KR100341203B1 - Pharmaceutical Composition Comprising Oily Vitamin and process for the preparation thereof - Google Patents

Abstract

The present invention relates to an oil-based vitamin-containing pharmaceutical composition excellent in skin permeability and stability. (A) an emulsion preconcentrate consisting of an oily vitamin, an organic solvent which is a cosurfactant, and a surfactant; (B) a hydrogel consisting of a gelling agent and purified water; And (C) an external preparation comprising the oil-based vitamin-containing pharmaceutical composition of the present invention, including an alkalizing agent, which is a pH adjusting agent, exhibits much better skin permeability than conventionally known external preparations, so that the active ingredient is applied when applied to the skin. Not only can it effectively reach the skin tissue, but also shows the dual effect of stably preserving the active ingredient in the emulsion.

Description

Pharmaceutical Composition Comprising Oily Vitamin and process for the preparation

The present invention relates to an oil-based vitamin-containing pharmaceutical composition having excellent skin permeability and stability, a preparation method thereof, and an external preparation including the composition.

Among the oil-based vitamins, vitamin A is an essential element in the biological function that plays a role in promoting cell differentiation and protein biosynthesis, and is a functional substance that exerts an excellent effect on wrinkles and restores elasticity and vitality of the skin. However, when formulated using this, there is a disadvantage in that stability is less likely to fall, and the skin penetrability is insufficient, thereby preventing its effectiveness.

Therefore, many formulation methods of such vitamin A have been studied. For example, Korean Patent Publication No. 98-021511 (98.06.25) using a double matrix capsule has a slight improvement in the manufacturing process. This complex, there is a severe foreign body due to microcapsules when applied to the skin, the absorption on the skin was poor and could not show a useful effect.

Accordingly, the present inventors continue to research to develop an external preparation having oil permeability and excellent skin permeability and stability while preparing an emulsion pre-concentrate of oily vitamin using co-surfactant and surfactant, The present invention was completed by discovering that the desired effect can be obtained by dispersing it homogeneously in a hydrogel.

It is an object of the present invention to provide an oil-based vitamin-containing pharmaceutical composition excellent in skin permeability and stability and a method of preparing the same.

Another object of the present invention to provide an external preparation containing the oil-containing vitamin composition.

1 is a graph showing the skin permeability of the formulation comprising the oil-based vitamin-containing pharmaceutical composition of the present invention compared to the conventional formulation.

In the present invention to achieve the above object,

(A) an emulsion preconcentrate consisting of an oily vitamin, an organic solvent which is a cosurfactant, and a surfactant;

(B) a hydrogel consisting of a gelling agent and purified water; And

(C) It provides a composition containing an alkalizing agent which is a pH adjuster.

In the present invention,

(A) preparing an emulsion preconcentrate by mixing an oily vitamin, an organic solvent which is a cosurfactant, and a surfactant;

(B) adding a gelling agent to purified water to prepare a hydrogel;

(C) It provides a method for producing an oil-based vitamin-containing pharmaceutical composition, characterized in that (A) and (B) is mixed and the pH is adjusted by adding an alkalizing agent.

In order to achieve the above another object, the present invention provides an oil-based vitamin-containing external preparation including the oil-based vitamin-containing pharmaceutical composition.

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

Since the composition of the present invention has an optimal skin permeability, when the formulation containing the same is applied to the skin, the active ingredient can effectively reach the desired skin tissue, and the dual effect of stably preserving the active ingredient in the emulsion Indicates.

Hereinafter, the characteristic and the kind of each component used for the composition of this invention are demonstrated.

(1) Active Ingredient

The oily vitamin, which is an active ingredient used in the composition of the present invention, acts as an oil component itself, and all of the oily vitamins that can be used for external use such as vitamin A, vitamin D, vitamin E, derivatives thereof, or mixtures thereof are applicable. In particular, vitamin A is preferable. The active ingredient in the composition of the present invention comprises 0.01 to 40% by weight, preferably 0.1 to 20% by weight based on the total weight of the composition.

(2) co-surfactant

The cosurfactant used in the composition of the present invention is an amphiphilic (having both hydrophilicity and lipophilic) solvent, and any emulsion can be used as long as the emulsion prepared therein can be easily dispersed in a hydrogel. Co-surfactant not only provides the solubility suitable for formulation to the active ingredient, but also has both hydrophilic and lipophilic properties in terms of physical properties, and thus aids in emulsification of the formulation so that the active ingredient can be uniformly dispersed in the hydrogel. It also provides the advantage that there is no change over time of the active ingredient even during the preservation of the formulation and ensure the uniformity of the composition. Particularly co-surfactants that meet this purpose include ethanol, isopropyl alcohol, transcutol (diethylene glycol monoethyl ether, boiling point = 196 ° C), dimethylisosorbide (boiling point = 234 ° C), N-methyl- 2-pyrrolidone (boiling point = 202 ° C), 1,2-propylene glycol (boiling point = 188 ° C) and propylene carbonate (boiling point = 242 ° C), each of which may be used alone or in combination of two or more. Cosurfactant in the composition of the present invention comprises 0.1 to 20% by weight, preferably 1 to 10% by weight.

(3) surfactant

The surfactant used in the present invention acts to stably emulsify the oil-based active component and co-surfactant, which are lipophilic components, to the hydrogel to form a uniform emulsion, and a pharmaceutically acceptable anionic system, Cationic, nonionic or amphoteric surfactants can be used.

Specifically, for example, (i) the reaction product of natural or hydrogenated vegetable oil with ethylene glycol, ie polyoxyethylene glycolated natural or hydrogenated vegetable oil, for example polyoxyethylene glycolated natural or hydrogenated castor Free (brand name: Cremophor, manufacturer: BASF),

(ii) polyoxyethylene-sorbitan-fatty acid esters, ie esters of mono or trilauryl, palmityl, stearyl or oleyl (trade name: Tween, manufacturer: ICI),

(iii) polyoxyethylene fatty acid esters, ie polyoxyethylene stearic acid ester (trade name: Myrj, manufacturer: ICI),

(iv) polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer, manufactured by BASF),

(v) sodium dioctylsulfosuccinate or sodium lauryl sulfate,

(vi) phospholipids,

(vii) propylene glycol mono or di-fatty acid esters, for example propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate or trade name Miglyol Propylene Glycol Caprylic-Capric Acid Diester, marketed as 840 (Miglyol 840, manufactured by Huls),

(viii) Trans-esterification reaction products of natural vegetable oil triglycerides and polyalkylene polyols, namely polyoxyethylene glycerol trioleate (trade name: Labrafil M, manufactured by Gattefosse) ),

(ix) sorbitan fatty acid esters, for example, sorbitan monolauryl, sorbitan monopalmityl, sorbitan monostearyl, sorbitan sesquioleate and the like.

Representative of these are the transesterification products of natural vegetable oils and polyethylene glycols sold under the trade name Labrafil (manufactured by Gattefosse), sorbitan sesquioleate, sorbitan fatty acid ester, and polyoxyethylene And sorbitan-fatty acid esters. Surfactants in the compositions of the present invention include 2 to 30% by weight, preferably 5 to 25% by weight based on the total weight of the composition.

(4) gelling agent

As the gelling agent in the composition of the present invention, any additive that can form a gel upon contact with water may be used. Generally, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose Cellulose derivatives such as (Na-CMC) and the like; Examples include carboxyvinyl polymer (trade name: Carbopol, manufacturer: BF Goodrich Chemical), polyoxyethylene-polyoxypropylene copolymer (trade name: Pluronic, BASF), and the like. Can be mentioned. Among these, carboxyvinyl copolymer is particularly preferable. The gelling agent in the composition of the present invention comprises 0.1 to 10% by weight, preferably 0.1 to 5% by weight based on the total weight of the composition.

(5) purified water

As the purified water used in the composition of the present invention, water of a pharmaceutically acceptable grade may be used. Purified water in the composition of the present invention contains 1 to 90% by weight, preferably 30 to 80% by weight based on the total weight of the composition.

(6) alkalizing agent

In the composition of the present invention, an alkalizing agent for appropriately adjusting the pH may be added. Suitable pH values for the compositions of the present invention may vary depending on the type of ingredients added to the composition, in particular the active ingredients, but in general it is preferred to adjust the pH in the range of 3-9. Alkaliating agents that can be suitably used for such pH control purposes include inorganic alkaline substances such as Na ₂ HPO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH, or organic alkaline substances such as amines such as basic amino acids or triethanolamines. . The alkalizing agent in the composition of the present invention comprises 0.01 to 5% by weight, preferably 0.01 to 3% by weight, based on the total weight of the composition.

In addition, a preservative or an antioxidant can be added to the composition of the present invention within a range that does not impair the effects of the present invention. As the preservative, any component having a pharmaceutically acceptable antiseptic property may be used, for example benzyl alcohol, parabens, sodium benzoate, and the like, and as the antioxidant, any pharmaceutically acceptable agent may be used. For example, butylated hydroxy toluene (BHT), butylated hydroxy anisol (BHA), and erythorbic acid.

Preparation of the composition of the present invention having the configuration as described above is as follows. First, the emulsion preconcentrate is prepared by dissolving the active vitamin as an active ingredient in a co-surfactant, and adding and mixing the surfactant component thereto. On the other hand, the gelling agent is added to purified water and stirred to uniformly dissolve to prepare a hydrogel. Subsequently, the oil-based vitamin-containing pharmaceutical composition of the present invention may be prepared by mixing the emulsion preconcentrate with the prepared hydrogel and then adjusting the pH to a range of 3 to 9 using an alkalizing agent.

The oil-based vitamin-containing pharmaceutical composition of the present invention may be formulated into an external agent such as an ointment, cream, gel, etc. by a conventional method using a conventionally used excipient or carrier such as a polymer, an oily base, an aqueous base, and an emulsifier. Can be.

The oil-based vitamin-containing pharmaceutical composition of the present invention may be appropriately administered once to several times so as to administer a generally known daily dosage for each oil-based vitamin.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

The homogenous emulsion preconcentrate was prepared by mixing and dissolving the component (A) having the following composition.

(A) emulsion preconcentrate

Retinol Palmitate 3.53 mg (3533 I.U.)

123.7 mg (123.7 I.U.) of dl-α-tocopherol acetate

Sorbitan Sesquioleate 20mg

Labrafil M 2125 CS 60mg

Tween 80 60mg

Ethanol 30mg

On the other hand, Carbopol 934 and the preservatives described in (B) was uniformly dissolved in purified water to prepare a hydrogel.

(B) hydrogel

Carbopol 934 7mg

690 mg of purified water

Methyl Paraben 1.5mg

Propyl Paraben 0.4mg

BHT 0.7mg

Subsequently, an oil-containing vitamin-containing pharmaceutical composition was prepared by mixing the emulsion preconcentrate prepared above with a hydrogel and adding a proper amount of sodium hydroxide while homogeneously stirring to adjust the pH to about 6.0.

Example 2

An oil-based vitamin-containing pharmaceutical composition was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Retinol 1.27 mg (2500 I.U.)

dl-α-tocopherol acetate 123.7 mg (123.7 I.U.)

Sorbitan Sesquioleate 20mg

Labrafil M 1944 CS 60mg

Tween 80 60mg

Ethanol 30mg

(B) hydrogel

Carbopol 940 4mg

690 mg of purified water

Methyl Paraben 1.5mg

Propyl Paraben 0.4mg

BHT 0.7mg

(C) sodium hydroxide appropriate amount

Example 3

An oil-based vitamin-containing pharmaceutical composition was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

Retinol Palmitate 5mg (5000 I.U.)

dl-α-tocopherol acetate 100 mg (100 I.U.)

Labrafil M 2125 CS 60mg

Tween 80 60mg

Transcutol 30mg

(B) hydrogel

Carbopol 934 7mg

690 mg of purified water

Methyl Paraben 1.5mg

Propyl Paraben 0.4mg

BHA 0.7mg

(C) sodium hydroxide appropriate amount

Example 4

An oil-based vitamin-containing pharmaceutical composition was prepared in the same manner as in Example 1 using the following ingredients.

(A) emulsion preconcentrate

dl-α-tocopherol acetate 500 mg (500 I.U.)

Sorbitan Sesquioleate 20mg

Labrafil M 2125 CS 60mg

Tween 80 60mg

Ethanol 30mg

(B) hydrogel

Carbopol 934 7mg

690 mg of purified water

Methyl Paraben 1.5mg

Propyl Paraben 0.4mg

(C) sodium hydroxide appropriate amount

Test Example 1: In vitro Active Ingredient Stability Test

In order to measure the stability of the oil-based vitamin-containing pharmaceutical composition prepared in Example 1, the preparation was left at 40 ° C. and 75% relative humidity and the residual content of oil-based vitamin at each time point was measured. As a control drug, a commercially available LAZER (R) cream (manufactured by Pedinol), which contains the same amount of vitamin A as the active ingredient (3533 I.U./g), was used. The results are shown in Table 1 below.

Specimen Early After one month 2 months later Example 1 98.3% 98.1% 95.5% Control agent 98.2% 68.3% 49.6%

As shown in Table 1, it can be seen that the formulation of the present invention is a highly stable formulation in which the content of vitamin A in the formulation is almost preserved even after 2 months of standing.

Test Example 2: In Vivo Skin Penetration Test

In order to measure the skin permeability of the preparation of the present invention, the concentration of oily vitamin in the stratum corneum was measured at each time using a hairless mouse according to the following method. As a control agent, IOPE 2500, which is commercially available from Pacific Chemical Co., Ltd., was used.

The abdomen of 5 week-old male hairless mice is fixed upward, and each preparation is applied to the skin area of the hairless mice in an amount corresponding to 100 mg of vitamin A, and left for 0.5, 1.5, and 4 hours, respectively, and washed thoroughly with ethanol and water. It was. The stratum corneum was then divided into upper and lower portions and stripped 10 times with 3M Scotch 810, respectively, to identify and eliminate experimental errors resulting from poorly washed drug remaining in the skin. Extraction with 5 mL of ethanol gave 2 mL of this. 1 ml of 10% KOH and ethanol mixture were added thereto, reacted at 50 ° C. for 30 minutes, and then cooled to room temperature. Subsequently, 4 ml of ether and 2 ml of water were added and mixed, followed by washing twice to remove the water layer, and the ether layers were collected and evaporated using nitrogen gas. The residue was dissolved in methanol, and HPLC (high pressure liquid) was used. chromatography). At this time, a column: Inertsil ODS-2 (5 μm, 4.6 × 150 mm), a detector: UV 325 nm, a mobile phase: an aqueous solution containing 90% methanol, a flow rate: 1.2 ml / min, and an injection amount: 20 μl.

The results are shown in FIG. 1 is a graph showing the skin permeability of the formulation comprising the oil-based vitamin-containing pharmaceutical composition of the present invention in comparison with the conventional formulation, as shown here, the formulation of the present invention in both the upper and lower portions of the stratum corneum compared to the conventional formulation Because of the high concentration of vitamin A, it can be seen that the oil permeation amount of the skin is very high.

As such, the external preparations comprising the oil-based vitamin-containing pharmaceutical composition of the present invention exhibit very excellent skin permeability than the externally known external preparations, and when applied to the skin, the active ingredient can effectively reach the desired skin tissue as well. The dual effect is that the active ingredient in the emulsion is stably preserved.

Claims (9)

(A) Oily vitamin selected from the group consisting of vitamin A, vitamin D and vitamin E, ethanol, isopropyl alcohol, transcutol (diethylene glycol monoethyl ether), dimethylisosorbide, N-methyl as cosurfactant Organic solvents selected from the group consisting of 2-pyrrolidone, 1,2-propylene glycol and propylene carbonate, and polyoxyethylene glycolated natural or hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, polyoxy Ethylene fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsulfosuccinate, sodium lauryl sulfate, phospholipids, propylene glycol mono or di-fatty acid esters, polyoxyethylene glycerol trioleate and sorbitan Emulsion consisting of surfactant selected from the group consisting of fatty acid esters Non-concentrate; (B) a hydrogel consisting of a gelling agent and purified water selected from the group consisting of cellulose derivatives, carboxyvinyl polymers and polyoxyethylene-polyoxypropylene copolymers; And (C) An oily vitamin-containing pharmaceutical composition comprising an alkalizing agent selected from the group consisting of Na ₂ HPO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH, basic amino acids and triethanolamine as pH adjusting agents. The method of claim 1, 0.01 to 40% by weight oily vitamin, 0.1 to 20% by weight organic solvent, 2 to 30% by weight surfactant, 0.1 to 10% by weight gelling agent, 1 to 90% by weight purified water, based on the total weight of the composition, and A composition comprising 0.01 to 5% by weight of an alkalizing agent. delete delete delete delete delete (A) Oily vitamin selected from the group consisting of vitamin A, vitamin D and vitamin E, ethanol, isopropyl alcohol, transcutol (diethylene glycol monoethyl ether), dimethylisosorbide, N-methyl as cosurfactant Organic solvents selected from the group consisting of 2-pyrrolidone, 1,2-propylene glycol and propylene carbonate, and polyoxyethylene glycolated natural or hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, polyoxy Ethylene fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsulfosuccinate, sodium lauryl sulfate, phospholipids, propylene glycol mono or di-fatty acid esters, polyoxyethylene glycerol trioleate and sorbitan Emulsion by mixing a surfactant selected from the group consisting of fatty acid esters Preparing a preliminary concentrate; (B) a hydrogel is prepared by adding a gelling agent selected from the group consisting of a cellulose derivative, a carboxyvinyl polymer and a polyoxyethylene-polyoxypropylene copolymer to purified water; (C) the emulsion preconcentrate prepared in (A) and the hydrogel prepared in (B) are mixed, and a group consisting of Na ₂ HPO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH, basic amino acids and triethanolamine A method of producing an oil-based vitamin-containing pharmaceutical composition, comprising the step of adjusting the pH by adding an alkalizing agent selected from. Oily vitamin-containing external preparation comprising the composition of claim 1 and a pharmaceutically acceptable excipient or carrier.