KR100867262B1 - Plaster Composition Containing Pelbinac - Google Patents

Abstract

In a composition of a plaster containing pelvinac (4-biphenylacetic acid), which is a nonsteroidal anti-inflammatory analgesic component, a soluble phenol and phenolic acid-based acrylic pressure-sensitive adhesive are mainly used in a formulation composed of a drug layer in matrix form. In order to improve the solubility of the drug and stabilize the dispersion of the composition, it is a pH adjuster and a dissolving agent of the main drug that fuses a transdermal absorption accelerator with excellent human safety and solid dispersion technology, which has low skin irritation, excellent permeability and long-term stability, and optimum adhesion. To provide a quality Pelbinak plaster composition of pH 6.5 to pH 8.0.

 Felbinac, 4-biphenylacetic acid, plaster, anti-inflammatory analgesic

Description

The composition of plaster containing felbinacs

1 (a) and 1 (b) are a plan view and a cross-sectional view of the a-a 'cut line of the plaster produced according to the present invention.

Figure 2 shows the transdermal permeability of Example 1 of the present invention, Comparative Example 1 and the product of H company.

Explanation of reference numerals for the main parts

1: support 2: primer layer

3: drug layer 4: release paper or release film

a-a ': perforation

The present invention relates to a plaster composition containing felbinac (4-biphenylacetic acid) having an anti-inflammatory analgesic effect, and in detail, in a plaster composition in which a soluble felbin and an acidic acrylic pressure-sensitive adhesive are formed in a matrix form , PH adjuster of base, percutaneous absorption accelerator which is safe for human body and solid dispersion technology by water-soluble polymer, low irritation to skin, high transdermal permeability of main drug, excellent time-lapse stability and adhesion of preparation, pH 6.5 to pH It relates to the Pelbinac plaster composition of 8.0.

Plaster preparation designed to absorb the drug effectively through the percutaneous structure is composed of the structure as shown in Figure 1, which maintains the drug layer and prevents contamination from the outside during patching (1), a primer for inhibiting the back despreading of the main drug To protect the drug layer (3) consisting of the layer (2), the main drug, percutaneous permeation accelerator, excipients, antioxidants and adhesives and the drug layer contained in the drug layer, so that it can be easily separated from the drug layer when using the product It is composed of a release paper or a release film (4). The plaster layer contains the main drug, and the drug layer (3) in direct contact with the skin of the human body has percutaneous permeability, which determines the safety of the skin, the efficacy of the drug, and long-term stability due to physical changes in the product. The importance of quality in securing, etc. may not be enough.

Pelbinac, which is used as a main drug in the present invention, is a nonsteroidal anti-inflammatory drug, represented by the following structural formula (I), and a poorly water-soluble substance having a chemical name of 4-biphenylacetic acid. Its molecular weight is 212.25 and its melting point is 164 ° C to 165 ° C. It is an acicular drug of acicular crystals.

Plasters containing such poorly soluble drugs must be particularly careful in the design of the formulation because they are extremely limited in the selection of the composition which constitutes the drug layer in the form of a matrix.

International Publication No. WO 98-24423, Japanese Patent Laid-Open Nos. 15-286162 and US 6,844,007 B2 disclose a conventional method for reducing the adhesive force due to surface leakage of a solubilizer, which is a problem of Japanese Patent Laid-Open No. 4-321624 using crotamiton as a solubilizer for felbinac. While explaining the technique of styrene-isoprene-styrene block copolymers, rosin-based resins and plasticizers are heated to about 110 ℃ to 200 ℃, the base is molten in the state of the addition of felbinac and mixed uniformly dissolved and then rolled on a release paper And, by incorporating this into the support, the hot melt technology to uniformly disperse felbinak in a semi-dissolved state in the formulation is introduced, there is no problem in the pH stability and initial adhesion of the hot melt base and the main drug, but disperse in the formulation over time The crystals of felbinac are grown on the surface of the drug layer, which may lower the adhesive strength when applied to the patch. This results in very different adhesion quality depending on the season and region. On the other hand, the core technology of plaster formulation research has been to find a way to promote the absorption of the optimal amount of the main drug in the percutaneous, and the main drug dissolved by the solubilization method or solubilization method is selected. Formulation studies have focused on the mechanisms of absorption in a formulation over time.

Korean Patent Laid-Open Publication No. 10-2005-0047194 contains alkanolamine as a dissolving agent for felbinac, N-alkyl-pyrrolidone as a cosolvent, and a transdermal absorption accelerator using nonionic surfactants, fatty acids and fatty acid derivatives. And a technique of a plaster having an acrylic drug layer having excellent adhesive quality. When alkanolamines are used, the solubility of the acidic drug felbinac may be enhanced to improve stability and adhesiveness, but the solubility of the main drug is lowered due to volatilization of co-solvent N-alkyl-pyrrolidone during the drying process. When the acrylic adhesive is used as the base of the drug layer, the compatibility is poor, so when a long time passes, transparent crystals of the drug are generated and the adhesive quality is lowered. Transparent crystals are produced at room temperature slower than harsh test conditions (40 ° C), but can be more easily found in compositions stored at room temperature to visually observe the resulting transparent crystals.

Accordingly, the present inventors use the acrylic adhesive having the advantages of skin safety, adhesion, flexibility, and physicochemical stability as a base for medical use as a base, and in the process of inventing a composition of a plaster containing a poorly soluble drug felbinac, the main drug. Pel with pH 6.5 to pH 8.0 with low skin irritation, excellent transdermal permeability, long-term stability, and adhesive quality by enhancing the compatibility with the acrylic adhesive and selecting a transdermal absorption accelerator that is safe for the human body as a dissolving agent of the main drug. The Vinak plaster composition was completed.

The present invention is a pH adjusting agent for improving the solubility of the main drug and stabilizing the dispersion of the composition in the composition of the plaster containing a poorly soluble drug Pelbinac, the main drug and the acidic acrylic pressure-sensitive adhesive is composed of a drug layer of the matrix form , As a dissolving agent of the main drug, fusing transdermal absorption accelerator with excellent human safety and solid dispersion technology using water-soluble polymer, low skin irritation, excellent transdermal penetration rate, long-term stability, and optimum adhesion quality of pH 6.5 to pH 8.0 It is to provide a felbinac plaster composition.

In the present invention, the composition of the drug layer containing the main drug in the composition of the plaster containing Pelbinac of pH 6.5 to pH 8.0 having low skin irritation, excellent permeability, long-term stability, and optimum adhesive quality A plaster composed of an accelerator, a pH adjuster, a water-soluble polymer, and an acrylic adhesive.

The percutaneous absorption accelerator used in the present invention not only serves as a dissolving agent of felbinac, the main drug, but also helps the drug to move smoothly into the living body when repeated physicochemical processes of manual diffusion and distribution occur through the skin. Solubility parameters proportional to partition coefficient or activity coefficient are very important.

In addition, transdermal absorption accelerators should be non-toxic and non-irritating, free of hypersensitivity and pharmacological action, and should be suitable for pharmaceutical or cosmetic aspects. In the present invention, propylene glycol, dipropylene glycol, 1,3-butylene glycol, sorbitol, glycerin, ethylene glycol, molecular weight 1,000, as a transdermal absorption accelerator having excellent solubility in felbinac, skin moisturizing effect, and excellent skin safety. One or two or more selected from the following polyethylene glycols can be selected and used, and it is preferable that the usage-amount adds 5.0 weight part-30.0 weight part.

The pH adjuster used in the present invention is added for the purpose of neutralizing the acidic drug layer composed of the main drug and the acrylic adhesive, triethylamine, trimethylamine, diisopropanolamine, aminoethanolamine, N, N-dimethylethanol 1 to 2 selected from inorganic bases such as amines, organic bases such as N, N-diethylethanolamine, ammonium chloride, ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and disodium phosphate It can be used, its amount is determined according to the content of the base and the acrylic pressure-sensitive adhesive to be selected. Preferred liquid phase of the drug layer is pH 6.5 to pH 8.0, more preferably the liquid layer of the drug layer is pH 7.0 to pH 7.5. The pH adjuster in the Example of this invention used diisopropanolamine. In the present invention, when the liquidity of the base is less than pH 6.5, transparent crystals are generated, and the adhesion quality is lowered. When the pH of the base liquid is exceeded, pH of the skin may cause itching, and white crystals are generated in the drug layer.

The water-soluble polymer in the present invention is chitosan, carboxyvinyl polymer, carboxymethyl cellulose or salt thereof, alginic acid or salt thereof, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or salt thereof, hydroxyethyl cellulose , N-vinylacetamide polymer, polyvinyl alcohol, polyvinyl methacrylate, carrageenan, xanthan gum, gelatin, methylvinyl ether maleic anhydride copolymer and the like can be used in combination of one or two or more, 3.0 parts by weight to 10.0 Preference is given to using parts by weight. The water-soluble polymers have the function of uniformly dispersing the dissolved drug in the formulation to inhibit aggregation and crystal formation between molecules, thereby maintaining long-term stability of the formulation. Almost no, when the content exceeds 10.0 parts by weight, the viscosity of the composition is high, making application difficult.

It is preferable that the adhesive in this invention consists of an acrylate polymer, and uses 40 weight part-70 weight part of acrylic adhesive whose liquidity is acidic. If less than 40 parts by weight, the adhesive strength at the time of the patch is easy to fall off, and the drug layer composition may be partially buried on the skin, and if it exceeds 70 parts by weight, the adhesive strength is strong and may cause pain when peeling the skin.

In the present invention, 0.1 parts by weight to 5.0 parts by weight of additives such as mint essential oil components such as menthol and camphor, surfactants, antioxidants, preservatives, inorganic fillers, viscosity modifiers and crosslinking agents may be used.

The structure of the plaster of the present invention prepared from the above composition is composed of four layers as shown in FIG.

In the present invention, the support 1 is used to maintain the drug layer and to prevent contamination from outside when using a woven or non-woven fabric made of polyester, polypropylene, polyethylene, etc., basis weight 30 g / ㎡ to 200 g Preference is given to using a support of / m 2.

In the present invention, the primer layer 2 is such that the main drug is not despread to the support, and the drug is released to the skin, and natural or synthetic rubber is used, and a thickness of 10 μm to 40 μm is preferable.

In the present invention, the drug layer (3) is made of felbinac, transdermal absorption accelerator, water-soluble polymer, antioxidant and acrylic pressure-sensitive adhesive, the coating weight is preferably 2.0 mg / cm 2 to 10.0 mg / cm 2.

In the present invention, the release paper or the release film 4 is a polyester, polypropylene, treated with 30 μm to 250 μm thick silicone or fluorine, etc. in order to protect the drug layer and to be easily separated from the drug layer when using the product. It is preferable to use a film or paper such as polyethylene.

Hereinafter, the present invention will be described in detail by Examples and Comparative Examples.

Examples and comparative examples in the present invention are intended to help the understanding of the present invention is not limited to the following examples and comparative examples, the addition order of each composition in the production method describes one example Since it is one thing, it is not limited to the manufacturing method of this invention.

Example  One.

10.2 parts by weight of felvinac, 9.6 parts by weight of diisopropanolamine and 5.0 parts by weight of ethyl alcohol were added and mixed uniformly at 50 ° C. to completely dissolve. 0.4 parts by weight of dibutylhydroxytoluene, 5.0 parts by weight of elmentol, and hydroxypropyl 4.0 parts by weight of cellulose and 4.0 parts by weight of poloxamer are added to 7.8 parts by weight of propylene glycol, a transdermal absorption accelerator, and 54.0 parts by weight of an acrylic pressure sensitive adhesive (a mixture of ethyl acetate), followed by stirring until complete dissolution. Thereafter, it is allowed to stand until bubbles generated during stirring disappear. This mixture is applied to a release paper using a coater so that the main drug content is 0.5 mg / cm 2, and dried at 95 ° C. for 2 minutes. The dried drug layer was laminated on a support treated with natural rubber, and then cut to a predetermined size.

Examples 2 to 5 and Comparative Examples 1 to 4

The compositions of Examples 2 to 5 and Comparative Examples 1 to 4 were prepared in the same manner except that the contents of Table 1 are different.

In the present invention, a method for preparing a plaster containing felbinac is mixed with a predetermined ratio of all components except the acrylic adhesive in the above composition, but first, by heating and dissolving diisopropanolamine, adding felbinac to completely dissolve the remaining components. These are added and stirred to dissolve. Finally, an acrylic adhesive is added and stirred to obtain a pressure-sensitive adhesive liquid in a uniform state. Thereafter, the mixture is allowed to stand at room temperature to remove bubbles, and then coated on a release paper, dried, and laminated with a primer treated with a primer to prepare a plaster.

As a result of confirming the stability of the prepared plaster, in Examples 1 to 5, the adhesion and quality of the formulation were excellent, whereas in Comparative Example 1, transparent needle crystals were formed at pH 6.4, thereby reducing the adhesion. A crystal of white spots was precipitated at pH 8.2. In Comparative Example 2, which was added by 2.9 parts by weight of hydroxypropyl cellulose, the stabilizing effect of the water-soluble polymer did not appear, thereby producing crystals in the form of white spots. In Comparative Example 4, which was added in 10.5 parts by weight, the viscosity of the composition was very high. The uniformity of the drug was not secured and not applied.

pH  Measure

Example 1 to Example 5 and Comparative Examples 1 to 4 prepared in Table 1 each one of the plaster was cut into a 100% 70% ethanol aqueous solution and then extracted to measure the pH and the results are shown in Table 2.

Transdermal Permeation Test

In order to compare skin permeability of Example 1, Comparative Example 1, and Pelbinac-containing plaster of H company, the skin of a hairless mouse and Franz diffusion cell (effective area: 1.767 cm 2, aqueous phase volume: 11.5 ml) were used. The skin permeation test was performed under sink condition.

The aqueous phase was filled with Franz diffusion cell using PBS buffer pH 7.4, maintained at 37 ± 0.5 ° C., and then skin was attached, and a plaster was attached to the epidermal layer of the skin to perform permeation experiment. The skin was extracted from the hairless mouse of 6-week-old hairless hair, and then used after removing the fat layer of the dermis layer. The skin was mounted on the diffusion device, and the aqueous phase was stirred at 600 rpm using a magnetic stirrer during the experiment. . After a certain period of time after application to quantify the drug permeated, 200 μl of the aqueous phase was taken to perform high performance liquid chromatography (HPLC), and the Franz diffusion cell was filled back into the aqueous phase by the amount taken. High performance liquid chromatography installed a ZORBOX XDB C18 (4.6mm × 250mm, Agilent technologies, USA) column in the HPLC column holder and set the flow rate to 1.0ml / min and the UV detector wavelength to 254nm. Phosphate buffer solution = 85: 15 was carried out using a mixed solvent. Phosphate buffer solution was prepared to be 0.05M phosphate (Phosphoric acid). 20 μl of the sample was injected, and the permeated drug was quantified using an HPLC system at a column temperature of 25 ° C. The analysis results are shown in FIGS. 2 and 3.

 As a result of the transdermal permeation test, Example 1 showed a better transdermal permeability than Comparative Example 1 and Pelbinac-containing plaster of H Company.

Stability experiment

 The Pelbinac-containing plasters prepared in Examples 1 to 5 and Comparative Examples 1 to 4 were sealed and shielded and subjected to stability experiments under accelerated conditions of 40 ° C. and 75% relative humidity. Shown in

According to the present invention, by applying a mixture of hydroxypropyl cellulose and diisopropanolamine can be obtained continuously for a long time anti-inflammatory analgesic effect by felbinac, excellent stability and adhesion of the formulation is useful as an effective medicine for anti-inflammatory analgesic Pelbinac-containing plaster can be provided.

Claims (3)

In the composition in which the poorly soluble drug Pelbinak and the acidic acrylic pressure-sensitive adhesive are composed of a drug layer in the form of a matrix, it contains a pH adjuster and a water-soluble polymer, the pH adjuster adjusts the pH of the formulation to 6.5 to 8.0 and the water-soluble polymer is a whole plaster A felbinac-containing plaster composition, characterized by using from 3.0% by weight to 10.0% by weight relative to the composition. According to claim 1, wherein the pH adjusting agent is used in the present invention to improve the stability of the drug consisting of felbinac and an acidic acrylic pressure-sensitive adhesive, triethylamine, trimethylamine, diisopropanolamine, aminoethanolamine, N, N -Mixtures of 1 to 2 types of inorganic bases such as dimethylethanolamine, organic bases such as N, N-diethylethanolamine, ammonium chloride, ammonium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate and disodium phosphate Pelbinac-containing plaster composition, characterized in that to adjust the pH of the formulation to 6.5 to 8.0 using. The method of claim 1, wherein the water-soluble polymer is a dispersion stabilizer having a function of uniformly dispersing felbinac in the formulation in the present invention to inhibit agglomeration and crystallization between molecules, chitosan, carboxyvinyl polymer, carboxymethyl Cellulose or salts thereof, alginic acid or salts thereof, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or salts thereof, hydroxyethylcellulose, N-vinylacetamide polymer, polyvinyl alcohol, polyvinyl meta A felbinac-containing plaster composition comprising at least one of acrylate, carrageenan, xanthan gum, gelatin, methylvinyl ether maleic anhydride copolymer, or a mixture thereof.

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