina, titanium dioxide, silicon dioxide, magnesium oxide, iron oxide and stearic acid.

If necessary, a preservative, refreshing agent, disinfectant, fragrance, coloring agent or the like can be added.

The base of the patch of the present invention is not particularly limited. As a basis, an elastic or rigid basis can be used.

In particular, a film or sheet formed from a synthetic resin such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, and polyurethane can be used; laminate, porous film, foam, woven fabric or non-woven fabric; or paper.

For a protective coating, polyethylene terephthalate can be used,

polypropylene or paper. In particular, polypropylene terephthalate (PET) is preferred.

The protective coating may, if necessary, be subjected to a silicone treatment so that the peel strength is appropriate.

Next, one example of the manufacturing method of the patch according to the present invention, as well as the medicament of the patch, will be described.

Specifically, an organic acid having 2 to 7 carbon atoms as a solubilizer, a fatty acid ester as a plasticizer and a surfactant are weighed in a mixer, and an organic solvent having a boiling point below 100°C is added to prepare an additive solution, for example ethyl acetate.

The acrylic adhesive and rupatadine are then added to this additive solution, and the mixture is twirled until homogeneous to obtain a rupatadine-containing adhesive solution (patch solution).

The resulting patch solution is then applied to a protective film (protective coating) or base and dried for 4-20 minutes in a dryer, the temperature of which in the drying oven is adjusted to 60°C or higher and lower than 80°C. After removing the organic solvent by drying, the patch layer is bonded to a base or protective film (protective coating) to obtain a patch according to the present invention.

The thickness of the patch layer may preferably be 30-200 µm, particularly preferably 80-150 µm and most preferably about 100 µm.

If the thickness of the patch layer is less than 30 µm, the drug release is not stable and the cohesive force is reduced. If it exceeds 200 µm, the amount of drug contained in the patch layer increases and the production cost increases.

The resulting patch is finally cut to the desired size and placed in a packaging bag to obtain the patch of the present invention.

The above manufacturing method is a specific example of the manufacturing method and is not limiting. Various modifications of this method are possible.

Examples

Hereinafter, the present invention will be described in detail by way of examples, comparative examples and test examples. However, the present invention is not limited to these examples to any particular extent.

Test Case 1: Examination of the degree of solubility of rupatadine free base in each ingredient

The degree of solubility of rupatadine free base (sometimes also referred to as "rupatadine base") as the active ingredient in each patch ingredient was investigated.

Levulinic acid was used as a solubilizer, oleyl oleate and isopropyl myristate (IPM) as a plasticizer, and lauromacrogol (BL-4,2:polyoxyethylene lauryl ether) as a surfactant. The degree of solubility of rupatadine base in each ingredient was examined.

For comparison, the degree of solubility of rupatadine base in an acrylic adhesive as an adhesive base was also investigated.

Test method

(1) HPLC method

To 5 ml of each sample of levulinic acid, oleyl oleate, isopropyl myristate (IPM) and lauromacrogol (BL-4.2), add an excess amount of rupatadine base and mix. The mixture is filtered through a 0.45 µm membrane filter to remove undissolved matter. Methanol is added to 200 µl of the filtrate using a volumetric flask to bring the volume to the desired volume. The mixture is analyzed by HPLC.

The concentration of rupatadine is measured from an external calibration curve and the degree of solubility is calculated by converting the specific gravity.

(2) Gravimetric method

The degree of solubility of the rupatadine base in the acrylic adhesive is checked gravimetrically.

Rupatadine base is added to 1 g (solid content) of the acrylic adhesive, and the mixture is stirred and sonicated.

The adhesive solution was applied so that it had a thickness of 100 µm and dried. The patch is examined under a microscope (manufactured by KEYENCE CORPORATION). The degree of solubility is determined by the presence or absence of crystals.

results

The solubility rates of rupatadine obtained by the test methods used are shown in Table 1 below.

Table 1

Components Purpose Solubility (wt%) Levulinic acid solubilizer 29 Oleyl oleate plasticizer 2 Isopropyl myristate plasticizer 2 Lauromacrogol (BL-4.2) Surface-active substance four Acrylic adhesive (OH group)*1 Adhesive base ≤15 to 16<

*1: Pressure-sensitive acrylic adhesive having an OH group.

As can be seen from the results, rupatadine base has a certain solubility in the acrylic adhesive used as an adhesive base, and in combination with a solubilizer, a more uniform solubility in the patch is provided.

Test Example 2: In Vitro Hairless Rat Skin Permeability Test

A permeation test on hairless rat skin was carried out with the topical patch for each of the Examples and Comparative Examples in the following manner.

Test method

The detached abdominal skin of a male hairless rat (HWY series, 7-9 weeks of age) is placed in a Franz diffusion cell and each test preparation (in the examples and comparative examples) cut in the shape of a circle (ϕ 14 mm) is attached to the skin. In the test, the receptor side was filled with phosphate buffered saline (PBS) containing 40% polyethylene glycol 400 and hot water, 37° C., was circulated in a water jacket. The receptor fluid was sampled over time and the content of rupatadine permeated through the skin was measured by liquid chromatography. The total skin penetration is calculated 24 hours after the start of the test.

results

The results are shown in each table.

Test Case 3: Patch Cohesion Strength Test

For the external patches in each of the Examples and Comparative Examples, the cohesive strength of the patch was evaluated as follows.

Test method

One hour after manufacture, the adhesive surface (patch surface) of each external patch preparation (in the Examples and Comparative Examples) was pressed with a finger, and the finger was detached from the surface. Visually examined whether the adhesive layer (patch) remains attached to the skin (remaining patch).

The result of the assessment was "yes" or "no".

results

The results are shown in each table.

Examples 1-6: Study of the ratio of the components of the patch

The ratio of the components of the patch in the patch for external use of the present invention was evaluated according to the method described in table 2 below.

table 2

Recipe Examples one 2 3 four 5 6 Levulinic acid 14.00 10.00 10.00 12.50 10.00 5.00 DL-Lactic acid - - - - - 5.00 Oleyl oleate 10.00 - 10.00 10.00 5.00 10.00 Isopropyl myristate - 21.00 11.00 11.00 16.00 11.00 Lauromacrogol (BL-4.2) 5.00 5.00 5.00 5.00 5.00 5.00 Acrylic adhesive (OH group) 54.00 52.00 52.00 46.50 52.00 52.00 Foundation of rupatadin 17.00 12.00 12.00 15.00 12.00 12.00 Rupatadine Organic Acid/Base (mole ratio) 2.95 2.99 2.99 2.99 2.99 3.42 Total amount of passed rupatadine (mcg/cm ² ) 84.9 148.7 196.5 188.8 138.4 163.8 Cohesive strength (Adhesive left on the finger) Not Not Not Not Not Does not mean.

Examples 7-10: Study of the ratio of solubilizer and plasticizer

The ratio of solubilizer to plasticizer additives in the topical patch of the present invention was evaluated and examined by the method described in Table 3 below.

Levulinic acid and oleyl oleate were chosen as the solubilizer and plasticizer, respectively. Their ratio was evaluated.

In addition, these examples were compared with example 3, in which good results were obtained.

Table 3

Recipe Examples 7 eight 9 ten 3 Levulinic acid 15.00 12.50 7.50 5.00 10.00 Oleyl oleate 9.44 9.72 10.28 10.56 10.00 Isopropyl myristate 10.39 10.69 11.31 11.61 11.00 Lauromacrogol (BL-4.2) 4.72 4.86 5.14 5.28 5.00 Acrylic adhesive (OH group) 49.12 50.56 53.44 54.88 52.00 Foundation of rupatadin
As can be seen from the results in the tables, even when oleyl oleate was used as a plasticizer and the amount of levulinic acid added as a solubilizer varied differently, good skin permeability of rupatadine as an active ingredient and physical properties of the patch were obtained. were excellent.
[0044]
Examples 11 to 15: Research and evaluation of an organic acid as a solubilizer.
The external patch of the present invention was investigated and evaluated depending on the kind of organic acid having 2 to 7 carbon atoms as a solubilizer.
External patches of the present invention were evaluated using the organic acids described in Table 4 below as a solubilizer.

WO2018/194183
fifteen
PCT/JP2018/016692
[TABLE 11.33 11.67 12.33 12.67 12.00 Rupatadine Organic Acid/Base (mole ratio) 4.74 3.84 2.12 1.41 2.99 Total amount of passed rupatadine (mcg/cm ² ) 1.6 1.3 0.7 0.5 1.0 Cohesive strength (Adhesive left on the finger) Not Not Does not mean. Does not mean. Not

As can be seen from the results in the tables, even when oleyl oleate was used as a plasticizer and the amount of levulinic acid added as a solubilizer was varied, good skin permeability for rupatadine as an active ingredient was achieved, and the physical properties of the patch were excellent.

Examples 11-15: Research and evaluation of organic acids as a solubilizer

The topical patch of the present invention is examined and evaluated depending on the kind of organic acid having 2 to 7 carbon atoms used as a solubilizer.

The topical patches of the present invention were tested with the organic acids described in Table 4 below as a solubilizer.

Table 4

Recipe Examples eleven 12 13 fourteen fifteen Acetic acid (C2) 5.50 - - - DL-Lactic acid (C3) - 7.60 - - - Propionic acid (C3) - - 6.70 - - Valeric acid (C5) - - - 9.00 - Hexanoic acid(C6) - - - - 9.80 Oleyl oleate 10.50 10.27 10.37 10.11 10.02 Isopropyl myristate 11.55 11.29 11.40 11.12 11.02 Lauromacrogol (BL-4.2) 5.25 5.13 5.18 5.06 5.01 Acrylic adhesive (OH group) 54.60 53.39 53.91 52.58 52.12 Foundation of rupatadin 12.60 12.32 12.44 12.13 12.03 Rupatadine Organic Acid/Base (mole ratio) 3.02 2.85 3.02 3.02 2.92 Total amount of passed rupatadine (mcg/cm ² ) 64.2 140.3 42.6 79.5 59.2 Cohesive Strength (Adhesive Remaining
on the finger) Not Not Not Not Does not mean.

Note: The numbers in brackets for organic acids refer to the number of carbon atoms.

As can be seen from the results in the table, when an organic acid having 2 to 7 carbon atoms other than levulinic acid is used as a solubilizer, and a fatty acid ester is added as a plasticizer, good skin permeability is achieved, and the physical properties of the patch are excellent. .

Example 16 Acrylic Adhesive Study

The topical patch of the present invention was studied and evaluated in which the type of acrylic adhesive was varied.

As the acrylic adhesive, the acrylic adhesive described in Table 5 below is used.

Acrylic adhesive (with OH group): pressure sensitive acrylic adhesive containing OH group (Note: used in Example 3 above).

Acrylic adhesive (non-functional): pressure-sensitive acrylic adhesive without a functional group (non-functional).

Table 5

Recipe Examples 16 3 Levulinic acid 10.00 10.00 Oleyl oleate 10.00 10.00 Isopropyl myristate 11.00 11.00 Lauromacrogol (BL-4.2) 5.00 5.00 Acrylic adhesive (OH group) - 52.00 Acrylic adhesive (no functional group) 52.00 - Foundation of rupatadin 12.00 12.00 Rupatadine Organic Acid/Base (mole ratio) 2.99 2.99 Total amount of passed rupatadine (mcg/cm ² ) 174.1 152.4 Cohesive strength (Adhesive left on the finger) Not Not

As can be seen from the results above, when an acrylic adhesive was used as the adhesive base, good skin permeability was achieved and the physical properties of the patch were excellent.

Comparative Examples 1-7: Study Depending on the Kind of Adhesive

Topical patches are being evaluated that use an adhesive other than an acrylic adhesive as an ingredient in the patch.

Patches for external use according to comparative examples 1-7 are prepared and evaluated in accordance with table 6.

The patches according to comparative examples 1-7 are prepared as follows.

An ester of glycerol and hydrogenated rosin is added to toluene and dissolved with stirring, a styrene-isoprene-styrene block copolymer (SIS) is added and the mixture is stirred. After complete dissolution is confirmed, liquid paraffin is added to prepare an adhesive solution. The additive described in the table and rupatadine are added to the resulting adhesive solution, and the mixture is mixed with stirring until homogeneous to obtain an adhesive solution containing rupatadine. Then, the rupatadine-containing adhesive solution was applied to a PET protective film, and the solvent was removed by drying to obtain an adhesive layer with a thickness of 100 μm. A PET film backing was attached to the adhesive layer to form a patch according to each of the Comparative Examples.

Table 6

Recipe Comparative examples one 2 3 four 5 6 7 Levulinic acid - - 10.00 10.00 5.00 10.00 10.00 Oleyl oleate - - - 3.00 8.00 15.00 - Lauromacrogol (BL-4.2) - - - - - - 5.00 SIS 19.77 20.23 18.14 17.44 18.84 13.95 16.28 Ester of glycerol and hydrogenated rosin 47.44 - 43.53 41.86 45.21 33.49 39.07 Saturated Aliphatic Hydrocarbon Resin - 48.56 - - - - liquid paraffin 17.79 18.21 16.33 15.70 16.95 12.56 14.65 Foundation of rupatadin 15.00 13.00 12.00 12.00 6.00 15.00 15.00 Rupatadine Organic Acid/Base (mole ratio) - - 2.99 2.99 2.99 2.39 2.39 Total amount of passed rupatadine (mcg/cm ² ) 22.6 10.1 15.3 11.9 ND ND ND Cohesive strength (Adhesive left on the finger) Not Not Not Does not mean. Yes Yes Yes

ND: Not tested

From the results described above, it can be seen that when an adhesive base other than an acrylic adhesive is used as the adhesive base, the skin permeability of rupatadine as an active ingredient is significantly lower than that of the acrylic adhesive used in the present invention.

Comparative Examples 8-12: study of the use as a solubilizer of organic acids other than those having 2-7 carbon atoms.

External patches in which the organic acid (medium and long chain fatty acid: having 8-18 carbon atoms) are investigated and evaluated are different from the organic acid having 2-7 carbon atoms.

Prepare and evaluate topical patches according to the Comparative Examples according to the procedure in Table 7.

Patches for external use according to comparative examples 8-12 are prepared as follows.

Weigh the medium and long chain fatty acid, plasticizer and surfactant described in the table, and add ethyl acetate to prepare an additive solution.

Acrylic adhesive and rupatadine are added to the resulting make-up solution, and the mixture is mixed with stirring until homogeneous to obtain an adhesive solution containing rupatadine. Then, the adhesive solution containing rupatadine was applied to a PET protective film, and the solvent was removed by drying to obtain an adhesive layer with a thickness of 100 μm. A PET film backing was attached to the adhesive layer to form the patch of each of the Comparative Examples.

Table 7

Recipe Comparative examples eight 9 ten eleven 12 Caprylic acid (C8) - - 12.25 - - 2-Ethylhexanoic acid(C8) - - - 12.25 - Nonanoic acid (C9) - - - - 13.30 Capric acid (CIO) 15.00 - - - - Oleic acid (C18) 24.50 - - - Oleyl oleate 9.44 8.39 9.75 9.75 9.63 Isopropyl myristate 10.39 9.23 10.73 10.73 10.60 Lauromacrogol (BL-4.2) 4.72 4.19 4.87 4.87 4.82 Acrylic adhesive (OH group) 49.12 43.62 50.70 50.70 50.09 Foundation of rupatadin 11.33 10.07 11.70 11.70 11.56 Rupatadine Organic Acid/Base (mole ratio) 3.20 3.58 3.02 3.02 3.02 Total amount of passed rupatadine (mcg/cm ² ) 15.8 7.2 20.3 20.3 11.9 Cohesive strength (Adhesive left on the finger) Not Does not mean. Not Not Does not mean.

Based on the results in the table above, in cases where an organic acid (medium and long chain fatty acid: 8 to 18 carbon atoms) other than an organic acid of 2 to 7 carbon atoms was used, it was not possible to obtain an external patch, having suitable skin penetration characteristics.

The results obtained in the examples and comparative examples are evaluated together. Compared with the patches of Comparative Examples 1 to 7 using an adhesive other than an acrylic adhesive and the patches of Comparative Examples 8 to 12 using an organic acid having more than 5 carbons as a solubilizer, the total amount of permeate in patches for external use according to examples 1-16 of the present invention was higher. This result clearly and sufficiently substantiates the specificity of the present invention.

Among the patches according to examples 1-16, each of which is a topical patch of the present invention, in the patches of examples 3-10, 12 and 16 using levulinic acid or DL-lactic acid as a solubilizer, oleyl oleate in combination with complex with a fatty acid ester such as isopropyl myristate as a plasticizer and lauromacrogol as a surfactant, the total amount of permeate after 24 hours was very high.

Industrial Applicability

As described above, the present invention describes a topical patch containing rupatadine, which has not been investigated so far.

The topical patch of the present invention contains rupatadine, which is a second generation antihistamine, as an active ingredient. This topical patch has excellent physical properties of the patch and is characterized by good transdermal absorption of rupatadine as an active ingredient. The topical patch has significant medical benefits.

Claims (9)

1. A topical patch containing rupatadine, in which an acrylic adhesive is used as an adhesive base, and the specified patch for external use additionally includes 3-20 wt.% of a solubilizer, 5-25 wt.% of a plasticizer and 3-10 wt.% surfactant, where the solubilizer comprises an organic acid having 2-7 carbon atoms selected from the group consisting of acetic acid, lactic acid, propionic acid, valeric acid, levulinic acid and hexanoic acid; the plasticizer is one or two or more fatty acid esters selected from the group consisting of oleyl oleate, isopropyl myristate, butyl stearate, isopropyl palmitate, dibutyl phthalate, diethyl phthalate, diisooctyl phthalate, diisobutyl phthalate, dicapryl phthalate, dinonyl phthalate, dimethylcyclohexyl phthalate, diethylhexyl phthalate, dibutyl sebacate, diethyl sebacate, diethyl sebacate, dinonyl sebacate, diisooctyl sebacate, polypropylene sebacate, dimethoxy-cyclohexyl sebacate, dibutyl adipate, diethylhexyl adipate, dinonyl adipate, polypropylene adipate, dimethylcyclohexyl adipate and dibutoxyethyl adipate; and the surfactant is one or a combination of two or more selected from the group consisting of glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether and polyoxyethylene hydrogenated castor oil. 2. A patch for external use according to claim 1, in which rupatadine is contained in an amount of 3-20 wt.% relative to the mass of the patch. 3. The topical patch according to claim 1, wherein the solubilizer is a substance selected from the group consisting of acetic acid, lactic acid, propionic acid, valeric acid, levulinic acid and hexanoic acid. 4. The topical patch according to claim 1, wherein the plasticizer is two or more fatty acid esters selected from the group consisting of oleyl oleate, isopropyl myristate, butyl stearate, isopropyl palmitate, dibutyl phthalate, diethyl phthalate, diisooctyl phthalate, diisobutyl phthalate, dicapryl phthalate, dinonyl phthalate , dimethylcyclohexyl phthalate, diethylhexyl phthalate, dibutyl sebacate, diethyl sebacate, diethylhexyl sebacate, dinonyl sebacate, diisooctyl sebacate, polypropylene sebacate, dimethoxy-cyclohexyl sebacate, dibutyl adipate, diethylhexyl adipate, dinonyl adipate, polypropylene adipate, dimethylcyclohexyl adipate and dibutoxyethyl adipate. 5. The topical patch according to claim 1, wherein the surfactant is one selected from the group consisting of glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester , polyoxyethylene alkyl ether, and polyoxyethylene hydrogenated castor oil. 6. A patch for external use according to claim 1, in which lactic acid or levulinic acid is used as a solubilizer, and oleyl oleate and isopropyl myristate are used as a plasticizer.