KR100369779B1 - Composition for transdermal administration of adrenergic bronchodilator and formulation containing the same - Google Patents

Abstract

The present invention is a sympathetic excitatory bronchial dilatation drug to be transdermally absorbed, a transdermal absorption accelerator comprising N-methyl-2-pyrrolidone and oleic acid, and a transdermal absorption administration composition comprising an adhesive substrate, and transdermal absorption containing the same It relates to a formulation for.

N-methyl-2-pyrrolidone and oleic acid, two components of the percutaneous absorption enhancer, act synergistically to significantly promote the absorption of the sympathetic stimulatory bronchodilator through the skin and thus persist in the formulation of simple matrix transdermal absorption. The effect of ensuring a constant drug absorption rate.

Description

COMPOSITION FOR TRANSDERMAL ADMINISTRATION OF ADRENERGIC BRONCHODILATOR AND FORMULATION CONTAINING THE SAME}

The present invention relates to a composition for transdermal absorption comprising a sympathetic excitatory bronchodilating drug to be percutaneously absorbed, a transdermal absorption accelerator including N-methyl-2-pyrrolidone and oleic acid, and an adhesive substrate, and a dosage form for transdermal absorption administration. It is about.

Drug delivery through the skin is a convenient route of administration for drugs that are not readily absorbed by oral administration. This method avoids the multiple steps of absorption and metabolism that occur during oral administration, resulting in higher bioavailability of the drug, resulting in desired drug effects at lower doses and at lower doses without adverse effects from metabolites. Can be obtained. In addition, by maintaining a constant pharmaceutical blood concentration can increase the pharmacological effect.

Most of the cells in the stratum corneum are keratinized, which acts as a real barrier to the penetration of drugs through the skin. Therefore, many absorption accelerators have been used to increase the skin absorption of drugs to improve this. For example, US Pat. Nos. 4,006,218, 3,551,554, 4,568,343, 4,746,515, 4,379,454, 4,906,463, 4,440,777, 4,783,450, 3,957,994, 4,346,086 and 5,212,199 Dimethyl sulfoxide (DMSO), dimethylformamide, polyethylene glycol monolaurate, glycerol monolaurate, ethanol, propylene glycol monolaurate, eucalyptol, lecithin, N-methyl-2-pyrrolidone, Oleic acid and sorbitan esters are disclosed, respectively.

Furthermore, linoleic acid and propylene glycol are disclosed in European Patent Publication No. 261429 as a skin permeation accelerator composed of two substances, and N- (hydroxyethyl) in US Pat. Nos. 4,537,776, 4,764,379 and 4,973,468, respectively. Pyrrolidone and oleic acid, ethanol and glycerol monolaurate, diethylene glycol monoethyl ether and propylene glycol monolaurate are disclosed, but have not been used as skin permeation accelerators for sympathetic excitatory bronchodilators.

Carboxylic acid and nonionic surfactants are disclosed in WO93 / 19708 as skin permeation promoters for sympathetic excitatory bronchodilators, and US Pat. Nos. 4,699,777, 4,888,362, and 5,290,561, respectively, in Azone and Urea. , Eugenol and straight chain hydrocarbon alcohols are disclosed.

Transdermal formulations are classified into drug storage type, simple matrix type and lamination type. Especially, in simple matrix type transdermal absorption type, the drug is dispersed in the substrate layer of the pressure sensitive adhesive, and is described in U.S. Patent Nos. 4,291,014 and 4,438,139. 4,839,174, and the like. This formulation can be easily produced at low production cost, but the rate of drug release is inversely proportional to the square root of time, so the rate of release is initially high, but may have a drawback of rapidly decreasing over time.

The present inventors have continued to develop a formulation that can reduce the rate of drug release, which may be a disadvantage of simple matrix formulations, and develop a formulation that maintains a constant skin absorption rate. As a result, the skin absorption rate is relatively low when only one absorption accelerator is used. By combining two or more low drug absorption promoters, a transdermal dosage form has been developed that has excellent skin absorption rate and maintains the drug release rate over time, and in particular, it has been applied to bronchodilator drugs to achieve the present invention. .

Oleic acid and N-methyl-2-pyrrolidone used as absorption promoters in the present invention, there are many prior arts used individually, and there are few examples of combining them as in the present invention, US Patent No. 4,537,776, The materials were used in 4,996,193, 5,154,922, 5,262,165, and 5,762,953, but used in drugs such as nonsteroidal anti-inflammatory agents, cyclosporine, estradiol, nitroglycerin, propentophylline, respectively, and sympathetic nerves. There is no use for excitatory bronchodilators and no formulations with compositions like the present invention.

The present invention is to provide a composition for the transdermal absorption administration of sympathetic excitatory bronchodilator drugs and to improve the percutaneous absorption rate in the skin and to ensure a constant drug absorption rate and a formulation for transdermal absorption containing the same.

1 is a cross-sectional view illustrating the structure of a simple substrate-type transdermal absorption formulation for the present invention.

2 is a graph showing an example of cumulative skin absorption amount of salbutamol depending on the composition of the absorption accelerator.

The present invention provides a composition for transdermal absorption comprising a transdermal absorption accelerator and an adhesive substrate, including a sympathetic excitatory bronchodilating drug, N-methyl-2-pyrrolidone and oleic acid which are percutaneously absorbed.

In addition, a transdermal absorption drug comprising a protective layer impermeable to the sympathetic excitatory bronchodilating drug to be transdermally absorbed, an adhesive substrate layer comprising the composition for transdermal absorption administration on the protective layer and a release layer on the adhesive substrate layer. Provide a delivery system.

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

The drug delivery system for transdermal absorption administration of the present invention protects the protective layer (c), the transdermal adhesive substrate layer (b), and the transdermal administration system from the external environment as shown in FIG. It consists of (a). In addition, an auxiliary adhesive layer (d) may be added to improve skin adhesion.

The adhesive substrate layer, which is a main component of the formulation according to the present invention, is constituted by undispersing N-methyl-2-pyrrolidone and oleic acid together with the drug in a certain ratio as an accelerator of absorption of the drug in a pressure-sensitive adhesive which is an adhesive polymer substrate. Pressure-sensitive adhesives include polyisobutylene, polyacrylate, polymethacrylate, polysiloxane, polyurethane-based adhesives, and polyacrylate-based adhesives include ethyl-, butyl-, 2-ethylhexyl acrylate, and the like. . In the case where N-methyl-2-pyrrolidone and oleic acid used as the absorption promoter are mixed and used, it is preferably 1: 4 to 4: 1, more preferably 1: 2 to 2: 1: The absorption promoting effect is further improved. In addition, the pressure-sensitive adhesive layer preferably contains 1 to 15% by weight of N-methyl-2-pyrrolidone and oleic acid, respectively.

Representative drugs that can be applied to the transdermal dosage form of the present invention are sympathetic excitatory bronchodilator drugs used for treating bronchial asthma, salbutamol, bitolterol, perbuterol, phenoterol, limiterol, terbutalin, bambuterol, and salmeterol , Formoterol, and when the salbutamol is used, the adhesive substrate layer is 100% by weight, the salbutamol is 1 to 10% by weight, the absorption promoter is 5 to 30% by weight, and the balance is one of the adhesive substrate layer. It is preferable to consist of a phosphorous adhesive. If it is out of the above ranges it is difficult to expect normal administration effect or effective absorption is difficult.

The composition of the present invention may include additives such as fragrances, preservatives, antioxidants, stabilizers, pigments.

On the other hand, the formulation of the transdermal absorption composition of the present invention can be selected not only in a simple matrix form, but also in drug storage and lamination.

Hereinafter, the present invention will be described in more detail based on the following examples. The following examples are only for illustrating the present invention, and the scope of the present invention is not limited only to the following examples.

Comparative Example 1

Absorbent having a composition as shown in Table 1 in 1% by weight of salbutamol, 89% by weight of a polyacrylate-based pressure-sensitive adhesive (Duro-Tak 87-2074, National Starch Chem. Co.) (adhesive and absorbent) Amount, except for the accelerator, and stirred sufficiently until the drug is dissolved or evenly mixed in the tacky polymer solution. The mixed solution was poured onto an impermeable protective layer (Scotch Pack 1109, 3M), and the substrate layer was coated, and then dried continuously, starting at 60 ° C. and gradually raising the temperature to 120 ° C. At this time, the wet coating thickness was 600 µm. The coated adhesive substrate layer was air dried for 1 hour, and then the release layer was laminated thereon and stored at room temperature.

For the skin absorption experiment of the formulation thus prepared, the human carcass skin is attached to the Valia-Chien diffusion cell so that the stratum corneum layer faces the outside of the cell, and the dry patch is attached on the skin and the cell high Fixed with regular screws. The cell was filled with a certain amount of phosphate buffered saline solution and stirred. Although a certain amount (150 μl) of the sample was taken at a predetermined time and quantified by a high performance liquid chromatograph, the experiment was performed three times for each formulation containing the composition to compare the skin absorption promoting effect between the skin absorption promoters. It was insignificant.

Salbutamol transdermal absorption formulation (% by weight) 1st brother Salbutamol Absorption accelerator 1-1 One% - 1-2 One% Dodecanol 10% 1-3 One% Squalene 10% 1-4 One% Sorbitan monolaurate 10% 1-5 One% Monoolein 10%

As a result, 1% by weight of salbutamol was dissolved in the composition, but the effect of the skin absorption accelerator was not known, and it was necessary to increase the content of the drug to examine the effect. Accordingly, the solubility in salbutamol of the dissolution aids usually used in the formulation for transdermal absorption is measured and the results are shown in Table 2.

Solubility of Salbutamol in Dissolution Aids Melting aid Solubility (mg / ml) Propylene glycol 39 Transcutol 64 Polyethylene Glycol 400 19 N-methyl-2-pyrrolidone 330

Since the dissolution aids of Table 2 have a skin absorption promoting effect, it is difficult to confirm the skin absorption promoting effect of the single absorption promoters, but N-methyl-2-pyrrolidone exhibiting a significantly higher solubility than other dissolution aids is salbutamol. It was necessary to increase the content.

Therefore, 100% by weight of salbutamol 2.5% by weight of N-methyl-2-pyrrolidone and a polyacrylate-based pressure-sensitive adhesive Durotax 87-2074, which is an absorbent accelerator and a tacky polymer material, are shown in Table 3. After mixing to make a formulation for transdermal absorption administration in the same manner as the above method, the experiment to compare the skin absorption promoting effect between the absorption accelerator was carried out three times for each formulation containing the composition and the results are shown in Table 3 below It was.

Comparison of skin absorption promoting effect according to the composition of absorption accelerator (unit: weight%) 1st brother Salbutamol Absorption accelerator (% by weight) Skin transmittance 2-1 2.5% - 0.07 ± 0.03 2-2 2.5% Menthol 10% 0.11 ± 0.01 2-3 2.5% 10% propylene glycol monolaurate 0.33 ± 0.16 2-4 2.5% Sorbitan monolaurate 10% 0.28 ± 0.08 2-5 2.5% Azon 10% 0.39 ± 0.07 2-6 2.5% Labra Fill 10% 0.40 ± 0.14 2-7 2.5% 10% oleic acid 0.48 ± 0.21

* Skin transmittance: Mean ± standard deviation (㎍ / ㎠ / hr)

As can be seen from the above, the formulation of the present invention has the greatest effect when using azon, labrafil, and oleic acid as absorption accelerators. However, adult daily necessity of salbutamol is about 4-6 mg, and the value of the percutaneous absorption should be much higher than 50 cm 2 due to the skin permeability. Therefore, by increasing the content of the drug to increase the transmittance, it can be clearly confirmed the skin absorption enhancement effect of the absorption accelerator.

Comparative Example 2

In order to clearly confirm the skin absorption enhancer effect of the absorption accelerator identified in Comparative Example 1, the salbutamol content was increased to 5% by weight and 10% by weight of N-methyl-2-pyrrolidone was added as shown in Table 4 below. The formulation for transdermal absorption administration was prepared in the same manner as in Comparative Example 1 after mixing a weight percent absorption accelerator and a polyacrylate-based adhesive Durotax 87-2074, which is a tacky polymer material corresponding to the remaining amount relative to 100% by weight of the total composition. To prepare, and experiments to compare the skin absorption promoting effect between the absorption accelerator was carried out three times for each formulation containing the composition is shown in Table 4 below the results.

Comparison of skin absorption promoting effect on the composition of absorption accelerator (unit: weight%) 1st brother Salbutamol Absorption accelerator Skin transmittance 3-1 5% Azon 10% 6.21 ± 0.90 3-2 5% Labra Fill 10% 3.03 ± 0.22 3-3 5% 10% of polyoxyethylene-10-lauryl ether 2.08 ± 0.72 3-4 5% Dodecanol 10% 3.36 ± 0.69 3-5 5% Tricapryline 10% 3.32 ± 0.57 3-6 5% 10% oleic acid 7.82 ± 1.47 3-7 5% Triolein 10% 1.99 ± 0.18 3-8 5% Ethyl oleate 10% 1.74 ± 0.37 3-9 5% Isopropyl myristate 10% 1.62 ± 0.36 3-10 5% 10% propylene glycol monolaurate 3.34 ± 0.96

* Skin transmittance: Mean ± standard deviation (㎍ / ㎠ / hr)

As seen above, it can be seen that skin permeability increases significantly with increasing drug content. N-methyl-2-pyrrolidone was essential for increasing salbutamol content, and oleic acid had the highest skin permeability. Indicated.

Example 1

In order to exclude the influence of N-methyl-2-pyrrolidone used in Comparative Examples 1 and 2, 2% by weight of salbutamol, a polyacrylate-based pressure sensitive adhesive durro as an adhesive accelerator having a composition as shown in Table 5 below Prepare a transdermal absorption formulation in the same manner as in Comparative Example 1 with a total coating weight of 87-2074 to 100% by weight and further mixing 20% by weight of this amount of methanol to a wet coating thickness of 1000 ㎛ -The experiment to compare the skin absorption promoting effect on salbutamol in human cadaver skin according to the change of the content of methyl-2-pyrrolidone and oleic acid was carried out three times for each formulation containing the composition and the results are shown in Table 5. Indicated.

Comparison of Skin Absorption Rate by the Change of N-Methyl-2-pyrrolidone and Oleic Acid Content (Unit: wt%) 1st brother Salbutamol Absorption accelerator (% by weight) Skin transmittance 4-1 2% - 0.32 ± 0.11 4-2 2% 5% oleic acid 0.60 ± 0.16 4-3 2% 10% oleic acid 1.05 ± 0.25 4-4 2% 15% oleic acid 1.54 ± 0.35 4-5 2% N-methyl-2-pyrrolidone 5% 0.45 ± 0.15 4-6 2% N-methyl-2-pyrrolidone 10% 0.62 ± 1.47 4-7 2% N-methyl-2-pyrrolidone 15% 1.01 ± 0.22 4-8 2% 7.5% oleic acid, 7.5% N-methyl-2-pyrrolidone 3.05 ± 0.84 4-9 2% 10% oleic acid, 5% N-methyl-2-pyrrolidone 1.37 ± 0.21 4-10 2% 5% oleic acid, 10% N-methyl-2-pyrrolidone 1.64 ± 0.11

* Skin transmittance: Mean ± standard deviation (㎍ / ㎠ / hr)

As described above, N-methyl-2-pyrrolidone and oleic acid were effective in promoting absorption of skin, respectively, in human carcass skin, but the effect of oleic acid was greater, and N-methyl-2-pyrrolidone and oleic acid were increased. It was confirmed that salbutamol skin absorption rate was better when used in a mixture of 1: 1 or 2: 1 than when used respectively. Salbutamol composition of 2% by weight could be prepared by using methanol which can be eliminated during drying to eliminate the effect, but salbutamol composition of higher composition could not be prepared. Therefore, it was confirmed that N-methyl-2-pyrrolidone, which is a skin absorption accelerator and a dissolution aid, should be included in order to include high concentration of salbutamol.

Example 2

In order to clearly confirm the skin absorption enhancement effect of the absorption accelerator identified in Example 1 to the salbutamol content 5% by weight of the absorption accelerator as shown in Table 6 to the polyacrylate-based adhesive Durotax 87-2074 pressure-sensitive adhesive After adding and mixing, the experiment prepared in the same manner as in Comparative Example 1 and comparing the skin absorption promoting effect according to the composition of each absorption accelerator was carried out three times for each formulation containing the composition and the results are shown in Table 6 and Fig. 2 is shown.

The results showed that N-methyl-2-pyrrolidone and oleic acid accelerated skin absorption of salbutamol, increased skin absorption rate and skin absorption pattern with increasing oleic acid content, and the skin absorption pattern was closer to the zeroth absorption rate. I can see

Comparison of Skin Absorption Rate by Units of N-Methyl-2-pyrrolidone and Ole` Phosphate (Unit: wt%) 1st brother Salbutamol Absorption accelerator Skin transmittance 5-1 5% 5% oleic acid, 10% N-methyl-2-pyrrolidone 4.77 ± 0.75 5-2 5% 10% oleic acid, 10% N-methyl-2-pyrrolidone 6.32 ± 2.21 5-3 5% 15% oleic acid, 10% N-methyl-2-pyrrolidone 8.38 ± 0.75 5-4 5% N-methyl-2-pyrrolidone 10% 2.06 ± 0.32 5-5 5% N-methyl-2-pyrrolidone 15% 2.48 ± 0.43 5-6 5% N-methyl-2-pyrrolidone 20% 3.00 ± 0.51

* Skin transmittance: Mean ± standard deviation (㎍ / ㎠ / hr)

The composition for transdermal absorption comprising the sympathetic nerve-exciting bronchial dilator to be transdermally absorbed, the transdermal absorption accelerator including N-methyl-2-pyrrolidone and oleic acid, and the adhesive substrate, and the formulation for transdermal absorption comprising the same It is not only easy to manufacture as a type, but also has a constant skin absorption rate, exhibits a skin absorption rate of zero order having persistence for at least one day, and has an absorption promoting effect by using two or more absorption accelerators in combination. By adjusting the content, the skin absorption rate can be easily controlled to select an appropriate dosage according to the person.

Claims (11)

For percutaneous absorption administration comprising a transdermal absorption accelerator comprising N-methyl-2-pyrrolidone and oleic acid in a weight ratio of 1: 2 to 2: 1, a sympathetic excitatory bronchial dilatation drug to be percutaneously absorbed, and an adhesive substrate Composition. (delete) (delete) (delete) The composition of claim 1, wherein the sympathetic excitatory bronchodilator drug to be percutaneously absorbed is included in the composition in an amount of 1 to 10% by weight. The composition of claim 1, wherein the adhesive substrate is a polyacrylate-based adhesive. The composition of claim 1, wherein the sympathetic excitatory bronchodilator drug to be transdermally absorbed is salbutamol. The composition of claim 1, wherein the composition for transdermal absorption has a formulation selected from the group consisting of drug storage, simple matrix, and lamination. A protective layer impermeable to sympathetic excitatory bronchodilator drugs to be transdermally absorbed; An adhesive substrate layer comprising a composition for transdermal absorption administration according to any one of claims 1 and 5 to the upper surface of the protective layer; And Peeling layer on the upper surface of the adhesive substrate layer Percutaneous absorption drug delivery system comprising a. 10. The drug delivery system according to claim 9, wherein the protective layer further comprises an auxiliary adhesive layer on the lower surface. (delete)