WO2019143114A1 - Hydrogel-patch-type pharmaceutical composition for transdermal administration - Google Patents

Abstract

The present invention provides a hydrogel-patch-type pharmaceutical composition comprising: a pharmaceutical active ingredient; a polyacrylic acid partial neutralizer as a gel former; a combination of acid and a cross-linking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; and 5-20 wt% of water.

Description

Pharmaceutical compositions for transdermal administration in the form of hydrogel patches

The present invention relates to a pharmaceutical composition for transdermal administration in the form of a hydrogel patch. More particularly, the present invention relates to a pharmaceutical composition in the form of a hydrogel patch comprising 5 to 20% by weight of water, comprising a specific gel-forming agent and a crosslinking agent.

Patches (commonly referred to as "patches") are divided into a cataplasma formulation in the form of a wetting poultice and a plasser, a solid formulation. In addition to the adhesive layer containing the drug, the cataplasma agent separately includes a tightly packed cell having a low expansion / contraction ratio due to the nature of the preparation. Acrylic resin or the like is a water-free preparation, which is disadvantageous in that it exhibits skin irritation as compared with a cataplasma agent. On the other hand, the cataplasma has a disadvantage in that the skin irritation is less than that of the plasters but the transdermal permeability of the drug is lowered.

As a percutaneous absorption preparation for overcoming the disadvantages of conventional cataplasma and plasters, hydrogel patches have been studied. For the hydrogel formation, various crosslinking attempts have been attempted. For example, crosslinking by metal ion-ion bonding, cross-linking by repeating crosslinking by formaldehyde, starch aldehyde or the like, aqueous solution of polyvinyl alcohol which is a synthetic polymer, Have been tried. However, the cross-linking by metal ion-ion bonding used in a conventional hydrogel formulation, which is generally commercially available and commercially available, requires a long period of about one week to three weeks until complete crosslinking is achieved, There is a problem that is difficult to control. Crosslinking by repeated freezing / thawing also has a disadvantage that it is difficult to apply to the manufacturing process and the product unit price becomes high because the crosslinking time is very long. In addition, crosslinking using aldehydes has toxicity problems due to the residual of crosslinking agents (aldehydes) and unreacted initiators.

The present inventors have developed a new type of percutaneous absorption preparation capable of fundamentally solving the disadvantages of conventional drug-containing cataract and plasters. That is, by designing a percutaneous absorption preparation having a hydrogel patch form by combining a specific gel-forming agent and a crosslinking agent, disadvantages of conventional cataplasma and plastase, for example, skin irritation, And / or toxicity problems due to unreacted monomers, and long-term crosslinking problems can be fundamentally avoided. In addition, the transdermal absorbent agent having the hydrogel patch form exhibits excellent transdermal permeability without causing problems such as crystal precipitation at the time of preparation and storage, uniform distribution of the drug at a high concentration, easy preparation and workability And the like.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition in the form of a hydrogel patch comprising a specific gel-forming agent and a crosslinking agent together with a pharmaceutically active ingredient.

In addition, the present invention includes a method for producing the pharmaceutical composition in the form of the hydrogel patch.

According to one aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically active ingredient; A polyacrylic acid partial neutralization product as a gel-forming agent; A combination of an acid salt with a crosslinking agent selected from the group consisting of an aluminum salt, a magnesium salt, and a calcium salt; And 5 to 20% by weight of water, in the form of a hydrogel patch.

In the pharmaceutical composition of the present invention, the pharmaceutically active ingredient is selected from the group consisting of ketoprofen or a pharmaceutically acceptable salt thereof, flurbiprofen or a pharmacologically acceptable salt thereof, Acceptable salt, diclofenac or a pharmaceutically acceptable indomethacin or a pharmacologically acceptable salt thereof, diclofenac epol amine or a pharmacologically acceptable salt thereof, felbinac or a pharmacologically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt, a pyroxycam or a pharmaceutically acceptable salt thereof, and a methyl salicylate or a pharmaceutically acceptable salt thereof.

The polyacrylic acid partial neutralized product may have a degree of neutralization of 25 to 70 mol%, and may be present in an amount of 3 to 8 wt% based on the total weight of the composition.

The crosslinking agent is selected from the group consisting of dry aluminum hydroxide gel, dihydroxy aluminum aminoacetate, aluminum hydroxide, aluminum sulfate, aluminum acetate, aluminum silicate, magnesium hydroxide, magnesium sulfate, magnesium acetate, calcium hydroxide, calcium carbonate, calcium chloride, calcium gluconate, Tartrate, and calcium pantothenate, and may be present in an amount of 0.5 to 3.0% by weight based on the total weight of the composition.

The acid is selected from the group consisting of tartaric acid, acetic acid, propionic acid, isobutyric acid, caproic acid, lactic acid, maleic acid, pyruvic acid, oxalic acid, succinic acid, tartaric acid, phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, methanesulfonic acid, ethanesulfonic acid, Butane sulfonic acid, and may be present in an amount of 1 to 12 wt% based on the total weight of the composition.

The pharmaceutical composition of the present invention may further comprise at least one dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol, and butylene glycol, and the dispersant may be present in an amount of 15 to 70 wt% Can exist.

The pharmaceutical compositions of the present invention may further comprise one or more solubility aids selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate, The adjuvant may be present in an amount of from 1 to 30% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention may further comprise one or more anti-leakage agents selected from the group consisting of polyacrylic acid and kaolin, and the anti-leak agent may be present in an amount of 1 to 15% by weight based on the total weight of the composition.

In one embodiment, the pharmaceutical composition of the present invention comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; And 5 to 20% by weight of water.

The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable additives selected from the group consisting of permeation enhancers, viscosity modifiers, chelating agents, and perfuming agents. The permeation enhancer may be at least one selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether And may be present in an amount of 0.5 to 20% by weight based on the total weight of the composition. The viscosity adjusting agent may be selected from the group consisting of gelatin, polyvinyl alcohol, carboxymethyl cellulose sodium, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, and may be selected from the group consisting of 0.2 to 5.0 wt% Can exist. The chelating agent may be edetic acid or a salt thereof, and may be present in an amount of 0.2 to 3% by weight based on the total weight of the composition. The perfume may be selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil, and may be present in an amount of 0.1 to 4% by weight based on the total weight of the composition.

In another embodiment, the pharmaceutical composition of the present invention comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; A permeation enhancer selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether; weight%; 0.2 to 5.0% by weight of at least one viscosity modifier selected from the group consisting of gelatin, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; From 0.2 to 3% by weight of edetic acid or its salt; From 0.1 to 4% by weight of one or more fragrances selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil; And 5 to 20% by weight of water.

The pharmaceutical composition in the form of a hydrogel patch of the present invention has the disadvantages of conventional cataplasma and plastase, for example, skin irritation, toxicity due to residual solvent and / or unreacted monomers, long term crosslinking The problem can be avoided fundamentally. In addition, the pharmaceutical composition in the form of a hydrogel patch of the present invention can uniformly distribute a drug at a high concentration while exhibiting excellent transdermal permeability without causing problems such as crystal precipitation during manufacture and storage. In addition, since the viscosity of the preparation liquid is lower than that of the conventional cataplasma (for example, since it has a viscosity in the range of about 28,000 to 33,000 cPs), it is easy to manufacture using a comma coater, Is excellent.

The present invention relates to a pharmaceutical composition comprising a pharmaceutically active ingredient; A polyacrylic acid partial neutralization product as a gel-forming agent; A combination of an acid salt with a crosslinking agent selected from the group consisting of an aluminum salt, a magnesium salt, and a calcium salt; And 5 to 20% by weight of water in the form of a hydrogel patch.

In the pharmaceutical composition of the present invention, the above-mentioned active pharmaceutical ingredients (APIs) are not particularly limited. Preferred pharmaceutically active ingredients include anti-inflammatory analgesics, such as, for example, ketoprofen or a pharmaceutically acceptable salt thereof, flurbiprofen or a pharmaceutically acceptable salt thereof, loxoprofen or its pharmaceutical (E.g., lorodicin hydrochloride), diclofenac or a pharmaceutically acceptable indomethacin thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutically acceptable salt thereof, a diclofenac epol amine or a pharmacologically acceptable salt thereof, felbinac or a pharmaceutically acceptable salt thereof, a feloxycam or a pharmaceutically acceptable salt thereof, a methyl salicylate or a pharmacologically acceptable salt thereof, Acceptable salts and the like. More preferably, the pharmaceutically active ingredient may be a flurbiprofen or a loxoprofen sodium salt (or a hydrate thereof).

The pharmaceutically active ingredient may be used in a therapeutically effective amount, and is not particularly limited. For example, when the pharmaceutical form of the active ingredient as a FLOURE hydrogel patch containing the pen as beef agent, a pharmaceutical composition of the present invention contains the pen as FLOURE beef of the sugar unit of claim of about 70cm ² of about 20 mg can do. Also, in the form of a hydrogel patch formulation containing rhodopsin sodium hydrate as a pharmaceutically active ingredient, the pharmaceutical composition of the present invention contains about 56.7 mg of rhodopsodium sodium hydrate per about 70 cm ² of the unit formulation can do. In addition, for example, in the pharmaceutical composition of the present invention containing a therapeutically effective amount of a pharmaceutically active ingredient, the pharmaceutically active ingredient may be present in an amount of 0.2 to 18% by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention comprises a partially neutralized poly (acrylic acid) as a gel-forming agent. When a partially neutralized polyacrylic acid is used as the gel-forming agent, the pharmaceutically active ingredient is not precipitated from the hydrogel, and excellent stability can be provided even when stored for a long period of time. The polyacrylic acid partial neutralized product preferably has a degree of neutralization of preferably 25 to 70 mol%, more preferably 30 to 50 mol%. The polyacrylic acid partial neutralized product having a neutralization degree in the above range can provide a viscosity of about 500 to 10,000 (mPa 占 퐏), so that a hydrogel having excellent physical properties can be produced. Examples of the partially neutralized polyacrylic acid neutralized in the above range include commercially available polyacrylic acid partial neutralizers such as Viscomate NP-600 ^TM (SHOWA DENKO KK), Viscomate NP-700 ^TM (SHOWA DENKO KK), Viscomate NP -800 ^TM (SHOWA DENKO KK). The polyacrylic acid partial neutralized product may be present in an amount of 3 to 8% by weight, preferably 3.3 to 7.5% by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention comprises a polyvalent metal salt selected from the group consisting of an aluminum salt, a magnesium salt, and a calcium salt as a crosslinking agent for crosslinking the gel-forming agent. For example, the crosslinking agent may be selected from the group consisting of dry aluminum hydroxide gel, dihydroxy aluminum aminoacetate, aluminum hydroxide, aluminum sulfate, aluminum acetate, aluminum silicate, magnesium hydroxide, magnesium sulfate, magnesium acetate, calcium hydroxide, calcium carbonate, Calcium, calcium lactate, and calcium pantothenate. The crosslinking agent may be present in an amount of 0.5 to 3.0% by weight, preferably 0.7 to 2.0% by weight, based on the total weight of the composition. The acid includes conventional organic acids or inorganic acids and includes, for example, tartaric acid, acetic acid, propionic acid, isobutylic acid, caproic acid, caprylic acid, lactic acid, maleic acid, pyruvic acid, oxalic acid, succinic acid, tartaric acid, phthalic acid, salicylic acid, Acetylsalicylic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, and butanesulfonic acid. The acid may be present in an amount of 1 to 12% by weight, preferably 2.8 to 10.5% by weight, based on the total weight of the composition. According to the present invention, when the gel-forming agent and the crosslinking agent are combined to form a hydrogel, the aging period can be greatly shortened to about 5 days.

The pharmaceutical composition of the present invention may further comprise at least one dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol, and butylene glycol. The dispersing agent may be present in an amount of 15 to 70% by weight based on the total weight of the composition.

The pharmaceutical compositions of the present invention may also be formulated for oral care compositions comprising propylene glycol, polysorbates (e.g., polysorbate 60, polysorbate 80, etc.), sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate One or more selected solubility aids from the group. The above-mentioned solubilizing aid can not only effectively dissolve in the aqueous medium but also prevent the drug from being precipitated from the hydrogel. The dissolution aid may be present in an amount of 1 to 30 wt.%, Preferably 1.5 to 20 wt.%, Based on the total weight of the composition. If the content of the solubilizing agent exceeds 30% by weight, crosslinking may be disturbed and hydrogel formation may be difficult.

The pharmaceutical compositions of the present invention may further comprise one or more anti-leaking agents selected from the group consisting of polyacrylic acid and kaolin. The leaking agent may be present in an amount of 1 to 15% by weight, preferably 1.3 to 10.0% by weight, based on the total weight of the composition.

In one embodiment of the invention, the pharmaceutical composition of the present invention comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; And 5 to 20% by weight of water.

The pharmaceutical composition of the present invention may further comprise additives commonly used in the field of percutaneous absorption preparations. For example, the pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients selected from the group consisting of permeation enhancers, viscosity modifiers, chelating agents, and perfuming agents.

The permeation enhancer includes conventional permeation enhancers used in percutaneous absorption preparations containing a drug. For example, when the pharmacologically active ingredient is a drug such as a sodium salt of loxoprofen, a specific penetration enhancer such as isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, It has been found by the present invention that diethylene glycol monoethyl ether and / or isostearyl glyceryl ether can significantly increase the skin penetration of the pharmaceutically active ingredient and cause little skin irritation. Thus, the penetration enhancer is isopropyl US straight, lauryl alcohol, polyoxyethylene lauryl ether [polyoxyethylene lauryl ether, e.g. BL2 ^TM (Note) Southeast synthesis, etc.], propylene glycol monolaurate [propylene glycol monolaurate, PGML , Diethylene glycol monoethyl ether (DGME), and isostearyl glyceryl ether (e.g., GE-IS ^TM (Kao Corporation), etc.) Or more. The permeation enhancer may be present in an amount of 0.5 to 20% by weight based on the total weight of the composition.

The viscosity adjusting agent may be selected from the group consisting of gelatin, polyvinyl alcohol, carboxymethyl cellulose sodium, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, and may be selected from the group consisting of 0.2 to 5.0 wt% Can exist.

The viscosity adjusting agent may be selected from the group consisting of gelatin, polyvinyl alcohol, carboxymethyl cellulose sodium, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose, but is not limited thereto. The viscosity modifier may be present in an amount of 0.2 to 5.0 wt.%, Preferably 0.5 to 4.5 wt.%, Based on the total weight of the composition. If the amount of the viscosity modifier is more than 5% by weight, the transdermal permeability of the drug may be lowered and the adhesion to the skin may be lowered.

The chelating agent may be edetic acid or a salt thereof (for example, sodium edetate, calcium edetate, etc.) and may be present in an amount of 0.2 to 3% by weight based on the total weight of the composition.

The perfume may be selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil, and may be present in an amount of 0.1 to 4% by weight based on the total weight of the composition.

In another embodiment of the invention, the pharmaceutical composition of the present invention comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; A permeation enhancer selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether; weight%; 0.2 to 5.0% by weight of at least one viscosity modifier selected from the group consisting of gelatin, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; From 0.2 to 3% by weight of edetic acid or its salt; From 0.1 to 4% by weight of one or more fragrances selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil; And 5 to 20% by weight of water.

The present invention also provides a method for preparing the pharmaceutical composition in the form of the hydrogel patch. For example, the present invention relates to a pharmaceutical composition comprising: (a) preparing a first solution by dissolving a pharmaceutically active ingredient or a pharmaceutically active ingredient and a permeation enhancer, optionally together with a fragrance, in a dissolution aid; (b) dissolving an acid, a chelating agent and a viscosity controlling agent in water to prepare a second solution; (c) dispersing the polyacrylic acid partial neutralized product, the crosslinking agent, and the leakage preventing agent into a dispersant to prepare a dispersion; And (d) mixing the first solution, the second solution, and the dispersion to form a hydrogel. The present invention also provides a method for preparing a pharmaceutical composition in the form of a hydrogel patch.

It will be apparent to those skilled in the art that the steps (a), (b), and (c) do not necessarily have to be performed sequentially in the manufacturing method of the present invention. The dissolution of step (a) is preferably carried out under heating. For example, the dissolution of step (a) can be carried out by stirring at 50-55 占 폚. The dissolution of step (b) is also preferably carried out under heating, for example, by stirring at about 40 < 0 > C. The mixing of step (d) may be performed, for example, by mixing the first solution and the second solution, followed by further mixing the dispersion, but is not limited thereto.

The pharmaceutical composition in the form of a hydrogel patch of the present invention can be formulated in the form of a patch (i.e., a hydrogel patch) or the like. For example, the hydrogel obtained according to the present invention may be coated on a release film, dried at 60 ° C to 100 ° C for 3 to 5 minutes, and then formed into a support layer to form a formulation having a patch form . Obtained formulations may be obtained an appropriate size, for example 70cm ^2/1-sheet, 25cm ^2/1 The pharmaceutical composition of the hydrogel patch form was cut to a size such as sheets of paper. The release film may be a commonly used release liner or a laminate thereof. Examples of the release film include polyethylene terephthalate, cast polypropylene, silicone resin or polyethylene coated with a fluororesin, polyester, polyvinyl chloride, Polyvinylidene chloride, and the like, paper, or a laminate thereof. Also, as the support layer (also referred to as a backing membrane), a drug-absorptive and flexible substance commonly used can be used. For example, nonwoven fabric, nonwoven fabric coated with polyurethane, polyolefin, Polyether, multi-layer ethylene vinyl acetate film, polyester, polyurethane and the like can be used.

 Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are for illustrating the present invention, and the present invention is not limited to these examples and test examples.

Examples 1-6: Preparation of hydrogels and patches containing them

Hydrogels were prepared according to the ingredients and contents in Table 1 below. The content of Table 1 represents the weight percentage of each component in the hydrogel. Flurbiprofen and L-menthol were dissolved in a solubilizing aid (propylene glycol, polysorbate 80, and / or sorbitan oleate (Span 80 ^™ )] And dissolved by stirring at 50-55 DEG C (solution A). (Sodium carboxymethylcellulose, and / or hydroxypropylcellulose) were added to purified water and dissolved by stirring at about 40 占 폚 (solution B). Polyacrylic acid partial neutralization product (Viscomate NP-800 ^TM , SHOWA DENKO KK) and a crosslinking agent [aluminum hydroxide and / or dihydroxy aluminum aminoacetate], leakage inhibitor [polyacrylic acid and / or kaolin] Polyethylene glycol] (Dispersion C). The solution A and the solution B were mixed, and then the dispersion C was mixed. The obtained mixed solution was applied to a polyethylene terephthalate separator film, dried at 100 DEG C for about 5 minutes, and then a nonwoven fabric was laminated as a support and aged at room temperature for about 5 days. After aging was cut (70cm ^2/1 sheet) was prepared in a pharmaceutical composition of the hydrogel patch form. The water (purified water) content in Table 1 represents the content (% by weight) in the composition obtained by cutting after aging.

	ingredient	Example
		One	2	3	4	5	6
chief ingredient	Flulubiprofen	0.81	0.81	0.81	0.81	0.81	0.81
Gel formers	Polyacrylic acid partial neutralization product	6.51	6.51	6.51	6.51	6.51	6.51
Dispersant	glycerin	68.4	38.4	68.23	69.16	58.4	68.4
	Polyethylene glycol	-	30	-	-	-	-
Crosslinking agent	Dried aluminum hydroxide gel	0.74	0.74	0.85	0.74	0.74	0.74
	Dihydroxy aluminum aminoacetate	0.49	0.49	0.55	0.49	0.49	0.49
	Tartaric acid	3.24	3.24	3.24	4.0	3.24	3.24
Dissolution aid	Propylene glycol	-	-	-	-	10	-
	Polysorbate 80	0.49	0.49	0.49	0.49	0.49	0.49
	Sorbitan oleate	1.09	1.09	1.09	1.09	1.09	1.09
Viscosity modifier	Carboxymethylcellulose sodium	0.63	0.63	0.63	0.63	0.63	-
	Hydroxypropylcellulose	-	-	-	-	-	0.63
Chelating agent	Sodium edetate	1.54	1.54	1.54	1.54	1.54	1.54
air freshener	L-menthol	0.61	0.61	0.61	0.61	0.61	0.61
Anti-leakage agent	Polyacrylic acid	0.97	0.97	0.97	0.97	0.97	0.97
	kaoline	0.85	0.85	0.85	0.85	0.85	0.85
water	Purified water	13.63	13.63	13.63	13.63	13.63	13.63

Examples 7 to 11: Preparation of hydrogel and patch containing it

Hydrogels were prepared according to the ingredients and contents in Table 2 below. The content in Table 2 represents the weight percentage of each component in the hydrogel. L-menthol was added to dissolution aids (propylene glycol, polysorbate 80, and / or sorbitan oleate (Span 80 ^™ )], and 50-55 Lt; 0 > C (solution A). (Sodium citrate or acetic acid), sodium edetate, and a viscosity regulator (carboxymethylcellulose sodium and / or gelatin) were added to purified water and dissolved by dissolution at about 40 ° C (solution B). Polyacrylic acid partial neutralization product (Viscomate NP-800 ^TM , SHOWA DENKO KK) and a crosslinking agent [aluminum hydroxide and / or dihydroxy aluminum aminoacetate], leakage inhibitor [polyacrylic acid and / or kaolin] Polyethylene glycol] (Dispersion C). The solution A and the solution B were mixed, and then the dispersion C was mixed. The obtained mixed solution was applied to a polyethylene terephthalate separator film, dried at 100 DEG C for about 5 minutes, and then a nonwoven fabric was laminated as a support and aged at room temperature for about 5 days. After aging was cut (70cm ^2/1 sheet) was prepared in a pharmaceutical composition of the hydrogel patch form. The water (purified water) content in Table 2 represents the content (% by weight) in the composition obtained by cutting after aging.

	ingredient	Example
		7	8	9	10	11
chief ingredient	Sodium losoprofen sodium hydrate	2.40	2.40	2.40	2.40	2.40
Gel formers	Polyacrylic acid partial neutralization product	6.74	6.74	6.74	6.74	6.74
Dispersant	glycerin	58.73	58.73	48.73	-	58.73
	Polyethylene glycol	-		-	58.73
Crosslinking agent	Dried aluminum hydroxide gel	0.85	0.85	0.85	0.85	0.85
	Dihydroxy aluminum aminoacetate	0.42	0.42	0.42	0.42	0.42
	Tartaric acid	3.17	-	3.17	3.17	3.17
	Acetic acid	-	3.17	-	-	-
Permeation accelerator	Isostearyl glyceryl ether	0.85	0.85	0.85	0.85	0.85
Dissolution aid	Propylene glycol	-	-	10	-	-
	Polysorbate 80	3.59	3.59	3.59	3.59	3.59
	Sorbitan oleate	3.59	3.59	3.59	3.59	3.59
Viscosity modifier	Carboxymethylcellulose sodium	0.66	0.66	0.66	0.66	-
	gelatin					0.66
Chelating agent	Sodium edetate	1.69	1.69	1.69	1.69	1.69
air freshener	L-menthol	0.42	0.42	0.42	0.42	0.42
Anti-leakage agent	Polyacrylic acid	1.01	1.01	1.01	1.01	1.01
	kaoline	0.88	0.88	0.88	0.88	0.88
water	Purified water	15	15	15	15	15

Test Example 1. Percutaneous permeation test

Percutaneous permeation tests on the pharmaceutical compositions in the form of hydrogel patches prepared in Examples 1 to 11 were carried out using Franz cell under the following conditions.

<Percutaneous penetration test conditions>

- Hairless mouse skin (female, 6 weeks old), 3 per group

- Temperature / stirring speed: 32 ° C / 600 rpm

- Buffer: pH 7.4

The results of the transdermal permeation test are shown in Tables 3 and 4 below.

	Percutaneous permeation rate (/ / cm 2 / hr)	Cumulative transdermal permeation (/ / cm 2 )
		6 hours	12 hours
Example 1	16.09	107.9	255.57
Example 2	18.2	99.8	238.2
Example 3	20.5	111.5	272.3
Example 4	15.2	99.8	148.2
Example 5	14.7	98.1	130.2
Example 6	15.3	100.02	138.96

	Percutaneous permeation rate (/ / cm 2 / hr)	Cumulative transdermal permeation (/ / cm 2 )
		6 hours	12 hours
Example 7	19.78	128.88	236.23
Example 8	14.8	90.2	154.5
Example 9	22.8	148.25	253.25
Example 10	18.36	110.35	225.29
Example 11	19.69	125.52	235.98

From the results of Table 3 and Table 4, it can be seen that the pharmaceutical composition in the form of a hydrogel patch according to the present invention shows excellent skin permeability.

Test Example 2. Skin irritation evaluation

Skin irritation was evaluated for the hydrogel patch preparations prepared in Examples 1-11. As a comparative example, commercially available flockpen ( ^TM) pastes (Dongfang Pharmaceutical Co., Ltd.) and Rocksona ^TM pastes (Dongfang Pharmaceutical Co., Ltd.) were used, respectively. Each formulation was attached to the arms of five healthy adult males and skin irritation was assessed after 30 minutes. The degree of redness was analyzed by checking the skin color (erythema, a value) before and after the attachment using a colorimeter (CHROMA METER CR400, KONICA MINOLTA). The results are shown in Table 5 and Table 6 below. The redness values in Tables 5 and 6 are the average values of each test group.

Skin irritation score	Redness [a value]
Flock pen attachment	5.24
Example 1	3.25
Example 2	2.89
Example 3	3.11
Example 4	2.98
Example 5	2.68
Example 6	2.21

Skin irritation score	Redness [a value]
Rock Sona Paste	5.52
Example 7	2.2
Example 8	2.52
Example 9	2.84
Example 10	2.41
Example 11	2.87

As can be seen from the results of Tables 5 and 6, the skin patch of the hydrogel patch according to the present invention was significantly reduced as compared with the conventional patch formulation (Comparative Example).

Test Example  3. Hydrogel  Viscosity measurement of composition

The hydrogel patch compositions prepared in Examples 1 to 7 were allowed to stand at room temperature for 2 hours, and their viscosities were measured using a Brookfield RV viscometer, Spindle 6 at 20 ° C and 10 rpm, Table 7 shows the results.

	Viscosity (cPs)
Example 1	28,000
Example 2	32,000
Example 3	29,000
Example 4	33,000
Example 5	28,600
Example 6	30,000
Example 7	30,000

From the results shown in Table 7, the pharmaceutical composition of the patch type obtained according to the present invention maintained a viscosity in the range of 28,000 to 33,000 cPs over 2 hours, which was easy to manufacture using, for example, a comma coater It is not only excellent in preparation and workability but also can be easily applied at the time of application.

Claims (18)

1. A pharmaceutically active ingredient; A polyacrylic acid partial neutralization product as a gel-forming agent; A combination of an acid salt with a crosslinking agent selected from the group consisting of an aluminum salt, a magnesium salt, and a calcium salt; And 5 to 20% by weight of water in the form of a hydrogel patch.
2. 3. The composition of claim 1 wherein the pharmaceutically active ingredient is selected from the group consisting of ketopropene or a pharmaceutically acceptable salt thereof, flurbiprofen or a pharmaceutically acceptable salt thereof, loxoprofen or a pharmaceutically acceptable salt thereof, , Lidocaine or a pharmaceutically acceptable salt thereof, diclofenac or a pharmaceutically acceptable indomethacin or a pharmacologically acceptable salt thereof, diclofenac eipolamine or a pharmaceutically acceptable salt thereof, felbinac or a pharmacologically acceptable salt thereof, A pharmaceutically acceptable salt thereof, an acceptable salt, a piroxycam or a pharmaceutically acceptable salt thereof, and a methyl salicylate or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition according to claim 1, wherein the polyacrylic acid partial neutralized product has a degree of neutralization of 25 to 70 mol%.
4. The pharmaceutical composition according to claim 1, wherein the polyacrylic acid partial neutralization is present in an amount of 3 to 8% by weight based on the total weight of the composition.
5. The method of claim 1, wherein the crosslinking agent is selected from the group consisting of dry aluminum hydroxide gel, dihydroxy aluminum aminoacetate, aluminum hydroxide, aluminum sulfate, aluminum acetate, aluminum silicate, magnesium hydroxide, magnesium sulfate, magnesium acetate, calcium hydroxide, calcium carbonate, Calcium gluconate, calcium gluconate, calcium lactate, and calcium pantothenate.
6. 2. The pharmaceutical composition according to claim 1, wherein the crosslinking agent is present in an amount of 0.5 to 3.0% by weight based on the total weight of the composition.
7. The method of claim 1, wherein the acid is selected from the group consisting of tartaric, acetic, propionic, isobutyric, caproic, caprylic, lactic, maleic, pyruvic, oxalic, succinic, tartaric, phthalic, salicylic, benzoic, acetylsalicylic, methanesulfonic, Sulfonic acid, sulfonic acid, sulfonic acid, propanesulfonic acid, and butanesulfonic acid.
8. 2. The pharmaceutical composition according to claim 1, wherein the acid is present in an amount of 1 to 12% by weight based on the total weight of the composition.
9. 3. The composition of claim 1, further comprising at least one dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol, wherein the dispersant is present in an amount of from 15 to 70% &Lt; / RTI &gt;
10. The composition of claim 1, further comprising a solubility aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate, Is present in an amount of from 1 to 30% by weight based on the total weight of the composition.
11. The pharmaceutical composition according to claim 1, further comprising at least one anti-leakage agent selected from the group consisting of polyacrylic acid and kaolin, wherein the anti-leak agent is present in an amount of 1 to 15% by weight based on the total weight of the composition .
12. The composition according to claim 1, which comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; And 5 to 20% by weight of water.
13. 13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising at least one pharmaceutically acceptable additive selected from the group consisting of a permeation enhancer, a viscosity modifier, a chelating agent, and a perfume.
14. 14. The method of claim 13, wherein the permeation enhancer is selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether One or more selected from the group; Is present in an amount of from 0.5 to 20% by weight, based on the total weight of the composition.
15. 14. The composition of claim 13, wherein the viscosity modifier is selected from the group consisting of gelatin, polyvinyl alcohol, carboxymethylcellulose sodium, hydroxypropylcellulose, and hydroxypropylmethylcellulose; Is present in an amount of from 0.2 to 5.0% by weight, based on the total weight of the composition.
16. 14. The pharmaceutical composition according to claim 13, wherein the chelating agent is edetate or a salt thereof and is present in an amount of 0.2 to 3% by weight based on the total weight of the composition.
17. 14. The method according to claim 13, wherein the perfume is at least one selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil and is present in an amount of 0.1 to 4% &Lt; / RTI &gt;
18. 14. The pharmaceutical composition according to claim 13, which comprises 0.2 to 18% by weight of a pharmaceutically active ingredient; 3 to 8 wt% of polyacrylic acid partial neutralized product; 0.5 to 3.0 wt% of a crosslinking agent selected from the group consisting of aluminum salts, magnesium salts, and calcium salts; 1 to 12% by weight of acid; 15 to 70% by weight of a dispersant selected from the group consisting of glycerin, polyethylene glycol, dipropylene glycol and butylene glycol; 1 to 30% by weight of a dissolution aid selected from the group consisting of propylene glycol, polysorbate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan stearate; A permeation enhancer selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether; weight%; 0.2 to 5.0% by weight of at least one viscosity modifier selected from the group consisting of gelatin, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; From 0.2 to 3% by weight of sodium edetate or its salt; From 0.1 to 4% by weight of one or more fragrances selected from the group consisting of L-menthol, DL-campa, eucalyptol, and peppermint oil; And 5 to 20% by weight of water.