KR100340710B1 - Patch comprising formoterol and preparing method thereof - Google Patents

Abstract

The formoterol patch according to the present invention is coated with a rubber primer layer for bonding strength with an acrylic adhesive, which is a drug layer binder, on a fabric (hereinafter referred to as a fabric) laminated with a polyester film and a thin nonwoven fabric, and contains a modified acrylic adhesive and formoterol. Formed by stacking a drug layer and a skin adhesion layer having a drug release control function, such formoterol patches are simpler to use and easier to penetrate as compared to inhalants or oral to date, and formoterol base itself Can be used as a drug to ensure stability, and the drug release control ability keeps the drug effect uniformly, has excellent adhesion to the skin, adheres to the skin, and adheres well to the skin, it has excellent drug delivery rate through the skin It is useful as a therapeutic agent for coronary disorders.

Description

Patch comprising formoterol and preparing method

The present invention relates to a patch containing a formoterol and a method of manufacturing the same, and more particularly, to a bronchial disorder therapeutic agent and a method for producing the same to allow transdermal administration of formoterol, a bronchodilator and a beta2 sympathetic stimulant It is about.

Asthma is an airway hyperresponsiveness caused by various stimuli and is an obstructive disorder of the airways accompanied by spasm of bronchial smooth muscle, increased mucus secretion, and difficulty in breathing.

Among the known asthma therapeutic drugs so far is excellent formoterol, which has been formulated and used in the form of an inhalator.

To date, no bronchial asthma treatment has been released as a transdermal patch, and some pharmaceutical industries have entered the preclinical phase using albuterol, and others are developing antihistamine transdermal formulations.

In Korea, asthma treatments based on formoterol are marketed as oral medications. Formoterol is a sympathetic nervous system β2-agonist (agonist) that has excellent selectivity to β2-receptors and acts on bronchial smooth muscle. Indicates.

In addition, formoterol was selected as a '1995 drug' in Spain in 1996, some time after its release, and it was once again known to the world for its safety and effectiveness. In terms of the therapeutic effect, it was shown to be superior to the β2-agonists such as salbutamol or albuterol, fenoteno, and terbutaline, and also to prevent bronchial asthma attacks. It has been shown to be excellent and has an organic effect of improving lung function.

The known daily dose of formoterol is 160 μg orally and 24 μg as an inhalant, which shows a great effect even in small amounts, and is a suitable drug for transdermal formulation.

In addition, formoterol is stronger than albuterol (albuterol) action and excellent duration and excellent therapeutic effect, unlike albuterol showed a strong effect on the prevention of seizures of bronchial asthma by fog and smog.

In general, patch-type preparations are simpler to use than in oral or inhaling agents, and it is known that infiltration of drugs is effective.

Therefore, if percutaneous patching with formoterol, in particular formoterol base, which has an excellent asthma treatment effect, it can technically emerge as a leader in the transdermal formulation of asthma treatment, in particular, the strong asthma treatment and prevention effect of formoterol patch Based on this, technology transfer, import substitution and export effect will be enjoyed at home and abroad.

The present invention is to patch the formoterol effective base for treating bronchial disorders such as asthma in the base state, the first object is the drug release control function in the formulation itself, the drug efficacy is continuously maintained uniformly and excellent adhesion to the skin It is to provide a novel formoterol patch in the form of a matrix that can be closely adhered to the skin and the drug can be sufficiently delivered through the skin.

The second object of the present invention is that formoterol base has been used for oral or injection as formoterol fumarate since the stability of the drug itself is very unstable. The present invention provides a method for preparing a patch into a patch so as to stably exist in the inside and to stably and continuously release the drug for a period of time.

The patch containing the formoterol of the present invention for achieving the above object is a rubber-like primer layer, foam, containing an acrylic component in order to increase the bonding force of the support layer, the nonwoven fabric and the drug layer laminated a thin nonwoven fabric on the polyester film It has a structure in which a drug layer containing a compound having a carboxyl group capable of hydrogen bonding with terrol, a drug layer in which formoterol is dissolved in an absorption accelerator, and a skin adhesion layer having a drug release control function are sequentially stacked. It is done.

The patch having the structure described above is a step of forming a primer layer by coating / drying an acrylic component-containing rubber type primer layer on a silicone release paper and then laminating the polyester film and a non-woven fabric to form a primer layer, forming a hydrogen bond with formoterol. Coating and drying the solution in which the drug is dissolved in an acrylic compound having a functional group and an absorption accelerator, and transferring the coating onto the primer layer to form a drug layer, and mixing and stirring an emulsifier or a skin penetration promoter with an acrylic pressure-sensitive adhesive to It is characterized in that it is manufactured through a step of forming a skin adhesion layer by transferring a coating on the drug layer and drying it on a release paper.

1 is a cross-sectional view of a formoterol patch according to the present invention,

Figure 2 is a graph measuring the matrix drug release in phosphate buffer solution for formoterol patches prepared according to the present invention,

3 is a graph measuring drug release through hairless mouse skin permeation of a formoterol patch prepared according to the present invention.

4 and 5 are cumulative release graphs of drug release via matrix release and hairless mouse skin permeation,

Figure 6 is a test result of the drug stability change for formoterol patch prepared according to the present invention under severe conditions for 2 months.

Explanation of symbols on the main parts of the drawings

10-polyester film + nonwoven fabric 20-primer layer

30-drug layer 40-skin adhesion layer

50-Release Paper

The present invention will be described in more detail as follows.

1 is a cross-sectional view of a formoterol patch according to the present invention. Referring to the drawings, the formoterol patch is laminated on the primer layer 20, the drug layer 30, the skin adhesion layer 40, and the release paper 50 sequentially on the fabric 10, the polyester film and the non-woven fabric laminated Structure.

(1) fabric

The fabric 10 serves as a support, which is intended to prevent separation of the patch from the skin from moisture penetration and to absorb sweat released from the inside of the attachment surface due to the nature of the patch to be attached for a long time. In order to satisfy the purpose for increasing, a laminate of a polyester film and a nonwoven fabric is used.

(2) Primer layer

The primer layer 20 is used as a rubber type, but in order to increase the bonding strength with the acrylic adhesive, it is prepared using a rubber containing about 30% of the acrylic component in natural rubber.

And, to prevent the back diffusion of the drug, and to use the hydrophobic rubber adhesive for binding to the drug layer, specifically, the addition of a hydrophobic resin and an anti-aging agent to the natural rubber to give the adhesive property. It is preferable that the thickness is 5-50 micrometers.

(3) Drug layer

The drug layer 30 is largely composed of an acrylic adhesive, an absorption accelerator, and a drug.

The acrylic pressure-sensitive adhesive should contain a compound having a functional group capable of hydrogen bonding with formoterol during drying to maximize the drug content without stable recrystallization of the drug in the drug layer. Such compounds, when dried, form hydrogen bonds with formoterol to inhibit the diffusion of drugs in the drug layer, thereby preventing recrystallization and enhancing solubility. Once attached to the skin, hydrogen bonds are destroyed by sweat emitted from the human body. This allows the drug to diffuse freely and be absorbed into the skin.

The compound having a functional group which plays such a role may be selected from N-vinyl-2-pyrrolidone, acrylamide, methacrylamide, 2-hydroxyethyl methacrylate, acrylic acid and methacrylic acid.

It is preferable that the thickness of an acrylic adhesive in a drug layer is 3-50 micrometers.

In addition, absorption accelerators for promoting the absorption of drugs include fatty alcohols, sorbitan monooleate, oleic acid, N, N-diethyl-m-toluamide, myristic acid, and N-methyl-2-pyrrolidone. , Isopyrophyll myristate, dodecylamine and N-dodecanol may be selected and added. Its content is preferably 10 to 50 parts by weight based on the solids content of the drug solution.

Formoterol, a therapeutic drug contained in the drug layer, may be contained in an amount of 10 to 50% by weight (in the solid content of the drug layer) based on the amount of the absorption accelerator.

On the other hand, in the case of asthma treatments mainly composed of formoterol as a main component, the stability of the drug itself is lowered in formoterol base, so it was used as an oral or inhalant using formoterol fumarate. not. Therefore, the use of a low molecular weight formoterol base is easy to transfer the drug when patched, for this purpose it is necessary to improve the stability of the formoterol base. Therefore, in the present invention, in order to solve the limitation that the drug itself is poor in its stability as a formoterol base, about 0.1 to 10 parts by weight of ascorbic acid and sorbic acid, which act as an antioxidant and drug stabilizer in the drug layer. In addition, it is also preferable to use a radical inhibitor in order to suppress denaturation by the reaction initiator present in a quenched state in the acrylic adhesive. At this time, the amount of the radical inhibitor is preferably 100 to 300 parts by weight based on the amount of the reaction initiator. Hydroquinone can be used as a radical inhibitor.

(4) skin adhesion layer

On the other hand, in the form mote patch of the present invention, the skin adhesion layer 40 is formed by mixing and stirring an emulsifier or skin penetration accelerator with an acrylic adhesive, coating and drying it on a silicone coated paper, and then transferring the coating onto the drug layer.

The skin adhesion layer 40 has a long delay time (Lag Time) for the drug is released if the pressure-sensitive adhesive thickening simply to increase the adhesive force with the skin. In other words, if the thickness is thicker than 40㎛ in order to increase the adhesive holding power, the drug release is not good, and if the thickness is less than 5㎛, the adhesive holding force on the skin falls off easily even during the initial sticking. Therefore, the skin adhesion layer 40 is preferably formed in 5 to 40㎛, preferably 10 to 20㎛ in order to release the drug at a constant rate while maintaining a strong adhesion to the skin.

In the skin adhesion layer, when acrylic adhesive emulsifier or skin penetration promoting agent is used to be 1 to 30% by weight in the skin adhesion layer composition, the cohesion of the polymer matrix is reduced, and the polyadhesion of the skin adhesion layer is made to make a constant micropath in the structure. It is possible to obtain the effect of releasing the medicine only by a certain amount in time.

In this case, oleyl alcohol and sorbitan monooleate may be used as the emulsifier, and when used in the range of 0.5 to 10% by weight of the skin adhesion layer composition, physical properties may be deteriorated due to the coupling of the carboxyl group contained in the adhesive layer in a large amount. It can prevent the drug and release the medicine uniformly within a certain time without losing adhesion.

In addition, the skin penetration accelerator may use the same compound as the absorption accelerator used in the drug layer.

As such, the formoterol patch according to the present invention enables the use of formoterol base by addition of ascorbic acid and sorbic acid, which serve as antioxidant and drug stabilizing agents contained in the drug layer, and the hydroxyl group of the drug contained in the adhesive layer. By containing a compound having a functional group capable of forming a hydrogen bond, it restricts the movement of the drug in the matrix to prevent recrystallization and breaks the hydrogen bond by sweat absorbed after skin adhesion, so that release occurs smoothly.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Example 1

A. Acrylic adhesive uses STC-1

B. Primer layer manufacturing

(1) Rubber containing about 30% of methyl methacrylate in natural rubber was dissolved in toluene at a solid content of 5 to 15%.

(2) A SIS (styrene-isoprene-styrene) rubber solution with 27% solids is added to the gastric solution, and 30 to 150 parts by weight of C5 hydrophobic resin such as cyclopentene, dicyclopentadiene, isoprene, etc. The formulation was carried out.

(3) An anti-aging agent was added after adding 0.1-10 parts by weight to the amount of rubber, and the solution was coated on a silicone coated paper and then dried on a fabric (polyester film + nonwoven fabric). At this time, the coating thickness was about 25㎛.

(4) At this time, drying condition is 120 ℃ and 2mins.

C. Formation of Formoterol-containing Drug Layer

After dissolving 2 g of formoterol in 22.22 g of the solvent-modified acrylic adhesive and 10 g of N-methyl-2-pyrrolidone (NMP), the solution contained 1 part by weight of ascorbic acid and sorbic acid as antioxidants, and the mixture was sufficiently stirred. After the coating on the silicon release paper to a thickness of 20㎛. At this time, the drying condition is 120 ℃, 3mins. The prepared drug layer was laminated on the primer layer.

D. Skin adhesion layer manufacture

0.135 g of sorbitan monooleate, 0.54 g of oleyl alcohol, 1.5 g of N, N-diethyl-m-toluamide are added to the modified acrylic pressure-sensitive adhesive of A, and 5 g of ethyl acetate is used as an auxiliary solvent, and the thickness is After drying, the coating was performed to 10 μm, and a transfer coating was performed on the drug layer to form a skin adhesion layer.

Example 2

A. The adhesive is the same as in Example 1

B. primer layer was also prepared in the same manner as in Example 1.

C. The drug layer was the same as in Example 1, but the drug layer thickness was 10㎛ and drying conditions were 120 ℃, 2 minutes.

D. The skin adhesion layer is the same as in Example 1 above.

Example 3

A. The adhesive is the same as in Example 1

B. primer layer was also prepared in the same manner as in Example 1.

C. The drug layer was dissolved in 22.22 g of the solvent-type modified acrylic adhesive and 10 g of N-methyl-2-pyrrolidone and 2 g of formoterol, and then ascorbic acid and sorbic acid, which are antioxidants, were dissolved in the solution. 1 part by weight was sufficiently stirred with a solution containing 0.375 g of hydroquinone, which is a radical inhibitor, and then coated on a silicon release sheet to a thickness of 15 μm. At this time, the drying conditions are 120 ℃, 2 minutes 30 seconds. The prepared drug layer was laminated on the primer layer.

D. The skin adhesion layer is the same as in Example 1 above.

Example 4

A. Acrylic adhesive used STC-2.

B. Primer layer was prepared in the same manner as in Example 1.

C. Formation of Formoterol-containing Drug Layer

The drug layer was dissolved 0.2 g of formoterol in 2.98 g of the acrylic adhesive and 1 g of NMP, and sufficiently stirred with the adhesive using 0.05 g of ethyl acetate as an auxiliary solvent. The coating thickness was 30 μm and the drying conditions were dried at 120 ° C. for 4 minutes.

D. Skin adhesion layer manufacture

0.045 g of sorbitan monooleate and 0.18 g of oleyl alcohol were added to 10.5 g of the pressure-sensitive adhesive, followed by coating with a thickness of 10 μm. The drying was carried out at 120 ° C. for 1 minute 30 seconds.

Example 5

A. The acrylic pressure-sensitive adhesive and the primer layer were prepared in the same manner as in Example 4.

B. Formoterol-containing drug layer

Drug layer was prepared in the same manner as in Example 4, the coating thickness was 35㎛.

C. Skin Bonding Layer

Prepared in the same manner as in Example 4, the absorption promoter was used 0.5g Labrafil (GATTFOSSE product), and after coating the transfer layer using a compression roll on the drug layer to form a skin adhesion layer.

Example 6

A. The adhesive was the same as in Example 4 and prepared in the same primer layer.

B. Formoterol-containing drug layer

Drug layer was prepared in the same manner as in Example 4, the coating thickness was 35㎛.

C. Skin Bonding Layer

Prepared in the same manner as in Example 4, 0.5g of isopropyl myristate was used as an absorption accelerator, and after coating, a transfer layer was formed on the drug layer by using a pressure roller to form a skin adhesion layer.

Example 7

A. The adhesive was the same as in Example 4 and prepared in the same primer layer.

B. Formoterol-containing drug layer

Drug layer was prepared in the same manner as in Example 4, the coating thickness was 40㎛.

C. Skin Bonding Layer

Prepared in the same manner as in Example 4, the absorption accelerator was used 0.5g of N, N-diethyl-m-toluamide, and after coating the transfer coating using a pressure-roll to form a skin adhesion layer on the drug layer. .

Example 8

A. The adhesive was the same as in Example 4 and prepared in the same primer layer.

B. Formoterol-containing drug layer

The drug layer was prepared in the same manner as in Example 4, but the coating thickness was 36㎛.

C. Skin Bonding Layer

Prepared in the same manner as in Example 4, 0.5 g of n-dodecanol was used as an absorption accelerator, and after coating, the coating layer was formed on the drug layer by transfer coating using a pressure roller.

Example 9

A. The adhesive was the same as in Example 4 and prepared in the same primer layer.

B. Formoterol-containing drug layer

Drug layer is the same as in Example 4, the coating thickness was 36㎛.

C. Skin Bonding Layer

The preparation was carried out in the same manner as in Example 4, but the absorption accelerator used 0.5 g of dodecyl amine, and the coating layer was formed on the drug layer by a transfer coating on the drug layer after the coating to form a skin adhesion layer.

Experimental Example 1

The drug content per unit area (Loading Amount), the drug release tendency experiment of the matrix, and the amount of drug release using hairless mouse skin were measured for the formoterol patch prepared according to the above example. The following Tables 1-6. And, the drug release trend with time is shown in Figures 2 and 3. 4 and 5 show the cumulative emission amount of the matrix emission and skin permeation amount, and the adhesiveness of the patch is shown in Table 4 below.

And the test results for improving the stability of the drug under long-term harsh conditions with or without the addition of a radical inhibitor are shown in Table 7, which is shown in the graph of FIG. At this time, the area of the sample in each experiment was 2 cm 2.

Example Drug content (mg / ㎠) One 0.617 2 0.312 3 0.292 4 0.711 5 0.851 6 0.869 7 0.818 8 0.948 9 0.951

Hourly Matrix Release (μ / 4/4 PBS) Hours 6 12 24 36 48 60 72 Example One 62.9 28.1 69.5 39.1 46.4 25.7 36.8 2 57.6 30.7 67.2 33.6 32.2 14.4 16.2 3 46.2 22.6 46.2 20.1 25.0 13.8 16.7 4 164.0 34.2 125.7 62.1 65.0 41.8 46.6 5 126.4 55.6 109.6 56.9 50.7 41.2 43.8 6 132.0 53.2 106.2 64.8 62.5 47.6 48.7 7 97.3 37.7 63.3 47.9 44.6 36.8 33.5 8 104.2 64.9 109.4 68.9 61.4 36.0 41.2 9 105.6 63.9 110.2 65.1 61.9 36.5 41.6

% Release of matrix by time for each drug content (% / drug content 100%) Hours 12 24 36 48 60 72 Example One 14.75 11.26 6.34 7.52 4.17 5.96 2 28.30 21.54 10.77 10.32 4.62 5.19 3 23.56 15.82 6.88 8.56 4.72 5.72 4 27.88 17.68 8.73 9.14 5.88 6.55 5 21.39 12.88 6.69 5.96 4.84 5.15 6 21.31 12.22 7.46 7.19 5.48 5.60 7 16.50 7.74 5.86 5.45 4.50 4.10 8 17.84 11.54 7.27 6.48 3.80 4.35 9 17.82 11.59 6.85 6.51 3.84 4.37

Hairless Mouse Skin Permeation Release by Hours (㎍ / 4㎖ PBS) Hours 6 12 24 36 48 60 72 Example 4 2.53 2.00 21.53 52.67 49.68 43.45 41.83 5 2.98 5.29 46.14 83.28 69.56 57.43 44.10 6 2.15 3.17 36.23 82.37 81.26 64.71 48.83 7 2.82 8.63 46.87 70.90 63.69 75.18 47.67 8 2.90 5.73 27.15 59.84 49.19 40.45 33.87 9 3.01 4.80 42.35 85.16 74.90 71.39 60.76

% Release of matrix by time for each drug content (% / drug content 100%) Hours 12 24 36 48 60 72 Example 4 0.64 3.03 7.41 6.99 6.11 5.88 5 0.97 5.42 9.79 8.17 6.75 5.18 6 0.61 4.17 9.48 9.35 7.45 5.62 7 1.40 5.73 8.67 7.79 9.19 5.83 8 0.91 2.86 6.31 5.19 4.27 3.57 9 0.82 4.45 8.95 7.88 7.51 6.39

Viscosity (g / 25mm) Ball Tack (No./mm) Example 1 638 14/64 Example 3 407 12/55

In Table 6, the experimental conditions were carried out at a temperature of 27 ℃, 18.8% humidity.

From the results of Tables 2 to 5, the formoterol patch prepared according to the embodiment of the present invention shows a different amount of release depending on the control of the skin adhesion layer, the drug concentration of the drug layer, and the type of absorption accelerator used. It can be adjusted efficiently. This can be more easily confirmed from the release amount of the drug solution using the release amount of the matrix and the hairless mouse skin shown in the accompanying Figures 2 and 3.

Drug stability evaluation (% drug content) The passage of time Early 1 month 2 months Example 3 1 (A-1) 100 100 100 2 (A-2) 100 99 97 Example 4 1 (B-1) 100 90 76 2 (B-2) 100 92 67

The results of Table 7 and the accompanying FIG. 6 are carried out on the patches obtained according to Examples 3 and 4, respectively, and show the results of repeated experiments for each patch.

From the results of Table 7 and Figure 6, it can be seen that in the case of formoterol patch according to the present invention, drug denaturation is more suppressed than when a radical inhibitor is contained in the drug layer so that the drug is stably present in the matrix for a long time. have.

As described in detail above, the formoterol patch according to the present invention has the ability to control drug solution release on its own, and thus can keep the drug continuously uniformly, and can be sufficiently delivered when the skin adheres to the drug. In addition, since the drug layer has a functional group capable of forming hydrogen bonds with the drug, recrystallization of the drug can be prevented, and when attached to the skin, the hydrogen bond is broken and the drug can be continuously released. In addition, when the radical inhibitor is added, drug denaturation may be suppressed to stably exist the drug in the matrix for a long time. In addition, the formoterol base itself can be added as a drug.

Claims (13)

A support layer in which a thin nonwoven fabric is laminated on a polyester film; A rubber type primer layer containing an acrylic component; An acrylic pressure-sensitive adhesive containing a compound having a carboxyl group capable of hydrogen bonding with formoterol, and a drug layer in which formoterol is dissolved in an absorption accelerator; And A patch containing formoterol having a structure in which a skin adhesion layer is sequentially laminated. The patch containing formoterol according to claim 1, wherein the primer layer is a rubber having an acrylic group within 30% by weight. The patch containing formoterol according to claim 1, wherein the primer layer contains a hydrophobic rubber adhesive. 4. The patch containing formoterol according to claim 3, wherein the hydrophobic rubber adhesive contains an acrylic component in natural rubber. According to claim 1, wherein the acrylic pressure-sensitive adhesive containing a compound having a carboxyl group capable of hydrogen bonding with formoterol in the drug layer is n-vinyl-2-pyrrolidone with respect to the solid content of the components added in the drug solution Patches containing formoterol, characterized in that it contains from 10 to 50 parts by weight. The method of claim 1, wherein the absorption accelerator in the drug layer is selected from oleyl alcohol, sorbitan monooleate, N, N-diethyl-m-toluamide, N-dodecanol, isopropyl myristate and dodecyl amine Patches containing formoterol, characterized in that. 7. The patch containing formoterol according to claim 1 or 6, wherein the absorption accelerator in the drug layer contains N-methyl-2-pyrrolidone in an amount of 100 to 1000 parts by weight based on the content of formoterol. The patch containing formoterol according to claim 1, wherein the content of formoterol in the drug layer is 10 to 50% by weight of the total solid content of the drug layer. The patch containing formoterol according to claim 1, wherein the acrylic pressure-sensitive adhesive in the drug layer is 3 to 50 µm thick. The patch containing formoterol according to claim 1, wherein the drug layer contains 0.1 to 10 parts by weight of ascorbic acid and sorbic acid. 11. The patch containing formoterol according to claim 1 or 10, wherein the drug layer contains hydroquinone as a radical inhibitor. Coating / drying an acrylic component-containing rubber type primer layer on a silicone release paper and then laminating the polyester film and a non-woven fabric to form a primer layer; Forming a drug layer by coating and drying a solution in which the drug is dissolved in an acryl-based compound having a functional group capable of hydrogen bonding with formoterol and an absorption accelerator, and transferring the coating onto the primer layer; And Preparation of a patch containing a formoterol of claim 1 comprising the step of mixing the emulsion or skin penetration promoter with an acrylic pressure-sensitive adhesive to form a solution, and drying the coating on a release paper and transferring it to the drug layer to form a skin adhesion layer Way. The method for producing a patch containing formoterol according to claim 10, wherein the skin adhesion layer is formed to have a thickness of 5 to 40 µm.