KR20060049598A - Novel transdermal preparation and its producing method - Google Patents

Abstract

The present invention relates to a transdermal absorbent formulation comprising a hydrophobic polymer adhesive matrix layer and a method for preparing the same. In the formulation of the present invention, the droplets containing the active ingredient are dispersed evenly in the polymer matrix, thus exhibiting high skin absorption, and the manufacturing process is simple and can contain a high concentration of the active ingredient without limitation depending on the solubility of the active ingredient. Applicable to eggplant drugs.

Matrix, Percutaneous Absorption Agent, Volatile Organic Solvent, Polar Aprotic Organic Solvent

Description

Novel transdermal preparation and its manufacturing method

1 is a schematic diagram of a matrix formation process in which droplets are dispersed.

Number 1 is the state before drying the volatile solvent, i.e. a single stable solution phase,

Step 2 is a state in which the volatile solvent is dried, that is, the liquid phase and the adhesive phase begin to separate.

3 shows the state after drying the volatile solvent, that is, the droplet containing the active ingredient is dispersed in the matrix,

2 is a cross-sectional view of a transdermal absorbent preparation incorporating a matrix of droplets dispersed therein,

(1, support; 2, matrix layer; 3, release paper; 4, support layer; 5, skin layer)

Figure 2a is a transdermal absorption preparation in which the matrix in which the droplets are dispersed is introduced,

Figure 2b is a transdermal absorbent preparation in which the matrix in which the droplets are dispersed and the support layer are introduced,

Figure 2c shows a transdermal absorbent preparation in which the droplet dispersion matrix, the support layer and the skin layer are introduced,

3A and 3B are optical micrographs of Comparative Example 1 (x200) and Example 3 (x1000), respectively.

The present invention relates to a transdermal absorbent formulation comprising a hydrophobic polymer adhesive matrix layer and a method for preparing the same.

The delivery of the active ingredient through the skin enhances the patient's compliance, and the active ingredient absorbed through the digestive system during oral administration is metabolized in the liver to avoid the first pass effect that halves the effect or causes side effects. There is an advantage that the patient can control the time to do. Therefore, a number of studies for obtaining a disease treatment effect using the delivery method of the active ingredient through the skin has been progressed, and the formulations invented as a result of the study collectively called transdermal absorption preparations.

With the exception of external preparations such as lotions and creams, transdermal absorption agents developed to date can be classified into two types: transdermal absorption agents operated by passive transfer system and active transfer system. It is a transdermal absorption agent that is operated by. Passive delivery mechanism is to deliver the active ingredient only depend on the distribution and diffusion depending on the concentration of the active ingredient, active delivery mechanism is to deliver the active ingredient by using physical external force such as electricity, ultrasound, heat, magnetic force.

Transdermal absorption preparations that deliver active ingredients by passive delivery mechanisms are largely classified into a reservoir type and a matrix type according to the structure of the preparation. Storage tank is easy to control the permeation rate of the active ingredient, it is easy to control the broad content of the active ingredient depending on the composition of the composition present in the reservoir. However, the storage mold has a disadvantage in that the production process is complicated, the thickness is thick, and the flexibility is inconvenient to use. On the other hand, the matrix type is made of a form in which the active ingredient is dissolved in the pressure-sensitive adhesive or polymer material, or the active ingredient particles are dispersed. The matrix type has the disadvantage that it cannot contain the active ingredient at a high concentration due to the influence of the material constituting the matrix containing the active ingredient, but the production process is simple, and the thickness is 100 μm or 1000 μm or less, and it is bent Good castle, easy to use. Especially when applied to the joint area, the matrix type is very advantageous. The matrix type is classified according to the position of the layer containing the active ingredient, the form containing the active ingredient, and whether or not a semipermeable membrane is used to control the rate of delivery of the active ingredient.

The present invention is one of the matrix type transdermal absorption agent for delivering the active ingredient through the skin. Conventional techniques for the matrix-type transdermal absorption agent which delivers the active ingredient by a passive delivery mechanism developed previously and do not physically damage the stratum corneum, which is the outermost layer of the skin, are as follows.

In the simplest, there is a technique (US Pat. No. 3,632,740) for dissolving the active ingredient below a saturation concentration in an acrylic adhesive or a rubber-based adhesive. This technique has a weak point that the content of the active ingredient is very limited and the possible active ingredient varies depending on the type of adhesive used. As a technique developed to overcome the limitations of the method of simply mixing the active ingredient and the pressure-sensitive adhesive in the preparation of a matrix for transdermal absorption preparations for the purpose of delivery of the active ingredient, the crystal state is obtained by excessively mixing the active ingredient in the pressure-sensitive adhesive or polymer material. (US Pat. No. 5,958,447, 5965154), technology for dissolving the active ingredient using a solvent and uniformly mixing it with the adhesive to contain an excessive amount of the active ingredient that is insoluble in the adhesive (US Patent 6211425, 5948433), A method of controlling the rate of delivery of the active ingredient and the amount of the active ingredient supported by a method of mixing polymers having different solubilities (US Patent 6235306, Republic of Korea Patent Application 2002-7016273, Republic of Korea Patent 194968, Republic of Korea Patent 0336975) Technology using a semipermeable membrane to control the rate of ingredient delivery (US Patent 4201211), transdermal Technology for controlling the drug delivery rate by using moisture such as sweat generated when attaching the homemade agent to the skin (US Patent 4668232, 5505956), diffusion to control the diffusion rate of the drug in the matrix carrying the drug Technology using accelerators (US Pat. No. 5164189), technology of encapsulating a drug active ingredient in polymer nanoparticles, and mixing the polymer nanoparticles with an adhesive (Korean Patent Application 2001-0019869), with liquid droplets forming liquid droplets in a matrix. Dispersion technology (Korean Patent 393478), an amphoteric polymer having heat-sensitive and water-sensitive, is used to prepare a matrix that can stabilize the active ingredients that are less stable to water or oil Technology (US Pat. No. 4997656).

Among them, technologies for dissolving an active ingredient in a solvent or a skin absorption enhancer and then mixing it with a polymer material including an adhesive have a disadvantage in that the skin adhesion performance of the transdermal absorption agent is drastically reduced when an excess solvent or skin absorption enhancer is used. In addition, the solvent or skin absorption enhancer to be used must be compatible with the pressure-sensitive adhesive or polymer material, there is a limit to increase the active ingredient content, there is a disadvantage that the type of pressure-sensitive adhesive can be used depending on the type of solvent used.

In the case of the prior art in which the liquid phase region is included on the matrix (Korean Patent 393478), a technique in which an organic solvent is present in a liquid region by mixing a surfactant having self-emulsifying ability with an aqueous adhesive containing water. There is a disadvantage that cannot be used in the matrix manufacturing process to be used.

The technology using nanoparticles or the technology using semi-permeable membranes for controlling the drug delivery rate has a disadvantage in that the manufacturing process is very complicated or the economic cost is excessive. The method of controlling water content by placing several layers also has a disadvantage in that the manufacturing process is complicated.

The inventors of the present invention in the development of a matrix-type transdermal absorption agent that delivers the active ingredient through the skin, can contain a high concentration of the active ingredient without limitation according to the solubility of the active ingredient, shows a high skin absorption, the manufacturing process is We wanted to create a simple system.

The present invention relates to a transdermal absorbent formulation comprising a hydrophobic polymer adhesive matrix layer and a method for preparing the same.

The present invention relates to a transdermal absorbent comprising a hydrophobic polymer adhesive matrix layer,

Droplets containing the active ingredient and alkanolamine are evenly dispersed in the hydrophobic polymer adhesive matrix,

The alkanolamine is a transdermal absorption agent that is a liquid substance represented by the following formula:

(Wherein R ¹ , R ² and R ³ are each independently alkyl or hydrogen having 2 to 9 carbon atoms substituted with one hydroxy group; at least one of R ¹ , R ² and R ³ is substituted with one hydroxy group) Alkyl having 2 to 9 carbon atoms.)

It is about.

The matrix layer of the transdermal absorbent preparation according to the present invention is 40 to 90% by weight of the hydrophobic polymer adhesive, 5 to 60% by weight of the alkanolamine, and 0.5 to 25% by weight of the active ingredient based on the total weight of the matrix layer after the preparation. It is preferable to include in a composition.

The thickness of the prepared matrix is preferably 10 to 120 ㎛.

As the hydrophobic polymer adhesive which can be applied to the preparation of the matrix layer of the transdermal absorbent according to the present invention, at least one component selected from the group consisting of an acrylic adhesive, a rubber-based adhesive, and a silicone adhesive may be used.

The acrylic pressure-sensitive adhesive is methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, Acrylic monomers to which an alkyl group having 1 to 18 carbon atoms is added, including decyl methacrylate, undecyl methacrylate, dodecyl methacrylate, and tridecyl methacrylate; And it is preferable that at least one monomer selected from the group consisting of acrylic acid, methacrylic acid and an acrylic monomer to which a hydroxy group is added is polymerized,

The rubber-based pressure-sensitive adhesive is preferably at least one component selected from the group consisting of natural rubber, styrene copolymer, polyisoprene, and polyisobutylene.

The alkanolamine which may be included in the matrix layer of the transdermal absorbent preparation according to the present invention preferably has a melting point of 0 ° C. to 35 ° C. under atmospheric pressure, and specifically, for example, ethanolamine, diethanolamine, Triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine and the like. These can be used as a single solvent or two or more mixed solvents.

The prior art using the composition of the most similar to the composition applied in the present invention is the use of tromethamine, one of alkanolamines, and dimethyl sulfoxide as a dissolution aid for the solubility of pyroxicam and skin absorption improvement (Korea 0332210). In the case of tromethamine, since it is not a liquid substance, it cannot be dispersed in the matrix layer of the transdermal absorbent preparation of the present invention to form droplets. Therefore, the drug cannot be prepared by containing a high concentration of the drug in the matrix layer without crystallization in the state of using a poorly soluble drug in the organic solvent applied to the common acrylic pressure-sensitive adhesive in the solution phase composition.

In the case of the technique using the alkanolamine used as the droplet-forming substance in the present invention as a skin absorption enhancer (Japanese Patent 2004-131495) presents an example of using alkanolamine and alkanolamide as a skin absorption enhancer of meloxycam Doing. However, alkanolamine alone cannot dissolve a poorly soluble drug such as meloxycamp in a pressure-sensitive adhesive solution using an organic solvent such as ethylacetate, and alkanolamine itself is also an organic solvent such as ethyl acetate or hexane. Due to the low compatibility with the solvent, it is impossible to form a uniform solution and thus formulation is impossible.

As an active ingredient included in the matrix layer of the transdermal absorbent preparation according to the present invention, an ionic, weak ionic or nonionic drug may be used. Examples of the applicable ingredients include clonidine and ricinopril. (lisinopril), nisoldipine, perindopril, terazosin and its derivatives, including terazosin and tetrazosin HCl, alprazolam, amlodipine and amlodipine besyl Its derivatives, including amlodipine besylate, its derivatives, including atrovastatin, auranofin, azatadine and azatadine maleate, bupivacaine and Derivatives thereof comprising bupivacaine HCl, derivatives including buprenorpine, buspione and buspioneHCl, Derivatives thereof, including cetirizine and cetirizineHCl, derivatives thereof, including cerivastatin and cerivastatin Na, clonazepam, colchicine , Cyclobenzaprine, cyclobenzaprine hydrochloride (cyclobenzaprine HCl), derivatives containing doxazosin and doxazosin mesyleate, felodipine, fentanyl, fentanyl, sufentanyl ), Finasteride, derivatives thereof, including goserilin and goserilin acetate, granisetron, granisetron HCl, hexoprenaline , Hexoprenaline HCl, indapamide, ketotifen fumarate, leucovorin, leucovorin Ca, levotilock (levothyroxine), levothyroxine Na, loratadine, metolazone, methroxyprogesterone, medroxyprogesterone acetate, medroxyprogesterone acetate, naltrexone, naltrexone hydrochloride ), Nitroglycerin, norgestrel, nogestgestrol, nomegestrol, nomegestrol HCl, olanzapine, simvastatin, celecoxib, celecoxib, lopecok Rofecoxib, meloxicam, tenoxicam, isoxicam, piroxicam, ketoprofen, ketoprofen and its derivatives, derivatives, flu Flurbiprofen, fenoprofen, naproxen, naproxen, indomethacin, aceclofenac, diclofenac, isosorbide, isosorbide (isosorbide) i sosorbide mononitrate, isosorbide dinitrate, suprofen, lidocaine, lidocaine, hydrocortisone, cortisone, indoprofen, tulobuterol, Tulobuterol HCl, tramadol, tramadol, tramadol HCl, oxybutynin, tolterodine and the like, and derivatives thereof or pharmaceutically acceptable salts thereof have.

The matrix layer of the transdermal absorbent preparation according to the present invention may further comprise one or more skin absorbents. The content of the additional component is preferably 0.5 to 15% by weight based on the total weight of the matrix layer after the matrix is prepared.

Skin absorption enhancers that can be used in the present invention, for example,

Fatty acids including linoleic acid, oleic acid, palmitic acid, stearic acid, capric acid, and myristic acid;

Polyhydric alcohols including propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, monoethyl ether and glycerol;

Surfactants including tween80, Labrasol, Cremophor;

Fatty acid alcohols including oleyl alcohol and stearyl alcohol;

Fatty acid esters including isopropyl myristate, propylene glycol caprylate, propylene glycol laurate, polyethylene glycol laurate;

And fatty acid alkanolamides including lauryl dimethanolamide.

The matrix layer of the transdermal absorbent preparation according to the present invention may further comprise one or more thickeners to enhance the coating comfort for preparing the matrix and to improve the formulation stability after drying. The content of the additional component is preferably 0.5 to 15% by weight based on the total weight of the matrix layer after manufacture.

Thickeners that can be used in the present invention include, for example, polyvinylpyrrolidone, polyethylene oxide, silicon oxide, aluminum oxide and titanium oxide.

The transdermal absorbent formulation including the matrix layer in which the droplets are dispersed, which is developed in the present invention, may further include a support and a release paper together with the matrix layer in which the droplets are dispersed. In addition, it may further include a tie-layer to increase the adhesion of the support and the matrix, and further includes a skin adhesion layer that can increase the adhesion retention time by increasing the adhesion with the skin. It may be. (Figure 2)

The support applied to the percutaneous absorption preparations described above is to maintain the appearance of the percutaneous absorption preparations, to prevent the loss of the active ingredient, and to increase convenience.

Moisture permeability or moisture ratio, consisting of one or more components selected from the group consisting of polyethylene, polyolefin including polypropylene, polyester, polyurethane and aluminum Permeable film; or

The above-described polyolefine, polyester, nylon (nylon) and cotton selected from the group consisting of a single or two or more components are composed of a woven or non-woven fabric.

The release paper may be a paper coated with silicon or fluorohydrocarbon resin, or a polymer film coated with silicon or fluorohydrocarbon resin.

The to-be-adhered layer and the support-adhesive layer, which may be included separately or in addition to the transdermal absorbent preparation according to the present invention, preferably have a composition of 70 to 99% by weight, based on dry weight, of the polymer adhesive. It contains 1 to 30% by weight of the additive used to improve the adhesive property, that is, the adhesive performance improving agent. In addition, each layer thickness is preferably 10 to 100 m.

Examples of the polymer adhesive that may be included in the skin adhesion layer and the support adhesion layer include an acrylic adhesive; Rubber-based pressure-sensitive adhesives including natural rubber, styrene copolymers, polyisoprene and polyisobutylene; And at least one component selected from the group consisting of silicone pressure sensitive adhesives.

Examples of the adhesive performance improving agent which may be included in the skin adhesion layer and the support adhesion layer,

Fatty acid esters including isopropyl myristate, propylene glycol caprylate, propylene glycol laurate, polyethylene glycol laurate, propylene glycol oleate and the like;

Polyethylene glycol;

Polyethylene glycol-polypropylene glycol copolymers;

Polyvinylpyrrolidone; And

Inorganic fillers including silicon oxide, aluminum oxide and titanium oxide

In the group consisting of a single or a mixture of two or more.

According to another aspect of the present invention, there is provided a method for preparing a transdermal absorbent preparation according to the present invention, which comprises a pharmaceutical ingredient, a volatile organic solvent, a polymer adhesive soluble in a volatile organic solvent, a polar aprotic organic solvent, and a solution mixture containing alkanolamine. Through the process of removing the volatile organic solvent, the method for producing a transdermal absorbent, characterized in that to prepare a matrix layer so that the droplet containing the drug active ingredient is dispersed evenly in the polymer matrix.

0.01 to 10% by weight of the active ingredient, 5 to 25% by weight of the polymer adhesive, 20 to 60% by weight of the organic solvent, 6 to 55% by weight of the polar aprotic organic solvent, and 1 of the alkanolamine in the solution mixture. It is preferably included in 15 to 15% by weight.

As the volatile organic solvent that can be applied to the present invention,

Hydrocarbons including hexane, heptane and the like;

Alcohols including methanol, ethanol, propanol and the like;

Halogenated hydrocarbons including methylene chloride, chloromethane and the like;

Aromatic hydrocarbons including benzene, toluene, xylene and the like; And

Polar organic solvents containing ethylacetate, acetone, tetrahydrofuran, etc.

A solvent alone or a mixture of solvents selected from the group consisting of atmospheric boiling point at 40 to 110 ° C is mentioned. The polymer adhesive applied to prepare the matrix may be used in a state dissolved in the volatile organic solvent.

Examples of polar aprotic organic solvents used in the present invention include dimethylsulphoxide, dimethylacetamide, dimethylformamide, dimethylisosorbide and the like, or a single solvent or a mixture of two or more thereof. Can be used as a solvent. It is preferable that the boiling point exceeds 150 degreeC.

By the way, although the boiling point of the polar aprotic organic solvent used in the present invention is preferably higher than 150 ℃, the volatile organic solvent and the polar ratio in the drying process of the volatile organic solvent in the matrix layer manufacturing process of the transdermal absorbent preparation according to the present invention. The magnetic organic solvent forms an azeotrope and dries considerably. Therefore, the transdermal absorption preparation of the present invention may contain some of the polar aprotic organic solvents described above or may not be included at all.

The polar aprotic organic solvent contained in the solution phase mixture for preparing the matrix layer of the transdermal absorbent preparation according to the present invention compensates for the low compatibility between the alkanolamine, which is a main component of droplet formation, and the organic solvent, thereby forming droplets in the solution phase mixture. Suppresses phase separation of solvent substances. By using a polar aprotic organic solvent, a homogeneous solution phase mixture containing droplet forming materials can be obtained, thus facilitating spreading or coating on release paper for matrix production.

The matrix in which the droplets developed in the present invention are dispersed may include, for example, a polymer adhesive dissolved in a volatile solvent, a polar aprotic organic solvent, an alkanolamine, and an active ingredient (as necessary, a skin absorption enhancer and / or a thickener). By coating) on a film material such as release paper to mix to a certain thickness, and then removing the volatile organic solvent through solvent evaporation.

The droplets in the matrix developed in the present invention are formed because the polymer adhesive forming the matrix has low compatibility with the active ingredient and alkanolamine forming the droplets. When the organic solvent in the solution prepared to form the matrix is removed, only the pressure-sensitive adhesive component and non-volatile components remain, and the polymer adhesive causes phase separation due to its low compatibility with the active ingredient and alkanolamine forming the droplets. At this time, the polymer material forms the outer phase of the matrix, and the liquid phase composed of the active ingredient and the alkanolamine and the like is dispersed while forming fine liquid microspheres, that is, droplets in the polymer matrix (FIG. 1).

The matrix in which the droplets described in the present invention are dispersed is not only easily prepared through the volatile organic solvent drying method, but also may contain a large amount of a wide range of active ingredients regardless of the polarity or dissolution characteristics of the active ingredients, and exhibits high skin absorption. In addition, while containing a large amount of the liquid in the matrix, it is possible to suppress the phenomenon that the liquid material, which is a weak point that appears easily in the matrix containing a large amount of liquid.

For example, a method for producing a matrix in which the droplets according to the present invention are dispersed is as follows. The active ingredient, the polymer adhesive, the polar aprotic organic solvent and the alkanolamine, and other additives, if necessary, are mixed according to the composition and stirred until a clear solution is formed. In this case, the polymer pressure-sensitive adhesive may be purchased and used as provided in a dissolved state in a volatile organic solvent, otherwise, if a solid polymer pressure-sensitive adhesive is purchased, it is first dissolved in a volatile organic solvent and then used for preparing the matrix layer of the transdermal absorbent of the present invention. Can be used. Bubbles in the solution composition prepared by stirring are removed and coated on a polyethylene terephthalate release paper coated with a silicone polymer to maintain a constant thickness after drying. After the coating is completed, the organic solvent is removed for 10 to 30 minutes in a heating oven set at 60 to 90 ° C. to prepare a matrix having droplets dispersed therein.

The support may be laminated to the prepared matrix to complete the transdermal absorbent preparation in which only the matrix in which the droplets are dispersed is introduced.

The amount of the volatile organic solvent used is preferably 20 to 60% by weight in the solution phase mixture immediately before removing the volatile organic solvent, and the optimum content thereof varies depending on the composition of the solution phase mixture.

Referring to the method of manufacturing the skin adhesion layer and the support layer is as follows. The pressure-sensitive adhesive and the physical property regulator are mixed according to the composition, and stirred until a clear solution is obtained. After stirring is complete, bubbles in the solution are removed, coated on a polyethylene terephthalate release paper coated with a silicone polymer so as to have a constant thickness after drying, and a volatile organic solvent is applied for 10 to 30 minutes in a heating oven set at 60 to 90 ° C. By removing, a skin adhesion layer or a support agent adhesion layer can be manufactured, respectively. The completed skin adhesion layer and the support adhesion layer may be laminated with a matrix of previously prepared droplets dispersed therein.

In order to evaluate the prepared transdermal absorbents, observations were made on adhesion properties, skin absorption of the active ingredient, and droplet formation in the matrix. Adhesion was carried out using a transdermal absorbent using a polyurethane nonwoven fabric as a support. Each sample was attached to the upper arm and knee of a healthy adult male, and the adhesion holding force was measured at the same time as the adhesion holding force was measured. In order to evaluate the skin absorption of the active ingredients, transdermal absorption preparations were prepared, and then the dosage of the active ingredients was measured by in-vitro skin absorption test using Franz diffusion cell. In addition, the droplet was observed using an optical microscope to confirm the dispersed state.

Physical property test of solvent

1 g of ethanolamine, diethanolamine, triethanolamine, isopropanolamine, and diisopropanolamine were placed in a transparent glass jar containing 9 g of ethyl acetate, dimethyl sulfoxide, ethanol, and n-hexane, respectively, and then closed. The mixture was stirred vigorously for 1 minute. The prepared mixture was left at room temperature, and after 1 hour, the presence or absence of phase separation was visually observed.

Observation on Compatibility of Alkanolamines and Organic Solvents Organic solvent Evaluation test One 2 3 4 5 Ethanolamine Diethanolamine Triethanolamine Isopropanolamine Diisopropanolamine Ethyl acetate x x x x x Dimethyl sulfoxide o o o o o ethanol o o o o o n-hexane x x x x x

   o: compatible, ie no phase separation occurs.

   x: incompatibility, ie phase separation occurs.

Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples, and Experimental Examples, but the present invention is not limited thereto.

Comparative Examples 1 to 6

Acrylic adhesive (87-2074, National starch, USA, 28% solids content, crosslinking type, main solvent: ethyl acetate) was 14.3, 17.9, 21.4, 25, 28.6, 32.1 g (4, 5, 6, 7, 8, 9 g), Meloxycam was divided into 0.5 g and dimethyl sulfoxide into 5.5, 4.5, 3.5, 2.5, 1.5 and 0.5 g, mixed and stirred until uniformly mixed. After the stirring was completed, the solution was stored at room temperature, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the droplets ooze toward the support.

Comparative Example 7

28.6 g (8 g dry weight) of acrylic adhesive (87-2074, National starch, USA, 28% solids content, crosslinking type, main solvent: ethyl acetate), 0.5 g of meloxycam, 1.5 g of diethanolamine Mix and stir. After stirring, it was confirmed whether the drug crystal precipitated and whether the phase of the mixture was uniform.

Examples 1-4 and Comparative Examples 8-9

14.3, 17.9, 21.4, 25, 28.6, 32.1 g of acrylic adhesive (87-2074) (4, 5, 6, 7, 8, 9 g, respectively, by dry weight), 0.5 g of meloxycamp, dimethyl sulfoxide and di The ethanolamine was mixed with 4/1 (w / w) in a solution of 5.5, 4.5, 3.5, 2.5, 1.5, and 0.5 g (the compositional composition is sequentially Examples 1-4 and Comparative Examples 8-9, respectively). Corresponding to), followed by stirring until uniformly mixed. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored for 2 months at room temperature to observe whether the droplets ooze toward the support.

Examples 5-8 and Comparative Examples 10-11

14.3, 17.9, 21.4, 25, 28.6, 32.1 g of acrylic adhesive (87-2074) (4, 5, 6, 7, 8, 9 g, respectively, in dry weight), 0.5 g of hydroxycampham, dimethyl sulfoxide, When dimethyl isosorbide and diethanolamine mixed with 3/1/1 (w / w) were separated into 5.5, 4.5, 3.5, 2.5, 1.5 and 0.5 g, mixed and then uniformly mixed. Stir until. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored for 2 months at room temperature to observe whether the droplets ooze toward the support.

Observation of the formation of drug crystals in the solution, the formation of droplets in the matrix and the seepage of liquid substances before poorly soluble drugs.  Prescription Adhesive (dry weight, g) Meloxycam (g) Dimethyl sulfoxide (g) Dimethyl isosorbide (g) Diethanol amine (g) Precipitation of solution phase before drying Droplet formation Oozing liquid material Comparative Example 1 4 0.5 5.5 0 0 x x o Comparative Example 2 5 0.5 4.5 0 0 o - - Comparative Example 3 6 0.5 3.5 0 0 o - - Comparative Example 4 7 0.5 2.5 0 0 o - - Comparative Example 5 8 0.5 1.5 0 0 o - - Comparative Example 6 9 0.5 0.5 0 0 o - - Comparative Example 7 8 0.5 0 0 0.5 o - - Example 1 4 0.5 4.4 0 1.1 x o o Example 2 5 0.5 3.6 0 0.9 x o x Example 3 6 0.5 2.8 0 0.7 x o x Example 4 7 0.5 2 0 0.5 x o x Comparative Example 8 8 0.5 1.2 0 0.3 o - - Comparative Example 9 9 0.5 0.4 0 0.1 o - - Example 5 4 0.5 3.3 1.1 1.1 x o x Example 6 5 0.5 2.7 0.9 0.9 x o x Example 7 6 0.5 2.1 0.7 0.7 x o x Example 8 7 0.5 1.5 0.5 0.5 x o x Comparative Example 10 8 0.5 0.9 0.3 0.3 o - - Comparative Example 11 9 0.5 0.3 0.1 0.1 o - -

* "O" in the above table: The phenomenon of the corresponding item occurs.

* "-" In the above table: Observation is not performed.

* "X" in the above table: The phenomenon of the item does not occur.

Examples 9-11 and Comparative Examples 12-14

14.3, 17.9, 21.4, 25, 28.6, 32.1 g of acrylic adhesive (87-2074) (4, 5, 6, 7, 8, 9 g, respectively, in dry weight), 0.5 g of hydroxycampham, dimethyl sulfoxide, When dimethyl isosorbide and diethanolamine mixed with 2/2/1 (w / w) were separated into 5.5, 4.5, 3.5, 2.5, 1.5 and 0.5 g, mixed and then uniformly mixed. Stir until. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Examples 12-14 and Comparative Examples 15-17

Acrylic adhesive (Gelva 2883, Solutia, USA, non-crosslinked, main solvent: ethyl acetate) was 10.5, 13.2, 15.8, 18.4, 21.1, 23.7 g (4, 5, 6, 7, 8, 9 g, respectively) , 5.5 g, 4.5, 3.5, 2.5, 1.5, 0.5 g of Meloxycam mixed with 2/2/1 (w / w) of dimethyl sulfoxide, dimethylisosorbide, and diethanolamine Separately, after mixing, the ethyl acetate was further added so that the same amount of ethyl acetate as used in the example using 87-2074 as the pressure-sensitive adhesive, and stirred until uniformly mixed. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 15

6 g of polyisobutylene (Oppanol-B100, BASF, USA) was dissolved in hexane to give a solution of 10% solids content, followed by 0.7 g of diethanolamine, 1.4 g of dimethyl sulfoxide, 1.4 g of dimethyl isosorbide, and hydroxy 0.5 g of cam was further mixed and stirred until homogeneous. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed. Then, the sample without the active ingredient crystal in the solution was coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Observation of the formation of drug crystals in the solution, the formation of droplets in the matrix and the seepage of liquid substances before poorly soluble drugs.  Prescription Adhesive (dry weight, g) Meloxycam (g) Dimethyl sulfoxide (g) Dimethyl isosorbide (g) Diethanol amine (g) Precipitation of solution phase before drying Droplet formation Oozing liquid material Example 9 4 0.5 2.2 2.2 1.1 x o x Example 10 5 0.5 1.8 1.8 0.9 x o x Example 11 6 0.5 1.4 1.4 0.7 x o x Comparative Example 12 7 0.5 1.0 1.0 0.5 o - - Comparative Example 13 8 0.5 0.6 0.6 0.3 o - - Comparative Example 14 9 0.5 0.2 0.2 0.1 o - - Example 12 4 0.5 2.2 2.2 1.1 x o o Example 13 5 0.5 1.8 1.8 0.9 x o o Example 14 6 0.5 1.4 1.4 0.7 x o x Comparative Example 15 7 0.5 1.0 1.0 0.5 o - - Comparative Example 16 8 0.5 0.6 0.6 0.3 o - - Comparative Example 17 9 0.5 0.2 0.2 0.1 o - - Example 15 6 0.5 1.4 1.4 0.7 x o x

* "O" in the above table: The phenomenon of the corresponding item occurs.

* "-" In the above table: Observation is not performed.

* "X" in the above table: The phenomenon of the item does not occur.

Example 16

Acrylic adhesive (87-2196, National starch, USA, solid content 35%, uncrosslinked, main solvent: ethyl acetate) 17.1 g (6 g in dry weight), dimethyl sulfoxide 1.4 g, dimethyl isosorbide 1.4 g, di 0.7 g of ethanolamine and 0.5 g of tolubuterol were mixed and stirred until it became clear. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a dry thickness of 30 μm. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 17

Acrylic adhesive (87-2979, National starch, USA, solid content 38%, uncrosslinked, main solvent: ethyl acetate) 15.8 g (6 g in dry weight), dimethyl sulfoxide 1.4 g, dimethylisosorbide 1.4 g, di 0.7 g of ethanolamine and 0.5 g of water-soluble tulobuterol hydrochloride were mixed and stirred until it became clear. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 18

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethyl sulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, and 0.5 g of tramadol were mixed and stirred until it became clear. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 19

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethyl sulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, and 0.5 g of tramadol hydrochloride were mixed and stirred until it became clear. . After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 20

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethylsulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, and 0.5 g of cerizine were mixed and stirred until clear. . After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 21

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethyl sulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, 0.5 g of cestriline hydrochloride are mixed and stirred until clear It was. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 22

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethyl sulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, 0.5 g of oxybutynin are mixed and stirred until it is clear It was. After stirring, the solution was stored at room temperature for 24 hours, and the presence or absence of the active ingredient crystal formation was visually observed and then coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 23

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethyl sulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, and 0.5 g of lidocaine were mixed and stirred until it became clear. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 24

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethylsulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, 0.5 g of pyrocampam are mixed and stirred until clear It was. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Example 25

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.4 g of dimethylsulfoxide, 1.4 g of dimethylisosorbide, 0.7 g of diethanolamine, 0.5 g of ketoprofen are mixed and stirred until clear It was. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 30 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplet formation was observed under a microscope. After completion of optical microscopic observation of the presence or absence of droplet formation, the polyurethane nonwoven fabric was laminated as a support. The prepared sample was stored at room temperature for 2 months to observe whether the liquid oozed out to the support.

Observation results of drug crystal formation, droplet formation in matrix and seepage of liquid substances before drying using various drugs.  Prescription  drug Adhesive (dry weight, g) Drug (g) Dimethyl sulfoxide (g) Dimethyl isosorbide (g) Diethanolamine (g) Precipitation of solution phase before drying Droplet formation Oozing liquid material Example 16 Tulobuterol 6 0.5 1.4 1.4 0.7 x o x Example 17 Tulbuterol Hydrochloride 6 0.5 1.4 1.4 0.7 x o x Example 18 Tramadol 6 0.5 1.4 1.4 0.7 x o x Example 19 Hydrochloric acid 6 0.5 1.4 1.4 0.7 x o x Example 20 Setrizine 6 0.5 1.4 1.4 0.7 x o x Example 21 Hydrochloric acid 6 0.5 1.4 1.4 0.7 x o x Example 22 Oxybutynin 6 0.5 1.4 1.4 0.7 x o x Example 23 Lidocaine 6 0.5 1.4 1.4 0.7 x o x Example 24 Piroxycam 6 0.5 1.4 1.4 0.7 x o x Example 25 Ketoprofen 6 0.5 1.4 1.4 0.7 x o x

* "O" in the above table: The phenomenon of the corresponding item occurs.

* "-" In the above table: Observation is not performed.

* "X" in the above table: The phenomenon of the item does not occur.

Example 26

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.2 g of dimethyl sulfoxide, 1.2 g of dimethylisosorbide, 0.6 g of diethanolamine, 0.5 g of meloxycham were mixed and stirred until it became clear. It was. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 60 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplets was confirmed under a microscope. After completion of optical microscopic observation of the presence of droplet formation, the polyurethane nonwoven fabric was laminated as a dried coating layer and a support. After the sample was completed, drug content measurement, in-vitro skin absorption test, in-vivo residual test, and adhesion performance test were performed.

Example 27

32.1 g of acrylic adhesive (87-2074) (9 g in dry weight) and 1 g of isopropyl myristate were mixed and stirred until it became clear. After the stirring was completed, the solution was coated on a release paper to have a thickness of 30 μm. After the coating was completed, the sample was dried at 80 ° C. for 20 minutes, and then the release paper of the sample prepared as described in Example 26 was removed and laminated to prepare a sample to which the skin adhesion layer was added. In-vitro skin absorption test, in-vivo residual amount test, and adhesion performance test were performed on the prepared samples.

Example 28

32.1 g of acrylic adhesive (87-2074) (9 g in dry weight) and 1 g of isopropyl myristate were mixed and stirred until it became clear. After the stirring was completed, the solution was coated on a release paper to have a thickness of 30 μm. After the coating was completed, it was dried at 80 ° C. for 20 minutes, and then the polyurethane nonwoven fabric was laminated as a support. After the lamination was completed, the release paper was removed and laminated with the pressure-sensitive adhesive layer prepared according to the pressure-sensitive adhesive layer manufacturing method shown in Example 26, to prepare a sample to which the support layer was added. In-vitro skin absorption test, in-vivo residual amount test, and adhesion performance test were performed on the prepared samples.

Example 29

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.2 g of dimethylsulfoxide, 1.2 g of dimethylisosorbide, 0.6 g of diethanolamine, and 1.5 g of pyrocampam are mixed and stirred until it is clear. It was. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 60 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplets was confirmed under a microscope. After completion of optical microscopic observation of the presence of droplet formation, the polyurethane nonwoven fabric was laminated as a dried coating layer and a support. After the sample was completed, drug content measurement, in-vitro skin absorption test, in-vivo residual test, and adhesion performance test were performed.

Example 30

21.4 g of acrylic adhesive (87-2074) (6 g in dry weight), 1.2 g of dimethylsulfoxide, 1.2 g of dimethylisosorbide, 0.6 g of diethanolamine, 0.5 g of ketoprofen, are mixed and stirred until clear It was. The stirred solution was stored at room temperature for 24 hours, and the presence of active ingredient crystals was visually observed and coated on a release paper to have a thickness of 60 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplets was confirmed under a microscope. After completion of optical microscopic observation of the presence of droplet formation, the polyurethane nonwoven fabric was laminated as a dried coating layer and a support. After the sample was completed, drug content measurement, in-vitro skin absorption test, in-vivo residual test, and adhesion performance test were performed.

Example 31

23.6 g of acrylic adhesive (87-2074) (6.6 g in dry weight), 5.6 g of dimethyl sulfoxide, 1.4 g of diethanolamine, 0.5 g of hydroxycampham, and 1 g of propylene glycol monocaprylate are mixed and become clear. Stir until. The stirred solution was stored at room temperature for 24 hours, and the presence or absence of active ingredient crystal formation was visually observed and coated on a release paper to have a thickness of 60 μm after drying. After the coating was completed, the resultant was dried at 80 ° C. for 20 minutes, and the presence of droplets was confirmed under a microscope. After completion of optical microscopic observation of the presence of droplet formation, the polyurethane nonwoven fabric was laminated as a dried coating layer and a support. After the sample was completed, drug content measurement, in-vitro skin absorption test, in-vivo residual test, and adhesion performance test were performed.

Example 32

23.6 g of acrylic adhesive (87-2074) (6.6 g in dry weight), dimethyl g of dimethyl sulfoxide, 1.4 g of diethanolamine, 0.5 g of meloxycampin, 1 g of propylene glycol monocaprylate, 0.5 polyvinylpyrrolidone g were mixed and stirred until clear. The stirred solution was stored at room temperature for 24 hours, and the presence or absence of active ingredient crystal formation was visually observed and coated on a release paper to have a thickness of 60 μm after drying. After the coating was completed dried for 20 minutes at 80 ℃, and confirmed the formation of droplets under a microscope. After completion of optical microscopic observation of the presence of droplet formation, the polyurethane nonwoven fabric was laminated as a dried coating layer and a support. After the sample was completed, drug content measurement, in-vitro skin absorption test, in-vivo residual test, and adhesion performance test were performed.

Experimental Example 1. In-vitro skin absorption measurement

In-vitro skin absorption test was carried out using Franz diffusion cell, and skin of hairless mice (females, 6-7 weeks old) was extracted and cut into squares of 2x2 ㎠ as a receptor. The stratum corneum was directed toward the dermis in the contact direction, and the stratum corneum was raised in the opposite direction to the accommodating part, and then the matrix sample cut into 1.5 × 1.5 cm 2 squares was attached to the transdermal and fixed. The receptor of the Franz diffusion cell was filled with phosphate buffer (pH 7.4), and the experiment was carried out by exchanging the phosphate buffer in the receiving part for 24 hours at 1, 3, 5, 7, and 12 with stirring at 600 rpm. The content of the active ingredient in the phosphate buffer in the collected portion was quantitatively analyzed using high performance liquid chromatography (HPLC).

Experimental Example 2. Determination of the content of active ingredients

The percutaneous absorption preparation prepared by the method of measuring the active ingredient content of the prepared percutaneous absorption matrix-type transdermal absorption preparation was cut into 2x2cm 2, extracted with 100 ml of methanol, and quantitative analysis was performed using high-performance liquid chromatography.

Experimental Example 3. Quantitative Analysis

High-speed liquid chromatography was used for quantitative analysis, and the measurement conditions were as follows for each active ingredient.

Meloxycam

Mobile phase: Acetonitrile / 0.05M sodium acetate aqueous solution (pH3.3) = 500/500 (v / v)

Stationary phase: Luna 5μ C18 (2) (Phenomenex, 150 × 4.60 mm, 5μ)

Mobile phase speed: 1 ml / min

Wavelength: 355 nm

Ketoprofen

Mobile phase: acetonitrile / methanol / distilled water = 400/300/300 (v / v)

Stationary phase: Luna 5μ C18 (2) (Phenomenex, 150 × 4.60 mm, 5μ)

Mobile phase speed: 1 ml / min

Wavelength: 254 nm

Piroxycam

Mobile phase: 0.05M diammonium phosphate / acetonitrile / methanol = 500/100/400 (v / v / v)

Stationary phase: Luna 5μ C18 (2) (Phenomenex, 150 × 4.60 mm, 5μ)

Mobile phase speed: 1 ml / min

Wavelength: 366 nm

The calibration curve used for the quantitative analysis was a reference solution prepared by measuring the mass of the active ingredient dissolved in methanol and analyzed using HPLC, and was prepared based on the area value of the chromatograph obtained therefrom.

Experimental Example 4. Adhesion Test

The prepared percutaneous absorbent preparation was cut into 4 × 4 cm 2 sizes, attached to the upper arm and knee of an adult male, detached after 24 hours, and the satisfaction of the adhesion was examined by a questionnaire about adhesion. The results are summarized in Table 5.

Content measurement, in-vitro skin absorption, adhesion performance test results for the prepared samples.   Prescription   drug  Drug content (㎍ / ㎠) 24 hours permeation amount (㎍ / ㎠) obtained in in-vitro skin absorption test   Adhesion performance test Comparative Example 7 Meloxycam 290 18.14 ± 4 24 hours Example 26 Meloxycam 450 30 ± 11 24 hours Example 27 Meloxycam 450 25 ± 4 24 hours Example 28 Meloxycam 450 32 ± 7 24 hours Example 31 Meloxycam 350 130 ± 11 24 hours

Example 32 Meloxycam 340 114 ± 9 24 hours Example 29 Piroxycam 1105 105 ± 8 24 hours Commercial item 1 (S company T patch) Piroxycam 2400 50 ± 12 24 hours Example 30 Ketoprofen 460 280 ± 41 24 hours Commercial item 2 (K company KL plaster)  Ketoprofen  430  140 ± 30 24 hours

Experimental Example 5. Optical Microscope Observation

The prepared matrix was observed with an optical microscope to confirm the shape and size of the droplets dispersed on the matrix. When the magnification was increased to 1000 times, it was observed by the liquefaction method using cedar oil. 3a and 3b are the results observed through an optical microscope performed for Comparative Example 1 and Example 3.

Experimental Example 6. Adhesion test 2 (180 ^o peel adhesion measurement)

In order to observe the adhesion of the prepared matrix for transdermal absorption, 180- ^o peel adhesion was measured by using TA-XT2iHR, a measuring device of Stable micro system Co., Ltd. The substrate used for the measurement was a stainless steel substrate of Chem Instruments, Co., Ltd. The measurement conditions are as follows.

Specimen Size: 10cmx2.5㎝

Measuring section: 10 ~ 40㎜

Measuring Speed: 2.0㎜ / s

Measuring Temperature: 25 ℃

Experimental Example 7. Stability Test

Cut the percutaneous absorbent preparation into 7x7㎠ and put it in a paper bag coated with aluminum and sealed it, and store it for 6 months at 40 ° C. Appearance evaluation was performed for the area change. The stability test results for Example 32 are shown in Table 6.

40 ℃, 6 months stability test results for the prepared sample. Item 0 months 2 months 4 months 6 months Crystallization none none none none area 49 ± 0.2 ㎠ 48.5 ± 0.1 ㎠ 48.3 ± 0.4 ㎠ 48 ± 0.2 ㎠ 180 ^o peel adhesion 980 ± 30g _f /2.5cm 907 ± 25g _f /2.5cm 882 ± 50g _f /2.5cm 804 ± 40g _f /2.5cm content 340 ± 4 ㎍ / ㎠ 333 ± 7 ㎍ / ㎠ 328 ± 4 ㎍ / ㎠ 320 ± 5 ㎍ / ㎠

Developed in the present invention is a matrix transdermal absorption agent that can be applied as a patch or plaster. According to the present invention, the droplets containing the active ingredient are dispersed evenly in the polymer matrix to exhibit high skin absorption, and the manufacturing process is simple and can contain a high concentration of the active ingredient without limitation depending on the solubility of the active ingredient. Provided is a transdermal absorption preparation applicable to a drug and a method of preparing the same.

Claims (24)

In the transdermal absorbent comprising a hydrophobic polymer adhesive matrix layer, Droplets containing the active ingredient and alkanolamine are evenly dispersed in the hydrophobic polymer adhesive matrix, The alkanolamine is a transdermal absorption agent that is a liquid substance represented by the following formula:

(Wherein R ¹ , R ² and R ³ are each independently an alkyl or hydrogen having 2 to 9 carbon atoms substituted with one hydroxy group; at least one of R ¹ , R ² and R ³ is one hydroxy group Substituted alkyl having 2 to 9 carbon atoms). According to claim 1, wherein the composition is 40 to 90% by weight of the hydrophobic polymer, 5 to 60% by weight of the alkanolamine, and 0.5 to 25% by weight of the active ingredient with respect to the total weight of the matrix layer after the preparation of the matrix layer Percutaneous absorption agent which is included. The transdermal absorption agent according to claim 1, wherein the matrix layer has a thickness of 10 to 120 µm. The transdermal absorption agent according to claim 1, wherein the hydrophobic polymer adhesive is at least one component selected from the group consisting of an acrylic adhesive, a rubber-based adhesive, and a silicone adhesive. The method of claim 4, wherein the acrylic pressure-sensitive adhesive is an acrylic monomer to which an alkyl group having 1 to 18 carbon atoms added; And at least one monomer selected from the group consisting of acrylic acid, methacrylic acid and an acrylic monomer to which a hydroxy group is added is polymerized, The rubber-based pressure-sensitive adhesive is a transdermal absorbent agent that is at least one component selected from the group consisting of natural rubber, styrene copolymer, polyisoprene and polyisobutylene. The transdermal absorbent according to claim 1, wherein the alkanolamine is at least one component selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, and triisopropanolamine. The method of claim 1, wherein the active ingredient is clonidine, ricinopril, nizoldipine, perindopril, terrazosin, terrazosin, alprazolam, amlodipine, amlodipine besylate, atorvastatin, auranopine, azatadine, aza Tadinemalate, bupivacaine, bubivacaine hydrochloride, bupurenorphine, busion, busion hydrochloride, cetrizine, cetrizine hydrochloride, cerivastatin, cerivastatin sodium, clonazepam, colchicine, cyclobenzaprine , Cyclobenzaprine, doxazosin, doxazosin mesylate, felodipine, fentanyl, sufentanyl, finasteride, gocyclillin, gocyclinyl acetate, granisetrone, granitose hydrochloride, hexoprelinin, hexoprene hydrochloride Nalin, Indafamide, Ketotifenfumarate, Luboboline, Luboborine calcium, Levothyroxine, Sodium levothyroxine, Loratadine, Metolazone, Medoxyprogesterone, Medoxyprogesterone acetate, Rexone, naltrexone hydrochloride, nitroglycerin, norgestrel, nomegestrol, nomegestrol hydrochloride, olanzapine, simvastatin, celecoxib, rofecoxib, meloxycamp, tenoxycamp, isoximecam, phyroxam, keto Propene, ketorolac, flurbiprofen, phenopropene, naproxen, indomethacin, aceclofenac, diclofenac, isosorbide, isosorbite nitrite, isosorbate nitrate, suprofen, lidocaine, hydrocortisone, A component selected from the group consisting of cortisone, indopropene, tulobuterol, tulobuterol hydrochloride, tramadol, tramadol hydrochloride, oxybutynin and tolterodine, and derivatives thereof or pharmaceutically acceptable salts thereof Percutaneous Absorption. The transdermal absorption preparation of claim 1, wherein the matrix layer further comprises one or more skin absorption enhancers. The method of claim 8, wherein the skin absorption enhancer is at least one component selected from the group consisting of fatty acids, polyhydric alcohols, surfactants, fatty acid alcohols, fatty acid esters and fatty acid alkanolamides, The skin absorption enhancer is 0.5 to 15% by weight based on the total weight of the matrix layer after the matrix preparation. 10. The method according to claim 9, wherein the fatty acid is at least one component selected from the group consisting of linoleic acid, oleic acid, palmitic acid, stearic acid, capric acid and myristic acid; The polyhydric alcohol is at least one component selected from the group consisting of propylene glycol, polyethylene glycol, dipropylene glycol, diethylene glycol, monoethyl ether and glycerol; The surfactant is at least one component selected from the group consisting of Tween 80, Labrasol and Cremofo; The fatty alcohol is at least one component selected from the group consisting of oleyl alcohol and stearyl alcohol; The fatty acid ester is at least one component selected from the group consisting of isopropyl myristate, propylene glycol caprylate, propylene glycol laurate and polyethylene glycol laurate; The transdermal absorption agent wherein the fatty acid alkanolamide is lauryl dimethanolamide. The transdermal absorption preparation according to claim 1 or 8, wherein the matrix layer further comprises one or more thickeners. The method of claim 11, wherein the thickener is at least one component selected from the group consisting of polyvinylpyrrolidone, polyethylene oxide, silicon oxide, aluminum oxide and titanium oxide, The amount of the thickener is 0.5 to 15% by weight based on the total weight of the matrix layer after the preparation of the matrix transdermal absorption. The transdermal absorption preparation according to claim 1, further comprising a support and release paper together with the matrix. The method of claim 13 wherein the support is A water-permeable or water-impermeable film comprising at least one component selected from the group consisting of polyolefins, polyesters, polyurethanes, and aluminum; or Woven or nonwoven fabrics comprising two or more components selected from the group consisting of polyolefins, polyesters, nylons and cotton Percutaneous absorption agent that is composed of. The transdermal absorption preparation according to claim 13, wherein the release paper is a paper coated with silicon or fluorocarbon resin, or a polymer film coated with silicon or fluorocarbon resin. The transdermal absorption preparation according to claim 13, further comprising at least one layer selected from the group consisting of a support adhesion layer and a skin adhesion layer. 17. The method according to claim 16, wherein the support layer comprises 70 to 99% by weight of the polymer adhesive, and 1 to 30% by weight of the adhesive performance improving agent on a dry weight basis, the layer thickness is 10 to 100 ㎛, The skin adhesion layer is a transdermal absorbent preparation containing 70 to 99% by weight of the polymer adhesive, and 1 to 30% by weight of the adhesive performance improving agent, the layer thickness of 10 to 100 ㎛ on a dry weight basis. The method of claim 17, wherein the polymer adhesive is at least one component selected from the group consisting of an acrylic adhesive, a rubber-based adhesive, and a silicone adhesive, The adhesive performance-improving agent is a transdermal absorption agent is one or more components selected from the group consisting of fatty acid esters, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymers, polyvinylpyrrolidone and inorganic fillers. 19. The method of claim 18, wherein the rubber-based pressure-sensitive adhesive is at least one component selected from the group consisting of natural rubber, styrene copolymer, polyisoprene and polyisobutylene, The fatty acid ester is at least one component selected from the group consisting of isopropyl myristate, propylene glycol caprylate, propylene glycol laurate, polyethylene glycol laurate and propylene glycol oleate, The inorganic filler is a transdermal absorbent agent which is at least one component selected from the group consisting of silicon oxide, aluminum oxide and titanium oxide. The droplet containing the active ingredient is removed through a process of removing the volatile organic solvent from a solution mixture containing the active ingredient, a volatile organic solvent, a polymer adhesive soluble in the volatile organic solvent, a polar aprotic organic solvent, and an alkanolamine. A method for producing a transdermal absorbent according to claim 1, wherein the matrix layer is prepared to be dispersed evenly in the matrix. 21. The method according to claim 20, wherein in the solution phase mixture, the active ingredient is 0.01 to 10% by weight, the polymer adhesive is 5 to 25% by weight, the organic solvent is 20 to 60% by weight, the polar aprotic organic solvent is 6 to 55% by weight, and Production process characterized in that the alkanolamine is contained in 1 to 15% by weight. 21. The method according to claim 20, wherein the volatile organic solvent is a solvent alone or a solvent mixture having a boiling point of 40 to 110 ° C under atmospheric pressure selected from the group consisting of hydrocarbons, alcohols, halogenated hydrocarbons, aromatic hydrocarbons and polar organic solvents. The method of claim 22, wherein the volatile organic solvent is at least one selected from the group consisting of ethyl acetate, hexane, heptane, methanol, ethanol, propanol, methylene chloride, chloromethane, benzene, toluene, xylene, acetone and tetrahydrofuran The manufacturing method will be a solvent. The method according to claim 20, wherein the polar aprotic organic solvent is at least one solvent selected from the group consisting of dimethyl sulfoxide, dimethylacetamide, dimethylformamide and dimethylisosorbide.

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