KR102600712B1 - Pharmaceutical composition for delivery of antirheumatic agent using body temperature-sensitive polymer, the patch comprising the same and method for preparing thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing a non-steroidal antirheumatic agent, a thermosensitive polymer, and a skin permeation enhancer as active drugs, a patch for transdermal administration containing the same, and a method for manufacturing the same. The patch for transdermal administration containing a temperature-sensitive polymer according to the present invention has excellent skin permeability, shows increased bioavailability, does not cause skin irritation, and allows sustained release of the drug, thereby showing excellent effects.

Description

Pharmaceutical composition for delivery of antirheumatic agent using body temperature-sensitive polymer, the patch comprising the same and method for preparing the same}

The present invention relates to a pharmaceutical composition for delivering anti-rheumatic drugs using a temperature-sensitive polymer, a patch containing the same, and a method for manufacturing the same.

So-called nonsteroidal antirheumatic drugs are the active substances considered to be acetic acid derivatives and propionic acid derivatives. Examples of acetic acid derivatives include, but are not limited to, indomedacin, acemetacin, tolmetin, diclofenac, and lonazolac, and examples of propionic acid derivatives (propene) include ibuprofen, flurbiprofen, and Examples include norprofen, ketoprofen, naproxen, and thiaprofen. Non-steroidal rheumatoid drugs are generally used as preparations for oral administration such as tablets, but this method has the problem of side effects in the gastrointestinal tract and the shortened half-life of the drug in the blood, requiring frequent administration. Therefore, the need to develop new formulations to solve these problems was emphasized.

Among them, preparations for transdermal administration that deliver drugs through the skin can avoid metabolism in the liver, unlike oral administration, and can reduce side effects because the active ingredients can be continuously delivered to the body at a constant rate. At the same time, it has the advantage of reducing the number of administrations, so it can be applied as a method to compensate for the above disadvantages, so commercialization and research on this are actively underway.

Already known patch-related technologies include drug release control patches using ionic bonds (reference: European Journal of Pharmaceutical Sciences, 115, 330-338), transdermal permeation enhancement patches using skin permeation enhancers (reference: European Journal of Pharmaceutical Sciences 107, 138-147), etc. In this regard, Republic of Korea Patent Publication No. 10-1796771 discloses a method of controlled release of a drug through a multilayer structure, Publication No. 10-1558043 discloses a method of drug release by preventing crystallization of the drug, and Publication No. 10-0956023 discloses a method of drug release using an acidic functional group. A method for controlling the drug release rate using an acrylate polymer having a composition for promoting absorption containing higher alcohols is disclosed in Republic of Korea Patent Publication No. 2014-0027782, but a complex structure is required for controlled release and the resulting production cost is high. There is a problem with the increase. In addition, there is no function to constantly control the amount of drug released, so there is a large amount of drug released initially after application to the skin, but the amount decreases over time, so there is a disadvantage that the drug dosage cannot be maintained consistently over time.

In addition, pressure-sensitive adhesives generally used in patches require adhesion to the skin and compatibility with drugs and other excipients. As an adhesive with these characteristics, Duro-Tak (Henkel, US) ) are commercially available, and these adhesives are manufactured by radical polymerization of acrylic acid or methacrylic acid and their derivatives. Also, possible monomers include, for example, vinyl-based compounds such as vinyl acetate or maleic acid. However, when such acrylic adhesive is used as an adhesive matrix for a transdermal absorption preparation, the drug diffusion within the adhesive layer is slowed due to the interaction between the drug and the acrylic polymer in the adhesive layer, and the transfer of the drug from the adhesive layer to the skin is also reduced. It is difficult to deliver the required amount of drug. Accordingly, a patch using a temperature-responsive polymer was invented, and the release rate can be controlled by manufacturing with a simple structure, causing little skin irritation, excellent skin permeability of the drug, and increased bioavailability, and the present invention was completed.

The purpose of the present invention is to solve the above problems by providing a pharmaceutical composition for delivery of a non-steroidal antirheumatic drug that has excellent skin permeability, increased bioavailability, does not cause skin irritation, and allows sustained release of the drug, and a pharmaceutical composition containing the same. The aim is to provide a patch for transdermal administration and a method for manufacturing the same.

The present invention relates to anti-rheumatic agents; Temperature sensitive polymer; A pharmaceutical composition for delivering an anti-rheumatic agent, comprising a skin permeation enhancer,

The temperature-sensitive polymer includes at least one selected from the group consisting of 2-ethylhexyl acrylate, 2-hydroxylethyl acrylate, ethyl methacrylate, acryloyl morpholine, and isobornyl acrylate. Provided is a pharmaceutical composition for delivery of an anti-rheumatic agent.

In one embodiment of the present invention, the skin penetration enhancer is one or more selected from the group consisting of fatty acid ethers, nonionic surfactants, isopropyl myristate, pyrrolidone derivatives, fatty acids, fatty acid alcohols, and fatty acid esters. You can.

In another embodiment of the present invention, the anti-rheumatic agent is a non-steroidal anti-rheumatic agent and may be at least one selected from the group consisting of ketoprofen, flurbiprofen, ibuprofen, and naproxen.

In another embodiment of the present invention, the temperature-sensitive polymer may be included in an amount of 70 to 95% by weight based on a total of 100% by weight.

In another embodiment of the present invention, the skin penetration enhancer may be included in an amount of 0.01 to 20% by weight based on a total of 100% by weight.

In addition, the present invention is a patch for transdermal administration containing the pharmaceutical composition,

a first layer containing the pharmaceutical composition; and a second layer comprising a support.

In one embodiment of the present invention, the support is one or more materials selected from the group consisting of polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum-treated polyester, non-woven fabric, cotton fabric, and fabric. It may include.

In addition, the present invention includes the step of mixing temperature-sensitive polymers (S1);

After mixing, preparing a composition to which an anti-rheumatic agent and a skin permeation enhancer are added (S2); and

Comprising the step of coating the composition on a support and drying it (S3),

The temperature-sensitive polymer includes at least one selected from the group consisting of 2-ethylhexyl acrylate, 2-hydroxylethyl acrylate, ethyl methacrylate, acryloyl morpholine, and isobornyl acrylate. Provided is a method for manufacturing a patch for transdermal administration.

The composition of the present invention can be simply produced as a patch for transdermal administration containing a non-steroidal antirheumatic agent and a temperature-sensitive polymer, while having excellent skin permeability and long-term persistence of drug efficacy, low skin irritation, and no side effects. Drugs can be delivered safely into the body with increased bioavailability, providing excellent therapeutic effects.

Figure 1 is a diagram showing the results of modulus evaluation to confirm the glass transition temperature of a temperature-sensitive polymer.
Figure 2 is a diagram showing the blood concentration profile in the body over time compared to a transdermal patch containing ketoprofen and flurbiprofen using a temperature-responsive polymer and a commercial product.

The present invention relates to anti-rheumatic agents; Temperature sensitive polymer; The present invention provides a pharmaceutical composition for delivery of an anti-rheumatic agent, including a skin permeation enhancer, a patch for transdermal administration containing the same, and a method for manufacturing the same.

Hereinafter, the present invention will be described in more detail.

The pharmaceutical composition for delivery of an anti-rheumatic agent according to the present invention includes an anti-rheumatic agent; Temperature sensitive polymer; and a skin penetration enhancer.

In the present invention, the temperature-sensitive polymer is one or more selected from the group consisting of 2-ethylhexyl acrylate, 2-hydroxylethyl acrylate, ethyl methacrylate, acryloyl morpholine, and isobornyl acrylate. You can.

The polymer may be contained in an amount of 70 to 95% by weight based on a total of 100% by weight, and more preferably, 60 to 75% by weight of ethylhexyl acrylate, 10 to 15% by weight of hydroxyethyl acrylate, and ethyl methacrylate. It may contain 3 to 15% by weight, and may contain 0.5 to 7% by weight of acroyl morpholine or 1 to 5% by weight of isobornyl acrylate. However, depending on the area where the patch is to be used, the degree of the disease, etc., the above It is not limited to the content range and can be included by changing the content.

The anti-rheumatic agent is a non-steroidal anti-rheumatic agent, and asteic acid derivatives, propionic acid derivatives, etc. can be used without limitation, and may be ketoprofen, flurbiprofen, ibuprofen, or naproxen, but are limited to the above types. That is not the case. The anti-rheumatic agent may be included in an amount of 1 to 10% by weight.

The skin penetration enhancer may be any compound that has a skin absorption promoting effect without limitation. Specific examples include C6-20 fatty acid, fatty alcohol, fatty acid ester, fatty acid amide, fatty acid ether, and aromatic organic acid. organic acid, aromatic alcohol, aromatic organic acid ester, and aromatic organic acid ether.

These compounds may be saturated or unsaturated, as well as straight, branched or annular. Absorption accelerators usable in the present invention include lactic acid ester, acetic acid ester, monoterpene compound, sesquiterpene compound, azone, and azone derivative. derivative), glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester (Span), polysorbate compound (Tween), polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil compounds (HCOs), polyoxyethylene alkyl ether, sucrose fatty acid ester (sucrose fatty acid ester), pyrrolidone derivative and vegetable oil.

Among these skin permeation enhancers, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, and octanoic acid. acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol ), myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, methyl laurate, hexyl laurate, Lauric acid diethanolamide, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid ( salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate ), lauryl lactate, ethyl acetate, propyl acetate, geraniol, thymol, eugenol, terpineol, 1-menthol, borneol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor (dl- camphor), glycerin monocaprylate, glycerin monocaprate, glycerin monolaurate, glycerin monooleate, sorbitan monolaurate, Sucrose monolaurate, polysorbate 20, propylene glycol, propylene glycol monolaurate, polyethylene glycol monolaurate, polyethylene glycol mono Stearate (polyethylene glycol monostearate), polyoxyethylene lauryl ether (N-methyl-2-pyrrolidone), HCO-6.0, pyrothiodecane, and olive oil (olive) oil), is preferred, isopropyl myristate, octanoic acid, sorbitan monolaurate, polysorbate 20, propylene glycol, N-methyl-2-pyrrolidone, lauryl alcohol, myristyl alcohol, isostearyl alcohol, lauric acid diethanolamide , glycerin monocaprylate, glycerin monocaprate, glycerin monooleate, propylene glycol monolaurate, polyoxyethylene lauryl ether ), and pyrothiodecane are more preferred.

These skin penetration enhancers can be used alone or as a mixture of two or more of them.

The amount of skin penetration enhancer used is not particularly limited, but is in the range of 0.01 to 20% by weight, preferably 0.05 to 10% by weight, and more preferably 0.1 to 20% by weight, based on the total weight of the pharmaceutical composition. It is a range. If the skin permeation enhancer exceeds 30% by weight, skin permeability is no longer improved and the physical strength of the patch may be reduced.

The pharmaceutical composition may optionally contain additional ingredients to the above compounds, such as antioxidants, fillers, crosslinking agents, antiseptic agents, ultraviolet absorbers. The antioxidant usable in the pharmaceutical composition may be any antioxidant as long as it is commonly used in patches. Specific examples of preferred antioxidants include tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, dibutyl. These are dibutylhydroxytoluene (BHT), and butylhydroxyanisole.

The formulation of the composition of the present invention can be prepared by a conventional pharmaceutical patch production method including conventional excipients.

In addition, the present invention is a patch for transdermal administration containing a pharmaceutical composition,

a first layer containing the pharmaceutical composition; A transdermal patch can be provided, comprising a second layer comprising a support. The patch for transdermal administration may further include a drug protection layer to prevent loss of the drug in the first layer.

The second layer including the drug protective layer and the support can be used as is, as is widely known in the technical field to which the present invention pertains. To explain this, the drug protective layer is used to prevent drug loss from the preparation while attached to the skin or stored. To prevent this, use something that is thin, flexible, and does not react with the skin, so it does not cause allergic reactions. As a drug protection layer, a single layer film of polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, and aluminum-treated polyester, or a moisture-absorbing ability to prevent the patch from falling off due to moisture emitted from the human body. Non-woven fabrics, cotton fabrics, fabrics, etc. can be used, and multi-layer laminate films made by stacking the above single films can be used, and any of the drug protection films used in conventional patches can be used.

In addition, the support serves to support the product when the patch is cut to an appropriate size and is removed when the product is applied to the skin. It is made up of aluminum, cellulose, polyester, polyethylene, and polypropylene used in conventional patches. The same film or a thin film made of paper can be used, and these films can be laminated as needed. In addition, it is desirable to use a peeling layer that is easily removed without leaving matrix residues in the peeling layer when removing the peeling layer from the patch. Any material or form commonly used in transdermal preparations may be used.

In addition, the present invention includes the step of mixing temperature-sensitive polymers (S1);

After mixing, preparing a composition to which an anti-rheumatic agent and a skin permeation enhancer are added (S2); and

Comprising the step of coating the composition on a support and drying it (S3),

The temperature-sensitive polymer includes at least one selected from the group consisting of 2-ethylhexyl acrylate, 2-hydroxylethyl acrylate, ethyl methacrylate, acryloyl morpholine, and isobornyl acrylate. Provided is a method for manufacturing a patch for transdermal administration.

Hereinafter, embodiments will be described in detail with reference to the attached drawings. However, various changes can be made to the embodiments, so the scope of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents, or substitutes for the embodiments are included in the scope of rights.

The terms used in the examples are for descriptive purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features. It should be understood that this does not exclude in advance the possibility of the existence or addition of elements, numbers, steps, operations, components, parts, or combinations thereof.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the embodiments belong. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless explicitly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.

In addition, when describing with reference to the accompanying drawings, identical components will be assigned the same reference numerals regardless of the reference numerals, and overlapping descriptions thereof will be omitted. In describing the embodiments, if it is determined that detailed descriptions of related known technologies may unnecessarily obscure the gist of the embodiments, the detailed descriptions are omitted.

<Examples 1 to 9> Patch containing ketoprofen using temperature-sensitive polymer

A temperature-sensitive polymer was prepared by mixing monomers in an ethyl acetate solvent at a composition ratio corresponding to the polymer among the compositions in Table 1. Afterwards, according to the composition in Table 1, the drug and skin penetration enhancer were coated on the lint cloth using a temperature-sensitive polymer.

Specifically, the composition according to the composition in Table 1 was placed on one side of the release film and coated at 25 ℃ with the blade of a bar-coater at a speed of 20 mm/s, and the solvent was dried at 80 ℃ for 10 minutes. did. The dried coating layer was coated to a thickness of 200 um. Afterwards, a patch was manufactured by laminating using lint cloth.

ingredient Example One 2 3 4 5 6 7 8 9 drug Ketoprofen 30 30 30 30 30 30 30 30 30 Skin permeation enhancer Isopropyl myristrate 50 50 50 50 30 40 - - - Octanoic acid - - - - - - 50 - - Propylene glycol - - - - - - - 50 - N-methyl-2-pyrrolidone - - - - - - - - 50 Temperature sensitive polymer Ethylhexyl acrylate 630 573 520 630 630 630 630 630 630 Hydroxyethyl acrylate 115 112 110 115 115 115 115 115 115 Ethylmethacrylate 40 80 120 40 40 40 40 40 40 Acryloyl morpholine 15 35 50 - 15 15 15 15 15 Isobornyl acrylate - - - 15 - - - - -

Unit: mg/70 cm ²

<Example 10> Patch containing flurbiprofen using temperature-sensitive polymer

The temperature-sensitive polymer was used by mixing monomers in an ethyl acetate solvent at a composition ratio corresponding to the polymer among the compositions in Table 2. Afterwards, according to the composition in Table 2, the drug and skin permeation enhancer were coated on the lint cloth using a temperature-sensitive polymer.

Specifically, the composition according to the composition in Table 1 was placed on one side of the release film, coated with the blade of a bar-coater at a speed of 20 mm/s at 25 ℃, and dried at 80 ℃ for 10 minutes to remove the solvent. It was dried. The dried coating layer was coated to a thickness of 200 um. Afterwards, a patch was manufactured by laminating using lint cloth.

ingredient Example 10 drug Fluviprofen 20 Skin permeation enhancer Isopropyl myristrate 50 Temperature sensitive polymer Ethylhexyl acrylate 630 Hydroxyethyl acrylate 115 Ethylmethacrylate 40 Acryloyl morpholine 15

Unit: mg/70 cm ²

<Comparative Examples 1 to 6> Patch using general polymers

A patch was prepared under the same conditions as Example 1 with the composition shown in Table 3 below.

ingredient Comparative example One 2 3 4 5 6 drug Ketoprofen 30 30 30 - - - Fluviprofen - - - 20 20 20 Skin permeation enhancer Isopropyl myristrate - 50 50 - 50 50 polymer Ethylhexyl acrylate 685 685 - 685 685 - Hydroxyethyl acrylate 115 115 - 115 115 - DURO-TEC (8076) - - 800 - - 800

Unit: mg/70 cm ²

<Comparative Example 7> Commercial product 1

Ketotop containing commercially available ketoprofen was used.

<Comparative Example 8> Commercial product 2

A commercially available phenostop containing flubiprofen was used.

<Experimental Example 1> Modulus measurements

This experiment was evaluated using a dynamic rheometer (Rheometer; MCR302, Atom Paar) to measure the glass transition temperature (Tg) of the temperature-sensitive polymer.

The temperature-sensitive polymers of Examples 1-10 of the present invention were measured at -20°C to 95°C and at a frequency of 1Hz.

As shown in FIG. 1, the glass transition temperature of the temperature-sensitive polymer prepared in the present invention was found to be at an inflection point of Tan δ at 37-39°C, whereas the glass transition temperature did not appear around 30-40°C in general acrylic polymers as shown in Figure 1. It was confirmed that a temperature-sensitive polymer was manufactured by confirming that it appeared near body temperature.

<Experimental Example 2> Dissolution evaluation

Take 6 sheets (35 cm2) of each of the patches of Examples 1 to 10 and Comparative Examples 1 to 8 and attach them to the center of the disk assembly of the elutor. Put 500 ml of phosphate buffer solution at pH 7.4 into the elution container, and collect samples at the time of elution at 0, 1, 3, 5, 7, 9, and 11 hours under the conditions of an elution temperature of 32 ± 0.5 ℃ and a paddle rotation speed of 50 rpm. , the dissolution amount was measured under the following HPLC conditions according to the paddle over disk method of the US Pharmacopoeia for transdermal preparations, and the test results are shown in Tables 4 and 5.

<Ketoprofen HPLC operating conditions>

Mobile phase: methanol-0.02M ammonium acetate = 55:45 (v/v)

Flow rate: 1.0 ml/min

Wavelength: 217 nm

Injection amount: 10 ul

Column: 250mm

Temperature: 35℃

<Flubiprofen HPLC operating conditions>

Mobile phase: methanol-0.02M ammonium acetate = 55:45 (v/v)

Flow rate: 1.0 ml/min

Wavelength: 217 nm

Injection amount: 10 ul

Column: 250mm

drug Emission rate (%) 30 minutes 4 hours 24 hours Ketoprofen Example 1 21.4 ± 3.4 78.5 ± 2.3 98.3 ± 2.1 Example 2 16.2 ± 2.6 70.3 ± 2.1 99.1 ± 1.7 Example 3 13.8 ± 1.4 65.1 ± 1.8 99.3 ± 2.3 Example 4 39.4 ± 3.4 82.6 ± 1.8 99.7 ± 1.5 Example 5 20.7 ± 2.9 77.3 ± 1.8 97.9 ± 1.6 Example 6 22.1 ± 2.6 80.0 ± 2.4 97.4 ± 3.1 Example 7 20.8 ± 1.9 79.1 ± 2.6 99.2 ± 1.8 Example 8 21.6 ± 1.9 78.1 ± 3.1 99.4 ± 2.4 Example 9 22.0 ± 2.8 77.9 ± 3.1 97.1 ± 1.5 Comparative Example 1 72.1 ± 3.9 94.3 ± 2.7 95.1 ± 1.6 Comparative example 2 67.4 ± 4.1 92.5 ± 3.1 97.1 ± 3.2 Comparative example 3 62.1 ± 4.2 93.6 ± 2.9 99.1 ± 1.4 Comparative example 7 53.5 ± 3.6 90.5 ± 1.5 98.5 ± 1.6 Fluviprofen Example 10 30.1 ± 2.9 68.4 ± 2.8 95.1 ± 1.9 Comparative Example 4 61.2 ± 3.6 88.5 ± 3.1 88.4 ± 2.4 Comparative Example 5 60.1 ± 2.9 83.1 ± 2.6 90.1 ± 1.9 Comparative Example 6 55.7 ± 2.9 88.3 ± 3.3 88.9 ± 3.4 Comparative example 8 56.4 ± 4.7 85.5 ± 3.7 89.7 ± 3.1

As can be seen in Table 4, Examples 1-10 using a temperature-responsive polymer showed that the temperature-sensitive polymer according to the present invention compared with Comparative Example 1-6 using a general polymer and Comparative Example 7-8, a commercial product. It was confirmed that the patch used exhibited sustained release. In addition, as the amount of Ethylmethacrylate, Acryloyl morpholine, and Isobornyl acrylate, which provide thermosensitive properties, increased, the initial release was lower.

<Experimental Example 3> Skin permeability evaluation

This experiment is a release evaluation experiment to evaluate the degree of skin penetration of the patch according to the present invention. The skin permeability of Examples 1 to 10 according to the present invention and Comparative Examples 1 to 8 were compared and evaluated.

A Franz diffusion cell (6 cell Manual Test System; Hanson Research) was used using hairless rat skin that was hydrated in a pH 7.4 phosphate buffer solution for 4 hours while maintaining the temperature and 600 rpm conditions of 37°C. The temperature of the receptor layer was maintained at 37 ± 0.5 °C and rotated at a constant speed of 250 rpm using a star-head magnetic bar. A pH 7.4 phosphate buffer solution was used as the receptor layer, the volume of the receptor layer was about 12 ml, and the area of the skin in contact with the receptor layer was 1.76 ㎠. A patch for transdermal administration containing ketoprofen or flurbiprofen and a commercially available patch were attached to the exposed part of the skin and then collected for up to 24 hours at each time period. The drug concentration in the collected samples was experimental example. It was analyzed using the HPLC method in 2.

As can be seen in Figure 1, the film-forming external preparation according to the present invention exhibited sustained drug release and it was confirmed that the degree of skin permeation could be appropriately adjusted depending on the amount of skin permeation enhancer used. Among them, the formulation containing the most glycerin in Example 9 showed the highest release rate and also showed significantly higher skin permeability compared to commercial products.

drug 24-hour cumulative skin permeation amount (ug/cm ² ) Ketoprofen Example 1 477 ± 41 Example 2 481 ± 37 Example 3 438 ± 41 Example 4 417 ± 25 Example 5 376 ± 35 Example 6 394 ± 47 Example 7 457 ± 48 Example 8 434 ± 27 Example 9 445 ± 27 Comparative Example 1 53 ± 5 Comparative example 2 103 ± 7 Comparative Example 3 153±10 Comparative Example 7 323 ± 24 Fluviprofen Example 10 211 ± 17 Comparative example 4 17±2 Comparative Example 5 57±6 Comparative Example 6 77 ± 8 Comparative example 8 130 ± 21

<Experimental Example 4> Evaluation of in vivo dynamics of patches for transdermal administration containing temperature-sensitive polymers (Pharmacokinetics)

To evaluate the bioavailability of the patch, Examples 1 and 7 and Comparative Examples 7 and 8 were administered percutaneously to SD rats, and blood was collected from the femoral artery using a heparinized disposable syringe. After separating the collected blood into plasma, in the case of ketoprofen, it is concentrated using the liquid-liquid extraction method, and then the plasma is pretreated using flurbiprofen as an internal standard. In the case of flurbiprofen, it is used as an internal standard using the protein method. Plasma pretreated using ketoprofen was analyzed under the following HPLC conditions.

<Ketoprofen HPLC operating conditions>

Mobile phase: Acetonitrile: 0.1% phosphoric acid aqueous solution = 45:55 (v/v)

Flow rate: 1.0 ml/min

Wavelength: 260 nm

Injection amount: 50 ul

Column: 250mm

Temperature: 25℃

<Flubiprofen HPLC operating conditions>

Mobile phase: methanol-0.02M ammonium acetate = 50:50 (v/v)

Flow rate: 1.0 ml/min

Wavelength: 254 nm

Injection amount: 10 ul

Column: 150mm

Temperature: 25℃

[Table 6] lists the pharmacokinetic parameters, and Figure 2 shows the blood drug concentration in the body over time.

AUC
(μg·h/ml) Cmax
(μg/ml) Tmax
(h) Example 1 60.4 ± 17.6 3.99 ± 0.96 6.70 ± 1.46 Example 10 53.7 ± 10.4 3.81 ± 0.70 3.00 ± 0.83 Comparative Example 7 25.6 ± 7.3 1.19 ± 0.67 8.30 ± 2.56 Comparative example 8 34.0 ± 16.1 1.10 ± 0.64 5.00 ± 1.41

<Experimental Example 5> Skin irritation assessment

In order to determine the skin irritation properties of patches using the temperature-sensitive polymers of Examples 1 to 10 of the present invention, the samples prepared in Examples 1 and 10 and commercial products were subjected to a primary irritation test on rabbit skin for Examples 7 and 8. was carried out.

The back fur of six adult white rabbits weighing 2.5 to 3.5 kg was removed. Divide the hair-removed back skin of a rabbit into left and right sides, with the left side as the administration compartment and the right side as the control section. The healthy skin or scraped skin is distributed diagonally to each other, so that there are two healthy skin areas and two scraped skin areas measuring 2.5 cm x 2.5 cm. It was done. Scratched skin was created by using the tip of a syringe needle to damage the epidermis but not the dermis, creating an abrasion to the extent that no bleeding occurred.

The sample was applied to the skin of the hair-removed back area of the rabbit, and the preparation was removed after 24 hours. Erythema and edema immediately after removal (24 hours after application) and 48 hours after removal (72 hours after application) were judged according to the skin irritation criteria below, and the sum of the obtained scores was the stimulation at each time. The score was calculated, and the average of the stimulation scores at each time was taken as the primary skin irritation index (PII value), as described later. The results are shown in Table 7.

<Skin irritation criteria>

Score 0: No erythema, no edema.

Score 1: Very mild erythema, very mild edema.

Score 2: Marked erythema, mild edema.

Score 3: Slightly severe erythema, moderate edema

Score 4: Severe erythema, mild crusting, severe edema

<Primary skin irritation index (PII value)>

0 ~ 0.5: Non-irritating

0.6 ~ 2.0: Mild irritant

2.1 to 5.0: Moderate irritant

5.1 ~ 8.0: Strong irritant

Primary skin irritation index (PII value) division Example 1 0.38 Non-irritating Example 10 0.37 Non-irritating Comparative Example 7 0.43 Non-irritating Comparative example 8 0.45 Non-irritating

As shown in Table 7, the primary skin irritation index of the patch using the temperature-sensitive polymer of the present invention was confirmed to be non-irritating to the skin, similar to that of commercial products.

Accordingly, it was confirmed that the patch for transdermal administration using a temperature-sensitive polymer according to the present invention has low skin irritation, exhibits sustained release, and has excellent skin permeability, thereby demonstrating excellent in vivo usability.

Although the embodiments have been described with limited drawings as described above, those skilled in the art can apply various technical modifications and variations based on the above. For example, the described techniques are performed in a different order than the described method, and/or components of the described system, structure, device, circuit, etc. are combined or combined in a different form than the described method, or other components are used. Alternatively, appropriate results may be achieved even if substituted or substituted by an equivalent.

Therefore, other implementations, other embodiments, and equivalents of the claims also fall within the scope of the following claims.

Claims (12)

anti-rheumatic drugs; Temperature sensitive polymer; A pharmaceutical composition for delivering an anti-rheumatic agent, comprising a skin permeation enhancer,
The temperature-sensitive polymer includes 2-ethylhexyl acrylate, hydroxyethyl acrylate, and ethyl methacrylate,
The anti-rheumatic agent is a non-steroidal anti-rheumatic agent, and is a pharmaceutical composition for delivering an anti-rheumatic agent, wherein the anti-rheumatic agent is ketoprofen or flurbiprofen. According to paragraph 1,
The skin permeation enhancer is one or more selected from the group consisting of fatty acid ethers, nonionic surfactants, isopropyl myristate, pyrrolidone derivatives, fatty acids, fatty acid alcohols, and fatty acid esters, a drug for delivery of an anti-rheumatic agent. Academic composition. delete According to paragraph 1,
A pharmaceutical composition for delivering an anti-rheumatic agent, wherein the temperature-sensitive polymer is contained in an amount of 70 to 95% by weight based on a total of 100% by weight. According to paragraph 1,
A pharmaceutical composition for delivering an anti-rheumatic agent, wherein the skin permeation enhancer is contained in an amount of 0.01 to 20% by weight based on a total of 100% by weight. A patch for transdermal administration containing the pharmaceutical composition of claim 1,
a first layer containing the pharmaceutical composition; and a second layer comprising a support. According to clause 6,
The support is characterized in that it contains at least one material selected from the group consisting of polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminized polyester, non-woven fabric, cotton fabric, and fabric. Patch for transdermal administration. Mixing temperature-sensitive polymers (S1);
After mixing, preparing a composition to which an anti-rheumatic agent and a skin permeation enhancer are added (S2); and
Comprising the step of coating the composition on a support and drying it (S3),
The temperature-sensitive polymer includes 2-ethylhexyl acrylate, hydroxyethyl acrylate, and ethyl methacrylate,
The anti-rheumatic agent is a non-steroidal anti-rheumatic agent, which is ketoprofen or flurbiprofen,
Method for manufacturing a patch for transdermal administration. According to clause 8,
A method for producing a patch for transdermal administration, wherein the skin penetration enhancer is at least one selected from the group consisting of fatty acid ethers, nonionic surfactants, isopropyl myristate, pyrrolidone derivatives, fatty acids, fatty acid alcohols, and fatty acid esters. . delete According to paragraph 1,
A pharmaceutical composition for delivery of an anti-rheumatic agent, wherein the temperature-sensitive polymer further includes at least one selected from the group consisting of acroyl morpholine and isobornyl acrylate. According to clause 8,
The temperature-sensitive polymer further includes at least one selected from the group consisting of acroyl morpholine and isobornyl acrylate,
Method for manufacturing a patch for transdermal administration.