KR20140069956A - Topical gel composition containing dexibuprofen emulsion with enhaced permeability - Google Patents

Abstract

The present invention provides an emulsion gel composition in which dexibuprofen having distinct pharmacological activity without a metabolic process or the like is finely dispersed in a gel carrier while being dissolved in an oil phase and a co-solvent. The present invention can increase the skin permeability of dexibuprofen by formulating dexibuprofen, which is a poorly soluble drug, into a fine emulsion (free acid) gel formulation, and can minimize the skin irritation by reducing an alcoholic solvent. Further, the emulsion gel composition of the present invention can improve the skin texture when being applied to the skin due to fine droplets.

Description

A topical gel composition containing dexibuprofen emulsion with enhanced absorption is disclosed.

The present invention relates to a new topical use external gel formulation containing a non-steroidal anti-inflammatory drug (NSAID) Dexibuprofen (S (+) - isomer ibuprofen) .

Nonsteroidal anti-inflammatory drugs (NSAIDs) are non-invasive, non-steroidal, but can be used to combat inflammation and pain.

At present, a variety of the latest drugs are available. Although the chemical structure of these newer formulations is quite different, the common structural feature of many of these compounds is the presence of carboxylic acid groups (COOH). For example, one group of NSAIDs is composed of a propionic acid derivative (so-called "profen", eg, ibuprofen) and the other NSAID group is composed of acetic acid derivatives (eg, indomethacin).

NSAIDs may cause gastric ulcers and bleeding during long-term oral use. Topical NSAIDs are usually used in the skin in the form of a typical gel or patch. Its purpose is to direct (deeply) the subcutaneous tissue (the drug) to arrive at the other side of the body, while taking direct treatment, away from the side effects of the drug. Thus, the goal of topical administration of NSAIDs is to deliver therapeutically effective levels of the drug to local targets (e.g., skin nociceptors and inflammatory cells) while bypassing the stomach and preventing systemic delivery, but regrettably, , It may not be absorbed well. Such topical formulations, which exhibit slight absorption through the skin, result in substantially systemic delivery and often fail to provide therapeutic levels to the skin.

In addition, acute inflammation and pain are often treated by topical administration of an anti-irritant. In this regard, the widely used formulation is methyl salicylate, which is often applied to the skin in the form of ointments or creams to induce a mild analgesic effect that sedatives. However, methyl salicylate has the disadvantage that it has an odor that can be regarded as discomfort for certain individuals in certain circumstances.

Ibuprofen is a compound represented by the following formulas (1) and (2), in particular, the S-form is called Dexibuprofen.

≪ Formula 1 >

(2)

Ibuprofen inhibits the cyclooxygenase enzyme and activates peroxisome proliferator-activated receptors. Both of these actions are drugs that alleviate inflammation, the least of the current NSAIDs It causes gastrointestinal damage. One feature of the ibuprofen which is used in many countries is the same amounts of R- and S (+) - and that it is a mixture of ibuprofen, in vitro (invitro) inert R- yinan Make-way dimmer of metabolic (metabolic) chiral (chiral ) It becomes S-shape by inversion. S (+) - isomer ibuprofen, dexibuprofen, is a pharmacologically effective binothiomer. In rodent studies, dexibupropene showed reduced gastrointestinal damage and improved analgesic effects compared to the standard ibuprofen in the racemate. Rodents treated with dexiburofen had a smaller size of swelling induced by carrageenan injection on the right foot, suggesting that dexibupropene may have a better anti-inflammatory effect.

U.S. Patent No. 4,185,100 describes a method of topical treatment of inflammatory conditions of the skin, comprising applying a non-steroidal anti-inflammatory agent to the site of infection and simultaneously a topically active anti-inflammatory corticosteroid. The formulations are applied in a dermatologically acceptable topical mediator selected from the group consisting of creams, gels, ointments, powders, aerosols and solutions suitable for topical administration.

U.S. Patent No. 4,533,546 discloses an aqueous alcoholic gel containing an NSAID (e.g., ibuprofen) having a pH in the range of 7.0 to 9.0. The gel ointment contains a phenylacetic acid anti-inflammatory compound, a carboxyvinyl polymer, a water-soluble organic amine (e. G., Triethanolamine) and water, wherein the amount of organic amine is in the range of 7.0 to 9.0, preferably 7.3 to 7.8 .

U.S. Patent No. 5,093,133 describes a hydroalcoholic gel containing ibuprofen, hydroxypropyl cellulose or a polyacrylic acid polymer in combination with propylene glycol, which is an optional but preferred ingredient. U.S. Patent No. 5,318,960 discloses a hydrogel- A transdermal delivery system containing propene, a surfactant and an auxiliary solubilizer is disclosed. However, the gel preparation contains an excessive amount of alcohol and thus has a problem of severe skin irritation.

WO 2001-073998 discloses low alcohol and clear and stable dexibupropen, and EP-A-0151953 discloses a process for preparing a supersaturated drug-containing gel, which is to be mixed together in situ prior to use, two liquids drug-containing phase to an illustrative example of a pharmaceutical composition for percutaneous absorption by topical application made, ibuprofen, propylene glycol, water, CARBOPOL ^® 940 (polyacrylic acid polymer) and ibuprofen CARBOPOL containing diisopropanolamine ^® gel system . ≪ / RTI > This European patent application discloses a non-alcoholic gel system for topically delivering ibuprofen.

U.S. Patent No. 5,093,133 teaches the desirability of addition of alkalizing agents, the desirability of water and the use of S-enantiomers in formulations for increased percutaneous absorption.

U.S. Patent No. 5,767,161 discloses a topical gel composition containing dexibupropene, ethanol, propylene glycol, an oil, a surfactant, and poloxamer as a thickening agent, but is liable to cause skin irritation due to its high co-solvent content.

U.S. Patent No. 6,368,618 discloses gel compositions containing dexibupropene, alcohol and menthol as a depressant, but it has a disadvantage in that the oil phase can not be finely retained due to the low ratio of the two-phase melt system and the surfactant.

In addition, Japanese Patent Publication No. 06199701 discloses a topical anti-inflammatory analgesic agent in which S-chain dexibupropene and a polyhydric alcohol are blended.

Thus, there is a need in the art for topical formulations that provide effective concentration delivery, minimal systemic delivery, and rapid epidermal and dermal delivery of active drugs that treat inflammatory skin conditions with beneficial rheological properties in external gel formulations containing dexibuprofen .

An object of the present invention is to provide an emulsion gel composition in which dexibupropene having a definite pharmacological activity without being metabolized and the like is finely dispersed in a gel carrier in a state dissolved in an oil phase and a cosolvent.

In order to achieve the above object, the present invention provides a dexibupropene gel composition containing dexibupropene as an active ingredient and containing a neutralizing agent for neutralizing only a solvent, a cosolvent, a surfactant, a thickening agent and an aging agent .

In the present invention, the oil phase plays a role of dissolving dexibupropene in the acid form and dispersing it in the aqueous phase, and isopropyl myristate, lauroglycol 90, pepermint oil, , One or two selected from among Labrafil 1944CS, Plurol Oleique, Maisine 35-1 or Labacfac PG, and is selected from among 3 ~ The cosolvent has a role of supporting the dispersibility of dexibupropene and the absorption of the skin, and it is preferable that the cosmetically active agent is an alcohol, such as ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol or transcutol, And 5-20% (w / w) based on the total weight of the surfactant. The surfactant serves to finely disperse dexibupropene, oil and co-surfactant in the aqueous phase, and polysorbate 20 , 40, 60, 80 (trade name: T selected from the group consisting of polyethylene glycol, polyoxyethylene castor oil (ween 20, 40, 60, 80), polyethylenehydroxystearate, polyoxyethylene castor oil derivatives (trade name Cremophore EL, RH40, RH60) and Labrasol, w / w).

The present invention contains a carbomer as a thickening agent. The incremental carbomer according to the present invention maintains viscosity and, surprisingly, greatly increases the absorption of dexibupropene. The neutralizer may also be selected from triisopropanolamine, diisopropanolamine, diethylamine, diethanolamine ammonia, arginine, triethanolamine, potassium hydroxide or sodium hydroxide for the purpose of increasing solubility of the carbomer only , And an agglomerating agent in an amount of 0.5 to 7% (w / w) relative to the carbomer.

In a most preferred embodiment of the present invention, dexibupropene, isopropyl myristate, propylene glycol, isopropyl alcohol, polysorbate 80, carbomer and diisopropanolamine are used in a ratio of 1: 1: 2: 1 to 2: 2: 0.5: 0.4 by weight.

The physicochemical properties of the external gel preparations according to the present invention were analyzed using a Texture Analyzer. In order to evaluate the anti-inflammatory and anti-nociceptive effects of the external gel formulation of the present invention, carrageenan-induced rats were examined for paw edema and paw pressure, and skin irritation tests The degree of edema was evaluated.

As a result, the emulsion containing a large amount of dexibupropene due to the emulsion preparation having excellent solubilization ability was prepared by adding an external gel preparation containing isopropyl myristate (IPM) as an oil, tween 80 as a surfactant, and propylglycol as a cosurfactant To obtain better physico-chemical properties, external gel preparations can be prepared using bioadhesives such as carbomer, poloxamer and PIV. In particular, the carbomer organic emulsion gel exhibited good physical properties in vitro. In vitro skin penetration data showed a 2 to 3 times greater rate of penetration than commercial products. In addition, the anti-inflammatory / analgesic efficacy was better in the body than the commercial product. In the skin irritation model experiment using the rabbit, the experimental agent showed no stimulation.

The present invention can increase the skin absorption of dexibupropene by formulating a poorly soluble drug, dexibupropene, into a fine-acid emulsion (Free acid) gel formulation, and minimize skin irritation by reducing the alcoholic solvent . Further, the droplet is fine, and the skin feeling can be improved when applied to the skin.

Fig. 1 shows the skin permeability of Example 1, Comparative Examples 1 and 2, and a commercially available product.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are for illustrative purposes only, and the scope of the present invention is not limited by the examples and the experimental examples.

< Example  1>

As shown in Table 1, 10 g of propylene glycol and 10 g of isopropyl alcohol were added to 5 g of isopropyl myristate and mixed and dissolved using an overhead stirrer. To this solution, 5 g of dexibupropene was added to completely dissolve, 10 g of polysorbate 80 and 0.2 g of benzyl alcohol were mixed and mixed to prepare an oily solution.

2.5 g of carbomer (Cabopol 934P) was added to 39.9 g of purified water, and the homomixer and the scraper were operated and dissolved using a vacuum emulsification mixer. 2 g of diisopropanolamine was added to the dissolved solution, the scorpion was activated to neutralize the carbomer, and the dexibupropene solution prepared above was added dropwise to the neutralized gel (water phase). The gel was mixed under vacuum conditions to remove bubbles in the gel, and a gel formulation containing dexibupropene emulsion in which the dexibupropene oily solution was finely dispersed in the gel was prepared.

< Example  2>

As shown in Table 1, a gel formulation containing dexibuprofen emulsion was prepared by the same composition and method, except that 5 g of isopropyl alcohol was used in Example 1.

< Example  3>

As shown in Table 1, a gel formulation containing dexibuprofen emulsion was prepared by the same composition and method, except that the amount of dexibupropene was changed to 2.5 g in Example 1.

< Example  4>

As shown in Table 1, a gel formulation containing dexibuprofen emulsion was prepared in the same manner as in Example 1 except that 2.5 g of dexibupropene and 5 g of propylene glycol were used.

< Comparative Example  1> Using an alkalizing agent Dexibupropene  Dissolved agent

A gel formulation was prepared by dissolving dexibupropene using an alkalizing agent by the method described in Example 2 of International Patent Publication No. WO 2001-073998.

< Comparative Example  2> Increasing agent Pollock Sarmer Formulation  One emulsion  Gel

An emulsion gel was prepared using poloxamer which is not a carbomer in the composition shown in Table 2, except that the step of adding poloxamer instead of carbomer and the step of adding diisopropanolamine was omitted. The same procedure as in Example 1 .

&Lt; Comparative Example 3 & Ethanol-rich formulation

A preparation containing dexibupropene and containing a large amount of alcohol was prepared as in Example 1 of U.S. Patent No. 5,093,133,

<Experimental Example 1> Skin permeability test

In order to examine the degree of skin permeability of the external gel for emulsion according to the present invention, a skin permeability test on the external gel described in Example 1 was conducted. The test was carried out using a Franz Diffusion cell. The hairless mouse was anesthetized and the abdominal skin was cut and used as a membrane with a Diffusion area of 0.71 cm 2. Cell Receoptor Medium was prepared using pH 7.4 phosphate buffer, and the sample was taken from the receptor cells of the Example 1, Comparative Examples 1 and 2 and commercially available Nurofen ^{® on} the hairless mouse skin at appropriate time intervals and analyzed by HPLC. The results are shown in FIG. 1.

Skin permeability evaluation results Example 1 of the present invention shows that skin permeability is significantly increased as compared with Comparative Example 1 which is dissolved with an alkalizing agent, Comparative Example 2 which uses Poloxamer as a gelling agent, and Nurofen ^{® which} is a typical commercial product.

<Experimental Example 2> Skin irritation test

In order to examine the degree of skin irritation of the external gel for emulsion according to the present invention, a skin irritation test on the external gel described in Example 1 was conducted. Experimental animals were divided into two groups: New Zealand white rabbits (2 to 3 kg), male (3 rats), and 0.5 g of the preparation in a square shape of 2.5 cm in length. ), 48 hours (2 days) and 72 hours (3 days), according to Table 3 below.

The evaluation results are shown in Table 4. As shown in Table 4, the preparation of the present invention had no skin irritation, whereas skin irritation was observed in Comparative Example 3 containing a large amount of ethanol and in the case of the commercial formulation Nurofen ^® .

Claims (9)

(W / w), 5 to 20% (w / w) of a co-solvent, 5 to 20% (w / w) of a surfactant, 3 to 15% 1 to 4% (w / w) and a neutralizing agent.
The method of claim 1, wherein the oil phase is selected from the group consisting of isopropyl myristate, Lauroglycol 90, Pepermint Oil, Labrafil 1944CS, Plurol Oleique, , Maicin 35-1 (Maisine 35-1), or Labracup PG (Labacfac PG).
The dexibupropene gel composition of claim 1 wherein the co-solvent is selected from ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol or transcutol.
The dexibupropene gel composition according to claim 1, wherein one or two surfactants selected from the group consisting of polysorbate, polyethylenehydroxystearate, polyoxyethylene castor oil derivative, or labrasol are selected.
The dexibupropene gel composition of claim 1, wherein the thickener is a carbomer.
The dexibupropene gel composition according to claim 1, wherein the neutralizing agent is selected from triisopropanolamine, diisopropanolamine, diethylamine, diethanolamine ammonia, arginine, triethanolamine, potassium hydroxide or sodium hydroxide.
7. The dexibuprophen gel composition of claim 6, wherein the neutralizing agent is to neutralize the thickening agent.
The dexibupropene gel composition according to claim 7, wherein the neutralizing agent contains 0.5 to 7% (w / w) of the enhancer carbomer.
Isopropyl myristate, propyleneglycol, isopropyl alcohol, polysorbate 80, carbomer and diisopropanolamine in a weight ratio of 1: 1: 2: 1 to 2: 2: 0.5: 0.4, &Lt; / RTI &gt;

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