JP6598619B2 - Skin external preparation specified by physical properties - Google Patents

Description

  The present invention relates to an external preparation for skin, and more particularly to an external preparation for skin specified by a thixotropy value.

  For external preparations for skin, usability is an important factor that affects the medicinal properties of external preparations. However, setting usability to the desired value is incompatible with other necessary factors that may impair the required stability. It had something to do. In particular, usability such as ease of conformity to the skin is an important factor for patients with atopic dermatitis.

  Steroid anti-inflammatory agents are also used for the treatment of atopic dermatitis and the like, but what becomes a problem when such a formulation is made is compatibility with the formulation components. For this reason, it has become a common practice to use an alcohol having an aromatic group such as benzyl alcohol as a component for improving compatibility and use it in an emulsified form. (For example, refer to Patent Document 1 and Patent Document 2.) In such a form, since the maintenance of the viscosity leads to the improvement of the stability, a thickener such as a carboxyvinyl polymer or an alkyl-modified carboxyvinyl polymer is used. It was often done.

  Such formulations were known to have thixotropic properties. The thixotropic property refers to a property that the viscosity changes with time. Specifically, it refers to the property that when the shear stress is continued, the viscosity gradually decreases and becomes liquid, and when it is stationary, the viscosity gradually increases and finally becomes solid. Therefore, a thixotropic skin external preparation is smooth and easy to spread on the skin in the process of application to the skin, but has a property that the film formed on the skin after application is difficult to drip.

  Thus, although the skin external preparation which has a thixotropy characteristic was known, it was not known that this characteristic would affect the familiarity to skin and the release property of active ingredients to the skin.

JP 2009-114081 A Special table 2007-500235 gazette

  The problem to be solved by the present invention is also to provide a skin external preparation excellent in usability. Moreover, when an oil-soluble active ingredient is included, it aims at providing the skin external preparation excellent in the release | release property to the skin.

The present invention for solving the above-mentioned problems contains a carboxyvinyl polymer which may be alkyl-modified and / or a salt thereof, and a nonionic surfactant, and has a thixotropic value greater than 4.0. It is an external preparation.
The external preparation for skin of the present invention is excellent in usability. Usability is preferably exemplified by familiarity with the skin.

The external preparation for skin of the present invention preferably contains an oil-soluble active ingredient.
The skin external preparation of the present invention characterized by having a thixotropy value greater than 4.0 is excellent in the release of oil-soluble active ingredients into the skin.

The skin external preparation of the present invention is preferably in an emulsifier form.
By using the emulsifier form, thixotropic characteristics can be maintained well, and the above effects can be stably maintained.

When the skin external preparation of the present invention is made into an emulsifier form, it is preferably emulsified only with a nonionic surfactant.
An emulsifier-type skin external preparation emulsified only with a nonionic surfactant has little irritation to the skin and can be used for sensitive skin.

The topical skin preparation of the present invention is an oil-in-water emulsion prepared at a temperature higher than the cloud point of the nonionic surfactant, cooled to a temperature below the cloud point of the nonionic surfactant, and then alkyl-modified. It is preferable that the product is prepared by adding a good carboxyvinyl polymer and then neutralizing the alkyl-modified carboxyvinyl polymer with an alkali agent.
The skin external preparation of this invention manufactured by such a manufacturing method is excellent in the said effect compared with the skin external preparation manufactured by the other manufacturing method with the same prescription.

The present invention is a method for evaluating an emulsifier-type skin external preparation containing a carboxyvinyl polymer and / or a salt thereof, which may be alkyl-modified, and a nonionic surfactant, and is a constant temperature condition of 32 ° C. An emulsifier type, characterized in that an apparent viscosity is measured with a cone plate viscometer, a thixotropy value is calculated, and when the thixotropy value is greater than 4.0, it is discriminated as a skin external preparation having excellent usability. It also relates to a method for evaluating an external preparation for skin.
According to the evaluation method of the present invention, it is possible to easily evaluate at least one of usability and release of active ingredients to the skin.

In addition, the present invention is an evaluation method for an emulsifier-type skin external preparation containing an oil-soluble active ingredient, an alkyl-modified carboxyvinyl polymer and / or a salt thereof, and a nonionic surfactant. Then, the apparent viscosity is measured with a cone plate viscometer under a constant temperature condition of 32 ° C., and the thixotropy value is calculated. If the thixotropy value is greater than 4.0, the usability and the release properties of the active ingredient to the skin The present invention also relates to a method for evaluating an emulsifier-type skin external preparation characterized by discriminating that it is a skin external preparation excellent in at least one.
According to the evaluation method of the present invention, it is possible to easily evaluate at least one of usability and release of active ingredients to the skin.

  The external preparation for skin of the present invention is excellent in usability. Usability is preferably ease of familiarity with the skin. Moreover, when an oil-soluble active ingredient is included, the skin external preparation of the present invention is excellent in the release of the active ingredient to the skin.

It is a figure which shows the chemical | medical agent release amount of an oil-soluble active ingredient after 12, 16, 20, and 24 hours.

  Thixotropy refers to the property that the viscosity changes over time. Specifically, it refers to the property that when the shear stress is continued, the viscosity gradually decreases and becomes liquid, and when it is stationary, the viscosity gradually increases and finally becomes solid. Therefore, a thixotropic skin external preparation is smooth and easy to spread on the skin in the process of applying to the skin (in a state where it is subjected to a shearing force), but the film (shearing force applied) formed on the skin after the application is completed. (The state of not receiving) has a property which is hard to sag. As an index of thixotropy, a thixotropy value represented by the following formula can be used. In general, the thixotropy value can be represented by the ratio of the viscosity by changing the rotation speed to 1:10.

  In calculating the thixotropy value, the apparent viscosity can be measured with a cone plate viscometer under a constant temperature condition of 32 ° C. Generally, since the surface temperature of the skin is around 32 ° C., it is preferable to measure the thixotropy value at the temperature.

In the skin external preparation of the present invention, the thixotropy value is greater than 4.0, preferably 4.5 or more, and more preferably 4.5 to 6.5.
Since the external preparation for skin of the present invention has a thixotropy value in the above-mentioned range, it has a feature that it is easy to spread and difficult to spread. Surprisingly, the skin external preparation of the present invention having a thixotropy value in the above range is excellent in usability such as ease of conformity to the skin.
Moreover, the skin external preparation of this invention which has the thixotropy value of the said range is excellent in the release | release property to the skin of an oil-soluble active ingredient.

The thixotropy value of the external preparation for skin can be arbitrarily adjusted by adjusting the content of the thickener. That is, the thixotropy value can be changed by increasing or decreasing the content of the thickener.
Further, when the skin external preparation is in the form of an emulsifier, the thixotropy value can be changed by reducing the particle size of the emulsified particles. The emulsified particle size can be arbitrarily adjusted by adjusting the stress during emulsification by stirring the oil phase and the aqueous phase.

Moreover, it is also preferable that the skin external preparation of this invention is equipped with the following physical properties.
Calculated from a relational expression of shear stress (S) with respect to shear rate (D) using a cone plate viscometer under a constant temperature condition of 32 ° C .; √S = a√D + b (a and b are coefficients) The residual viscosity (square of the slope a) is 200 mPa · s or less, more preferably 190 mPa · s or less, more preferably 100 mPa · s or more, 120 mPa · s or more, and Casson (Casson) The yield value (square of intercept b) is 40000 mPa or more, more preferably 42000 mPa or more, and additionally 60000 mPa or less, more preferably 50000 mPa or less.
Moreover, it is preferable that the skin external preparation of this invention shows favorable linearity in the 1-15 region of the square root of a shear rate. That is, in the Casson plot, it is preferable that the square value of the correlation coefficient in the region where the square root of the shear rate is 1 to 15 is 0.98 or more.

  In the case of having the physical properties as described above, the external preparation for skin of the present invention has a feature that, in use, there is very little change in feeling of use such as spreadability from the start of use to the end of use. Thereby, it is guessed that it will become a skin external preparation with a low physical stimulus given also to sensitive skin.

Further, the viscosity at 25 ° C. when measured with a cone plate viscometer of the external preparation for skin of the present invention is preferably 600 mPa · s or more, more preferably 8000 mPa · s or more, further preferably 1000 mPa · s or more, Particularly preferably, it is 1200 mPa · s or more, and in addition, it is preferably 4000 mPa · s or less, more preferably 3000 mPa · s or less, and further preferably 2500 mPa · s or less.
The external preparation for skin of the present invention having such a viscosity can form a coating film excellent in occlusive properties on the skin.

  The skin external preparation of the present invention is preferably in an emulsifier form. The external preparation for skin of the present invention in the form of an emulsifier can be prepared as follows. That is, a polymer having a thickening property such as a carboxyvinyl polymer bearing the structure is contained in an emulsified composition in which the emulsified structure is fixed, and neutralized to form a cross-linked structure, thereby constructing a firm cross-linked structure. Specifically, it can be prepared by the following procedure.

  Prepare an oil-in-water emulsion at a temperature higher than the cloud point of the nonionic surfactant, cool to a temperature below the cloud point of the nonionic surfactant, add the carboxyvinyl polymer, and then add the carboxyvinyl polymer. Neutralize with an alkaline agent.

  As a temperature higher than the cloud point of the nonionic surfactant, when a plurality of nonionic surfactants are present, it is preferable to employ the highest cloud point temperature among these cloud point temperatures. A temperature of 0C is applied. In addition, as the temperature below the cloud point of the nonionic surfactant, when a plurality of nonionic surfactants are present, it is preferable to employ the lowest cloud point temperature among these cloud point temperatures, and generally 25 It is preferable that it is -35 degreeC.

  The carboxyvinyl polymer is preferably added after being dissolved at a water addition amount close to the minimum level showing fluidity, and specifically, it is preferably added after being dissolved in 5 to 65% by mass of water. The amount of water is preferably 35 to 60% by mass with respect to the entire external preparation for skin. Further, the alkali agent added thereafter is preferably diluted with water to such an extent that the dispersion is not inhibited. Specifically, it is preferably diluted with 1 to 5% by mass of water. The remaining water is preferably added as an aqueous phase for preparing an oil-in-water emulsion. Hereinafter, the preparation procedure will be described in steps.

<Step 1>
In advance, the carboxyvinyl polymer is dissolved in a small amount of water to prepare a carboxyvinyl polymer solution. Similarly, an alkaline agent aqueous solution is prepared. These two liquids are adjusted to temperatures below the cloud point of the nonionic surfactant to be added.

<Process 2>
The remaining water and an aqueous component such as a polyhydric alcohol or a water-soluble additive are combined and adjusted to a temperature higher than the cloud point which is the emulsification temperature. At the same time, the oil component containing the nonionic surfactant is combined and adjusted to a temperature higher than the cloud point which is the emulsification temperature.

<Step 3>
To the aqueous phase adjusted to a temperature higher than the cloud point of the nonionic surfactant, the oil phase adjusted to a temperature higher than the cloud point is gradually added with stirring to prepare an oil-in-water emulsion, which is stirred and cooled. And cool to below the cloud point. When the temperature becomes lower than the cloud point, the carboxyvinyl polymer solution is gradually added with stirring. After the addition, the skin external preparation can be obtained by stirring until uniform, and then gradually adding an aqueous alkaline agent solution.
Here, the addition of the alkaline agent aqueous solution can be performed so that the pH of the external preparation for skin of the present invention is preferably 4-8. Moreover, the lower limit of the pH of the composition of the present invention is preferably 4.3, and more preferably 4.5. The upper limit of the pH of the composition of the present invention is preferably 6.5, more preferably 6.

  The external preparation for skin thus obtained is a composition having a small temperature gradient of viscosity because the thickened crosslinked structure of the carboxyvinyl polymer is not easily affected by the decrease in the surface active action due to the cloud point of the nonionic surfactant. . In addition, a small amount of thickener makes the system stable even at high temperatures. Moreover, when apply | coating and forming a membrane | film | coat, it becomes a membrane | film | coat with high obstruction | occlusion property and excellent in the effect | action which suppresses TEWL.

  The external preparation for skin of the present invention contains the following components as essential or preferred components.

  The external preparation for skin contains a carboxyvinyl polymer which may be alkyl-modified. Examples of the carboxyvinyl polymer which may be alkyl-modified include “Pemlen TR-1”, “Pemlen TR-2” or “Carbopol 1382” in addition to the usual carboxyvinyl polymer (all are Lubrizol Advanced Materials). An alkyl-modified carboxyvinyl polymer into which a long-chain alkyl group has been introduced, such as those manufactured by Komatsu Ltd., can also be used. The long chain alkyl group is preferably one having 10 to 30 carbon atoms. The carboxyvinyl polymer is neutralized and functions as a thickener, stabilizes the emulsifying system, and has an effect of strengthening a film formed after the skin external preparation is applied. In order to achieve such an effect, the carboxyvinyl polymer is preferably contained in an amount of 0.3 to 1.2% by mass, more preferably 0.5 to 1.0% by mass. The carboxyvinyl polymer is preferably a carboxyvinyl polymer having a viscosity of 1500 to 50000 mPa · s at 20 ° C. and a 0.2% aqueous solution in a neutral region.

  In order to thicken the carboxyvinyl polymer, the external preparation for skin preferably contains an alkaline agent that should neutralize the carboxyvinyl polymer. As the alkali agent, an organic amine is preferable, and for example, triethanolamine, triethylamine, monoethanolamine, diisopropanolamine and the like can be suitably exemplified. Of these, diisopropanolamine is particularly preferable. The organic amine is preferably 0.01 to 1.5% by mass, more preferably 0.01 to 1.0% by mass, more preferably 0.01 to 0.8% by mass in the skin external preparation. Particularly preferably 0.05 to 0.6% by mass is contained. By setting the content of the organic amine in the above range, the pH of the external preparation for skin can be adjusted to 4.5-6. Moreover, in the manufacturing method mentioned above, in order to adjust the range of pH to a preferable range, the quantity and kind of neutralizing agents, such as organic amine, can be adjusted.

The external preparation for skin of the present invention preferably contains a nonionic surfactant.
Nonionic surfactants include monoglycerides such as stearic acid monoglyceride and oleic acid monoglyceride, sorbitan fatty acid esters such as sorbitan stearate and sorbitan oleate, ester nonions such as POE stearate and POE oleate Surfactants, POE hardened castor oil, POE sorbitan fatty acid esters such as POE sorbitan oleate, POE sorbitan stearate, ether-based nonionic interfaces such as POE oleyl ether and POE cetyl ether Activators and the like can be preferably exemplified, and as the hydrophilic nonionic surfactant, POE hydrogenated castor oil and / or ether-based nonionic surfactants can be preferably exemplified, and these Form of both content are particularly preferred. Moreover, as a lipophilic surfactant, fatty acid monoglyceride can be illustrated preferably. In the present invention, it is preferable that substantially only a nonionic surfactant is used as the surfactant. This is because the cloud point can be clearly estimated. The total content of the surfactant is preferably 3 to 7% by mass, and more preferably 3 to 5% by mass.

  The external preparation for skin of the present invention can contain any component that is usually used for external preparations in addition to the above components. Such optional components include, for example, hydrocarbons such as squalane, petrolatum, ester oils such as jojoba oil, cetyl isooctanoate, isopropyl myristate, olive oil, triglycerides such as medium chain fatty acid triglycerides, 1,3 -Polyhydric alcohols such as butanediol, propylene glycol, glycerin, polyethylene glycol, alkyl-modified thickeners such as xanthan gum, fatty acids such as stearic acid, myristic acid, myristic acid, lauric acid or the like And higher alcohols such as cetostearyl alcohol, behenyl alcohol, isostearyl alcohol and oleyl alcohol. Among these, since fatty acids may impair the crosslinked structure of the carboxyvinyl polymer, a form containing substantially no fatty acid is preferable. The dosage form is preferably an emulsified form in which the outer phase is an aqueous phase, and such dosage forms are collectively referred to as an oil-in-water emulsifier form. The dispersed droplets may be oil droplets or emulsions.

  The skin external preparation of the present invention can contain an active ingredient. The active ingredient is preferably used in atopic dermatitis, for example, steroids such as hydrocortisone, prednisolone, dexamethasone, beclomethasone, betamethasone, non-steroidal anti-inflammatory agents such as indomethacin, suprofen, and anti-inflammatory agents such as nalfrafin. Suitable examples include itching agents, moisturizers such as heparin-like substances and urea, vitamins such as vitamins A, vitamins B and vitamins C. These contents vary depending on the respective effective amounts, but are generally preferably 0.0001 to 10% by mass.

  The above-listed components are oil-soluble and are preferably in a form containing such active ingredients. The external preparation for skin of the present invention is excellent in the release of oil-soluble active ingredients into the skin.

  Here, addition of the alkaline agent aqueous solution can be performed so that the pH of the composition of the present invention is preferably 4 to 8. Moreover, the lower limit of the pH of the composition of the present invention is preferably 4.3, and more preferably 4.5. The upper limit of the pH of the composition of the present invention is preferably 6.5, more preferably 6.

The evaluation method of the present invention discriminates and evaluates whether or not the prepared emulsifier-type skin external preparation has the usability of the emulsifier-type skin external preparation of the present invention. Specifically, the apparent viscosity is measured with a cone plate viscometer under a constant temperature condition of 32 ° C., and the thixotropy value is calculated. When the thixotropy value is greater than 4.0, the useful and oil-soluble active ingredients It is characterized by discriminating that it is an emulsifier-type external preparation for skin that is excellent in at least one of release properties to the skin.
Usability includes easy compatibility with skin.

  Further, when evaluating an external preparation for skin containing an oil-soluble active ingredient by the evaluation method of the present invention, if the thixotropy value calculated by the above-described method is greater than 4.0, the usability and the release of the active ingredient to the skin It is judged that it is a skin external preparation excellent in at least one of the above.

  Hereinafter, the present invention will be described in more detail with reference to examples.

<Production example>
According to the formulation shown in Table 1, the skin external preparations of Examples 1 to 4 were prepared by the manufacturing method described above. That is, the components of (A), (B), (C) and (D) are weighed, and among these, (C) and (D) are stirred and mixed at room temperature, and (A) and (B) are The mixture was stirred and dissolved at 75 ° C., and kept at each dissolution temperature. Under stirring (b), (i) is gradually added to emulsify, and stirred and cooled. When cooled to 30 ° C., stirring (c) is gradually added and mixed uniformly. Further, (d) Was gradually added to neutralize to obtain a skin external preparation of the present invention. Table 1 also shows the pH values of the external preparations for Examples 1 to 4. In addition, each prescription component in a table | surface is displayed by weight% with respect to the composition whole quantity.

  The prescription components were not different from those for the skin external preparation of the examples, and only the production method was changed to produce the skin external preparations for Comparative Examples 1 to 4. That is, (b), (b), and (c) shown in Table 2 are weighed, and among these, (b) and (b) are stirred and mixed at 75 ° C., and (c) is stirred and mixed at room temperature. And kept at each dissolution temperature. Under stirring (b), (i) is gradually added to emulsify. When uniform, the mixture is cooled by stirring and cooled to 30 ° C. An external preparation for skin was obtained. The pH of Comparative Examples 1 to 4 is shown in Table 2. In addition, each prescription component in a table | surface is displayed by weight% with respect to the composition whole quantity.

<Test Example 1> Measurement of thixotropy value The external preparation for skin of Examples and Comparative Examples is a cone plate viscometer (apparatus model name: RE-80R, manufacturing company name: Toki Sangyo, condition: rotor: 3 ° × R14, Using the measurement temperature: 32 ° C., rotation speed: 10 and 100 rpm, measurement time: 3 minutes, the apparent viscosity was determined, and the thixotropy value (TI value) from the relational expression; (10 rpm apparent viscosity) / (100 rpm apparent viscosity) ) Was calculated. The results are shown in Table 3.

<Test Example 2> Usability Evaluation Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 3 and Comparative Example 3, and Example 4 and Comparative Example 4 were applied temporarily. The panelists who are easy to feel the irritation were asked to compare and evaluate their usability. As a result, it was evaluated that the skin external preparations of the examples were more familiar with the skin than the comparative examples in any combination.
This result indicates that a skin external preparation having a thixotropy value of greater than 4.0 is excellent in familiarity with the skin.

<Test Example 3> Release test An experiment was conducted using a Franz diffusion cell (manufacturer name: Hanson Research) under the following conditions using the external preparation for skin of Example 3 and Comparative Example 3 as a donor, and 12 hours from the start of the experiment. The amount of clobetasone butyrate eluted in the receptor fluid at 16 hours, 20 hours, and 24 hours was measured by HPLC. The experiment was performed three times for Example 3 and twice for Comparative Example 3, and the amount of clobetasone butyrate ester per unit area released from the external pharmaceutical composition to the receptor solution was calculated, and the average value was calculated. The results are shown in FIG.

・ Dose of external preparation for skin: about 100 mg
・ Membrane: Polyvinylidene fluoride membrane (manufacturer name: Nihon Millipore, thickness: 125 μm, pore diameter: 0.45 μm)
・ Temperature: 32 ℃
・ Receptor solution: 1% polysorbate 80 aqueous solution ・ Stirrer rotation speed: 500 rpm

As shown in FIG. 1, the external preparation for skin of Example 3 having a thixotropy value of 6.0 was compared with the external preparation for skin of Comparative Example 3 having a thixotropy value of 3.4. The rate and amount of elution are large.
As a result, by improving the thixotropy value of an external preparation for skin containing an oil-soluble active ingredient, the release of the active ingredient from the oil phase in an oil-in-water emulsifier form can be improved. Is shown.

  Moreover, as shown in FIG. 1, the skin external preparation of Example 3 hardly shows a decrease in the release rate of clobetasone butyrate even when 24 hours have passed since the start of the experiment. This result suggests that when the external preparation for skin of the present invention is applied to the skin, the release of the oil-soluble active ingredient to the skin continues for a long time. Therefore, it is considered that the external preparation for skin of the present invention is excellent in therapeutic effect when it is in a form containing an oil-soluble active ingredient.

  The results of Test Examples 1 to 3 indicate that a skin external preparation having a thixotropy value greater than 4.0 is excellent in usability and has excellent release properties when it contains an oil-soluble active ingredient. Is shown.

The present invention can be applied to the preparation of pharmaceutical products.

Claims (3)

Preparation and alkyl-modified which may be a carboxyvinyl polymer and / or a salt thereof, and a nonionic surfactant, the active ingredient of the oil-soluble, contain thixotropic value is rather greater than 4.0, by the following steps An emulsifier type skin external preparation characterized by the above-mentioned.
<Process>
After preparing an oil-in-water emulsion containing a nonionic surfactant and an oil-soluble active ingredient at a temperature higher than the cloud point of the nonionic surfactant, and cooling to a temperature below the cloud point of the nonionic surfactant, The carboxyvinyl polymer which may be alkyl-modified and / or its salt is added, and then the carboxyvinyl polymer which may be alkyl-modified and / or its salt is neutralized with an alkali agent. Characterized in that it is emulsified only nonionic surfactants, skin external agent of claim 1. An emulsifier-type skin external preparation comprising an oil-soluble active ingredient, an alkyl-modified carboxyvinyl polymer and / or salt thereof, and a nonionic surfactant, comprising a constant temperature of 32 ° C. conditions, measures the apparent viscosity at a cone plate type viscometer, and calculating the thixotropy value, if the thixotropy value is larger than 4.0, the skin external preparation having excellent release to the skin of effective components of the oil-soluble An evaluation method of an external preparation for skin in the form of an emulsifier, characterized by discriminating the presence.