JP4060347B2 - Oil-in-water emulsion lotion containing 22-oxa-1α, 25-dihydroxyvitamin D3 - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a lotion which has the high transdermal absorbability of maxacalcitol, can contain maxacalcitol in a chemically stable state and suffers from little dripping when applied to the head. <P>SOLUTION: A basic oil-in-water type emulsion lotion contains 22-oxa-1&alpha;, 25-dihydroxyvitamin D<SB>3</SB>, a medium-chain fatty acid triglyceride, a nonionic surfactant and a water-soluble thickener. <P>COPYRIGHT: (C)2007,JPO&amp;INPIT

Description

The present invention relates to an oil-in-water emulsion lotion containing 22-oxa-1α, 25-dihydroxyvitamin D ₃ (hereinafter referred to as maxacalcitol or OCT) useful as an external preparation for skin. More specifically, the present invention is superior in transdermal absorbability of maxacalcitol, and even if its liquidity is made basic in order to improve the chemical stability of maxacalcitol, it still has little skin irritation. The present invention relates to an oil-in-water emulsion lotion.

  Maxacalcitol is widely used as a therapeutic agent for psoriasis because it has a skin epidermal cell proliferation inhibitory action, a differentiation-inducing action, and the like, and is highly evaluated in the medical field in Japan.

  Maxacalcitol is chemically unstable, and it is known to decompose rapidly in aqueous solution, so an ointment that is an oily base ensures the chemical stability of maxacalcitol. The dosage form has been considered to be excellent in transdermal absorbability and easy to apply to the trunk.

  However, psoriasis is likely to occur not only in the trunk but also in hair such as the head, so if maxacalcitol is used as an oil-based ointment, the ointment tends to adhere to hair in the hair Therefore, there is a drawback that it is difficult to apply a sufficient amount of maxacalcitol to the affected skin. For this reason, it is required to make maxacalcitol into a preparation that easily reaches the skin of the hair. An example of such a preparation is a lotion. However, lotion preparations are generally less transdermally absorbable than ointments, and as mentioned above, maxacalcitol is chemically unstable in water, so a lotion preparation that needs to contain purified water is prepared. There are many problems to overcome. In general, a solution lotion is easier to apply than an ointment, but when applied to the head, it tends to sag and enter the eye.

  WO99 / 29325 (Patent Document 1) proposes a solution lotion containing maxacalcitol and an ether type surfactant. This lotion preparation has been adjusted so that maxacalcitol can exist chemically and stably, but there is an expectation for further improvement in transdermal absorbability.

WO99 / 44617 (Patent Document 2) is a lotion preparation that is easy to sag and easily enter the eyes, and tacalcitol (1α, 24-dihydroxyvitamin D ₃ ), the same active vitamin D ₃ derivative as maxacalcitol, is used. As an active ingredient, a solid oil composed of white petrolatum and 0.2-1.0% higher alcohol, a liquid oil composed of squalane; an aqueous phase component composed of ionic polysaccharides; and a nonion having an HLB value of 10 or more Oil-in-water emulsion lotions composed of water-soluble surfactants. In this oil-in-water emulsion lotion, since tacalcitol was stable for a long time, it was expected to be chemically stable in the same way even if maxacalcitol was used as an active ingredient instead of tacalcitol. . However, the expected chemical stability was not obtained in experiments using maxacalcitol. Maxacalcitol was still poorly transdermally absorbed.

  Regarding the chemical stability of maxacalcitol in aqueous injections, WO02 / 017932 (Patent Document 3) states that when the liquidity is made basic at pH 8.0, it becomes chemically more stable than neutrality. It is described. However, with lotions that are often exposed to the open air, this level of stabilization by making the liquid basic is insufficient, and when basic, the preparation is very irritating to the skin. There is also a problem that it becomes characteristic (Patent Document 1).

Therefore, it has excellent percutaneous absorption of maxacalcitol, it is chemically stable enough, does not cause skin irritation problems, and has little dripping problem even when applied to the head. Development of agents is desired.
WO99 / 29325 WO99 / 44617 WO02 / 017932

  The present invention has excellent transdermal absorbability of maxacalcitol, which can exist chemically and sufficiently stably, does not cause skin irritation problems, and can be applied to the head. An object of the present invention is to provide a lotion preparation with less problem of dripping.

  As a result of diligent research on the composition of an oil-in-water emulsion lotion containing maxacalcitol, the present inventors have formulated a medium-chain fatty acid triglyceride and made the liquid basic, thereby dripping the liquid. While maintaining the advantages of an oil-in-water emulsion lotion with a low amount of water, it has excellent maxacalcitol transdermal absorption, so that maxacalcitol can exist chemically and stably and is basic. Despite the fact, we succeeded in obtaining a lotion preparation with little skin irritation.

  That is, the present invention provides a basic oil-in-water emulsion lotion comprising maxacalcitol, medium-chain fatty acid triglyceride, nonionic surfactant, and water-soluble thickener.

In one embodiment of the present invention, the lotion further contains a water-soluble polyhydric alcohol.
In the present invention, as a result of improving the chemical stability of maxacalcitol by making the liquidity of the lotion agent basic with an organic amine, no preservatives such as parabens that tend to cause skin irritation are added. As a result, safety has been improved.

  Since maxacalcitol contained as an active ingredient is a known compound, it can be synthesized, for example, by the method described in JP-A-61-267550. The amount of maxacalcitol contained in the lotion of the present invention may be any amount as long as it is therapeutically effective for the skin disease to be applied. Usually, it is 1 to 200 μg / g, preferably 2 to 100 μg / g, more preferably 5 to 50 μg / g.

The oil phase portion of the lotion of the present invention is composed of maxacalcitol, medium chain fatty acid triglyceride, nonionic surfactant, and oil base.
The medium chain fatty acid triglyceride is contained in the oil phase part of the lotion of the present invention as a solubilizer of maxacalcitol, and greatly contributes to the improvement of transdermal absorbability of maxacalcitol of the present invention. We believe this is because medium chain fatty acid triglycerides cause maxacalcitol to be present in solution in the lotion. However, since the percutaneous absorbability of maxacalcitol tends to decrease when the amount of medium chain fatty acid triglyceride is increased, it is desirable to relatively reduce the amount in order to enhance the percutaneous absorbability. On the other hand, the medium-chain fatty acid triglyceride has a role of forming the oil phase portion of the lotion of the present invention. Therefore, if the amount is too small, the lotion of the present invention cannot be made into an emulsion. For these reasons, the blending amount is 0.5 to 25% by weight, preferably 1 to 20% by weight, more preferably 1 to 10% by weight, based on the weight of the whole lotion of the present invention. The medium-chain fatty acid triglyceride referred to in the present invention mainly comprises a triglyceride of a saturated fatty acid represented by the formula CH ₃ (CH ₃ ) _n COOH (n = 4 to 12). Specific examples of medium-chain fatty acid triglycerides include ODO (registered trademark) (Nisshin Eulio), Coconut (registered trademark) (Kao), Sunfat (registered trademark) MCT-6 (Taiyo Kagaku), Derios (registered trademark), Myrritol. (Registered Trademark) 318 (Cognis Japan), Panaceto (Registered Trademark) (Nippon Yushi), Miglyol (Registered Trademark) 810, Miglyol (Registered Trademark) 812 (Mitsuba Trading), and Pharmaceutical Supplement Panaceto (Registered Trademark) (Oilization Industry) ).

  When maxacalcitol is difficult to dissolve in these solubilizers, it may be dissolved in a solubilizer after being dissolved in a solubilizer. As the solubilizer, for example, a lower alcohol can be used, preferably absolute ethanol or isopropanol, more preferably absolute ethanol. Since the solubilizing agent is a factor that adversely affects the emulsion stability, the blending amount is preferably a small amount, that is, a minimum amount capable of dissolving maxacalcitol. The blending amount is 0.001 to 0.1% by weight, preferably 0.01 to 0.1% by weight, based on the weight of the whole lotion of the present invention.

  The nonionic surfactant is preferably one having an HLB value of 7 to 15, preferably 8 to 11. The structure is not limited as long as it is nonionic, but an ester type is preferable. For example, as the ester type nonionic surfactant having an HLB value of 8 to 11, monostearate polyoxyethylene glycerin such as polystearate polyoxyethylene (5) glycerin, monostearate polyoxyethylene (15) glycerin, etc. , Self-emulsifying glyceryl monostearate, polyoxyethylene (10) glycol monostearate, polyoxyethylene (20) hydrogenated castor oil, hexaglyceryl monomyristate, sorbitan monolaurate, polyoxyethylene tristearate (20) sorbitan And polyoxyethylene (30) sorbite tetraoleate, and polyoxyethylene (5) glyceryl monostearate is preferred. These can be used alone or in combination of two or more.

  The blending amount of the nonionic surfactant affects the transdermal absorbability of maxacalcitol, and when the blending amount is decreased, the transdermal absorbability tends to increase. However, emulsification becomes impossible if it is lowered too much. Therefore, the blending amount is 0.001 to 5% by weight, preferably 0.01 to 2.5% by weight, more preferably 0.05 to 1% by weight, based on the weight of the whole lotion of the present invention. .

  The oily base is not particularly limited as long as it is a base generally used as a skin external preparation or skin cosmetic. For example, petrolatum, paraffin, white beeswax, gelled hydrocarbon, carnauba wax, ceresin wax, stearic acid, mono Examples include batyl stearate, behenic acid, and behenyl alcohol, with batyl monostearate being preferred. The blending amount is 0.001 to 5% by weight, preferably 0.01 to 2.5% by weight, more preferably 0.05 to 0.5% by weight, based on the weight of the whole lotion of the present invention. .

The aqueous phase portion of the lotion of the present invention is composed of water, a water-soluble thickener, and a pH adjuster.
In addition to being emulsion, the lotion of the present invention is adjusted to an appropriate viscosity that does not cause dripping problems by using a water-soluble thickener. Examples of the water-soluble thickener include water-soluble polymers, such as carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. A carboxyvinyl polymer is preferred from the feeling of use during coating. Specific examples of the carboxyvinyl polymer include AQUPEC (registered trademark) (Sumitomo Seika), Carbopol (registered trademark) 980, Carbopol (registered trademark) 981 (BF Goodrich, CBC, Nikko Chemicals), Junron (registered trademark). (Nippon Pure Chemicals), and Hibis Wako (registered trademark) (Wako Pure Chemical Industries). In order to prevent dripping, it is effective to increase the amount of the water-soluble thickener, but this causes problems such as a decrease in feeling of use due to stickiness and a decrease in transdermal absorbability of maxacalcitol. Care should be taken with the amount. The blending amount of the water-soluble thickener is 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight, more preferably 0.1 to 0. The amount is 3% by weight.

  Examples of the pH adjuster include organic amines, preferably C1-C6 mono, di or trialkanol amines, such as monoethanolamine, diisopropanolamine, triethanolamine, and diisopropanolamine. preferable.

  The lotion preparation of the present invention stabilizes maxacalcitol, which is an active ingredient, by making its liquidity basic. The basic degree is pH = 8 to 11, preferably pH = 8.5 to 11, more preferably pH = 9 to 10.5. As described above, WO02 / 017932 (Patent Document 3) describes that maxacalcitol becomes chemically stable when the liquidity of an aqueous solution is made basic. However, according to the disclosure, maxacalcitol is basic and most stable at around pH 8.0, and the lotion of the present invention has sufficient chemical stability even when the pH is greatly exceeded. What was obtained was unexpected from the above prior art documents. In order to adjust to such a pH value, the above pH adjuster can be used. In addition, when pH becomes larger than 11, it is thought that skin irritation usually arises.

  In the present invention, the term “stable” maxacalcitol means that the residual ratio of maxacalcitol in the lotion after storage at 50 ° C. for 12 weeks is 90% or more, preferably 95% or more, more preferably Means 96% or more. Alternatively, it means that the residual ratio of maxacalcitol after storage for 24 months at 25 ° C. and 60% RH is 95% or more, preferably 99% or more.

  The aqueous phase portion of the lotion of the present invention can further contain a water-soluble polyhydric alcohol. The water-soluble polyhydric alcohol has two or more hydroxyl groups in the molecule and is not particularly limited as long as it is generally used as a skin external preparation or skin cosmetic. For example, glycerin, propylene glycol, diethylene glycol, diethylene Examples include propylene glycol, 1,3-butylene glycol, polyglycerin, polyethylene glycol 300 to 1500, and sorbitol, xylitol, and mannitol. Propylene glycol or 1,3-butylene glycol is preferred, and 1,3-butylene glycol is preferred. More preferred. The percutaneous absorbability of maxacalcitol is also affected by the amount of water-soluble polyhydric alcohol. Increasing the amount improves the percutaneous absorbability. descend. Therefore, these can be used alone or in combination of two or more, but the blending amount is 5 to 50% by weight, preferably 10 to 30% by weight, based on the total weight of the lotion of the present invention Preferably it is 15-25 weight%.

  In a preferred embodiment, the lotion of the present invention comprises 2-100 μg / g maxacalcitol, 1-20% by weight medium chain fatty acid triglyceride, 0.01-2.5% by weight, based on the total weight of the lotion. An ester-type nonionic surfactant having an HLB value of 8-11, 0.1-0.5% by weight carboxyvinyl polymer, 10-30% by weight propylene glycol or 1,3-butylene glycol, and pH Comprises diisopropanolamine in an amount such that = 8.5-11.

  In a more preferred embodiment, the lotion of the present invention comprises 5-50 μg / g maxacalcitol, 1-10 wt% medium chain fatty acid triglyceride, 0.05-1 wt% mono, based on the weight of the lotion. Polyoxyethylene (5) glyceryl stearate, 0.1-0.3% by weight carboxyvinyl polymer, 15-25% by weight 1,3-butylene glycol, and an amount such that pH = 9-10.5 Of diisopropanolamine.

  As described above, the oil-in-water emulsion lotion of the present invention has a preservative effect without adding a preservative, but a preservative such as parabens may be added if necessary. Furthermore, surfactant assistants such as L-arginine, L-histidine, sodium cetyl sulfate, sodium N-acyl-L-glutamate, stabilizers such as DL-α-tocopherol, sodium citrate, dibutylhydroxytoluene Can be blended. When a surfactant auxiliary is blended, the amount is preferably a trace amount. The trace amount is 0.0001 to 0.1% by weight, preferably 0.001 to 0.1% by weight, based on the weight of the whole lotion of the present invention. When blending the stabilizer, the amount is 0.01-0.5 wt%, preferably 0.05-0.2 wt%, more preferably based on the total weight of the lotion of the present invention. 0.1 to 0.2% by weight. Moreover, a pigment | dye, a fragrance | flavor, a pigment, a ultraviolet absorber, etc. can be mix | blended suitably as needed.

The oil-in-water emulsion lotion of the present invention is a lotion defined in the 14th revised Japanese Pharmacopoeia General Rules for Preparations.
The method for producing the oil-in-water emulsion lotion of the present invention is not particularly limited. For example, a predetermined amount of maxacalcitol is dissolved in a predetermined amount of a solubilizing agent such as ethanol. Separately, a predetermined amount of a nonionic surfactant is dissolved in a medium chain triglyceride which is an oily base component. Next, a predetermined amount of polyhydric alcohol, water-soluble thickener, pH adjuster, etc. are added to and mixed with purified water in the mixed solution obtained by mixing these solutions, and finally the whole amount is prepared with the same oily base component as above. Thus, an oil-in-water emulsion lotion can be obtained.

  The oil-in-water emulsion lotion of the present invention can be used for the treatment of skin diseases such as psoriasis vulgaris, ichthyosis group, and palmokeratosis. Although the dosage varies depending on the degree of the disease, for example, an oil-in-water emulsion lotion containing 1 to 200 μg / g, preferably 2 to 100 μg / g, more preferably 5 to 50 μg / g of maxacalcitol. Is preferably administered once a week to 10 times a day, preferably once every two days to four times a day.

  INDUSTRIAL APPLICABILITY According to the present invention, a lotion preparation having a high chemical stability of maxacalcitol useful as an external preparation for skin, excellent percutaneous absorption, and few problems of dripping is provided.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

[Examples 1 to 5]
Monostearic acid having an HLB of 9.5 (5) Polyoxyethylene glycerin, batyl monostearate, dibutylhydroxytoluene, and medium chain fatty acid triglyceride (Miglyol 810) were weighed and heated in the proportions listed in Table 1 below. After melting, an oil phase was prepared by adding maxacalcitol in absolute ethanol to the melt. On the other hand, 1,3-butylene glycol, L-arginine and diisopropanolamine in the proportions shown in Table 1 were dissolved in an appropriate amount of purified water to prepare an aqueous phase 1. Separately, a carboxyvinyl polymer (Carbopol 981) was dissolved in an appropriate amount of purified water to produce an aqueous phase 2. An oil phase heated to 80 ° C. and an aqueous phase 2 heated to 60 ° C. are sequentially added to the aqueous phase 1 heated to 60 ° C., and further stirred, and an oil-in-water emulsion having the pH shown in Table 1 is added. A lotion was obtained. These pH values are obtained by directly measuring the liquidity of the lotion using a pH meter manufactured by Horiba. The same measurement was performed in the following.

[Examples 6 to 11]
An oil-in-water emulsion lotion in the same manner as in Example 5 except that the polyoxyethylene (5) glyceryl monostearate of Example 5 was changed to the ester type nonionic surfactant shown in Table 2 below. Was prepared.

[Comparative Example 1]
According to the method disclosed in WO99 / 44617, maxacalcitol-containing oil-in-water emulsion lotion was obtained with the formulation shown in Table 4 below. Maxacalcitol did not dissolve in any of these bases, so it was used after dissolving in absolute ethanol.

[Example 12 and Comparative Example 2]
In the formulation of Example 5 in Table 1, the amount of diisopropanolamine was changed as shown in Table 4 below, thereby changing the pH of the preparation from near neutral to basic.

[Examples 13 to 18]
A lotion preparation was prepared in the same manner as in Example 4 except that the amount of diisopropanolamine in the lotion preparation of Example 4 was changed as described in Table 8 below.

[Comparative Examples 3 to 6]
The following commercially available lotion formulations:
Bonalpha (registered trademark) lotion 2 μg / g; lotion preparation containing 0.0002% tacalcitol (manufactured by Teijin Pharma Limited) (Comparative Example 3);
Linderon (registered trademark) -VG lotion; 1.2 mg betamethasone valerate / 1 mg gentamicin sulfate (manufactured by Shionogi & Co., Ltd.) (Comparative Example 4);
Lidomex (registered trademark) Kowa Lotion; lotion preparation containing 0.3% prednisolone acetate valerate (manufactured by Kowa Co., Ltd.) (Comparative Example 5); and delmovate (registered trademark) scalp; (SmithKline) (Comparative Example 6).

[Test Example 1] Skin permeability test A skin permeability test was conducted on the preparations of Examples 1 to 5 and Comparative Example 1. A plastic frame (4 cm ² ) was fixed to a hairless mouse shaved from the back of the neck under anesthesia. After transdermally administering 20 mg of sample into the frame, the frame was fixed with an adhesive bandage. After 1 hour and after 4 hours, the skin surface of the administration site was wiped with cut cotton soaked with 70% ethanol under anesthesia. After the mice were exsanguinated, the skin of the administration site was collected. After the collected skin was homogenized in methanol, the liquid phase was collected. After drying the liquid phase, ether and water were added. The ether layer was collected and dried, and then redissolved in ethanol to obtain a sample solution. This was measured by reversed-phase high performance liquid chromatography (column; Inertsil ODS-3 (manufactured by GL Science), detection wavelength: 265 nm, mobile phase; 50 mM ammonium acetate aqueous solution: acetonitrile = 60: 40), and in the skin relative to the dose. The percentage of maxacalcitol amount was calculated.

  The results are shown in Tables 1 and 4. The item represented by “skin OCT concentration” is the skin permeability test result. The greater this value, the higher the transdermal absorbability. Examples 1 to 5 containing medium chain fatty acid triglycerides (Miglyol 810) show high maxacalcitol transdermal absorbability.

[Test Example 2] Maxacalcitol stability test 1
The formulations of Examples 3-12 and Comparative Examples 1-2 were tested for maxacalcitol stability under accelerated conditions.

  The maxacalcitol content was measured when the sample was stored in a constant temperature and humidity chamber set at 40 ° C. and 75% RH and in a constant temperature oven at 50 ° C. for a certain period. The maxacalcitol content was measured by adding a silver nitrate solution, an internal standard solution and ethanol to about 1 g of each sample and stirring. Furthermore, after adding a sodium chloride solution, a part of the supernatant obtained by centrifugation was used as a sample solution. This is included in each sample by reversed-phase high-performance liquid chromatography (column; YMC-Pack A-303 (manufactured by YMC), detection wavelength: 265 nm, mobile phase; water: acetonitrile: tetrahydrofuran mixture = 7: 4: 1) The amount of maxacalcitol that was measured was measured, and the maxacalcitol residual rate (%) relative to the initial value was determined.

[Test Example 3] Maxacalcitol stability test 2
The formulation of Example 4 was tested for stability of maxacalcitol under long-term stability test conditions.

  The maxacalcitol content was measured when the sample was stored for a certain period in a constant temperature and humidity chamber set at 25 ° C. and 60% RH. The method for measuring the maxacalcitol content was the same as in Test Example 2. The results are shown in Table 2.

  The results of Test Examples 2 and 3 are shown as OCT residual ratios in Tables 1 to 5. From these results, it can be seen that maxacalcitol in each preparation of the present invention is stable even when the pH exceeds 8.5. In Comparative Example 1 in Table 4, a formulation having excellent chemical stability with tacalcitol is applied to maxacalcitol, but it can be seen that chemical stability is poor with maxacalcitol. Table 5 also shows that in the oil-in-water emulsion lotion of the present invention, a decrease in the content of maxacalcitol was observed near neutrality, but it was stable in basicity.

[Test Example 4] Viscosity and flowability test The lotion agents of Example 4 and Comparative Examples 3 to 6 were subjected to a viscosity test and a flowability test by the following methods.

Viscosity test: Viscosity was measured using a B-type viscometer (B8H, rotor: HH-12, measurement temperature 25 ° C.).
Flowability test 1: 0.5 mL of each sample was dropped onto a slide glass inclined at an angle of 45 °, and the time taken to move 50 mm was measured.

Fluidity test 2: 0.5 mL of each sample was dropped on a vertically standing plastic plate for property observation (length: 300 mm), and the distance moved for 30 seconds was measured.
The results are shown in Table 6. From these results, it can be seen that the lotion preparation of Example 4 has a higher viscosity and less sagging (small fluidity) than the lotion preparations of Comparative Examples 3-6.

[Test Example 5] Irritation test (primary irritation test on rabbit eye mucosa)
One ml of a fixed rabbit was instilled with 0.1 ml of the preparation of Example 4 and evaluated 1, 3, 24, 48 and 72 hours after the instillation (non-eyewash). In addition, a group which was washed with warm water for 1 minute 30 seconds after administration of the preparation was evaluated in the same manner. Evaluation is based on the criteria of Draize (Draize, JH, Appraisal of the safety of chemical in foods, drugs and cosmetics, Association of Food and Drug Officials of the United State, 49-51, 1959), and Kay-Calandra (Kay JH and Valandra, JC, Interpretation of eye irritation tests, J Soc. Cosm. Chem., 281-289, 1962).

The results are shown in Table 7. As a result, the non-eyewash was evaluated as unstimulated, and the eyewash was evaluated as almost unstimulated.
[Test Example 6] Preservative Efficacy Test Regarding the lotion preparations of Example 4 and Examples 13-18, a preservative efficacy test was conducted in accordance with Reference Information for Preservation Efficacy Test (Category IB): It was. That is, S. aureus (bacteria) and A. niger (fungi) were cultured by the method described in the pharmacopoeia to obtain an inoculum solution. After each inoculum was mixed evenly with each preparation, it was stored at 30 to 35 ° C. for S. aureus and 20 to 25 ° C. for A. niger for 2 weeks. The inoculum and the number of bacteria in the preparation after 2 weeks were measured by the Kanteng plate pour method, and the number of inoculum in the preparation and the number of bacteria in the preparation after 2 weeks were calculated. For S. aureus, when the number of bacteria after 2 weeks has decreased to 1% or less compared to the number of inoculated bacteria, and for A. niger, Was determined to have a preservative effect.

  Table 8 shows the storage efficacy test results for S. aureus and A. niger. It was judged to have storage efficacy at any pH tested against S. aureus and A. niger. The oil-in-water emulsion lotion of the present invention, which is adjusted to basic by blending an appropriate amount of diisopropanolamine, is a preparation having sufficient preservative efficacy without blending a highly irritating preservative such as parabens. It turns out that it is.

Claims (4)

22-oxa-1 alpha, 25-dihydroxyvitamin _{D 3,} met medium chain fatty acid triglyceride, a nonionic surfactant, and oil-in-water pH8.5~11 comprising water-soluble thickener emulsion lotion Lotion agent whose pH is adjusted by adding organic amine .   The lotion preparation according to claim 1, wherein the proportion of medium-chain fatty acid triglyceride is 0.5 to 25 wt% based on the weight of the whole lotion preparation. The lotion according to claim 1 or 2 , wherein the nonionic surfactant has an HLB value of 8 to 11. The lotion according to any one of claims 1 to 3 , further comprising a water-soluble polyhydric alcohol.