KR20010068955A - Epidermal preparations - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for external use is provided, which is a high water-content gel preparation, gives light touch without stickiness of pharmaceutical preparation by production of drops of water when you rub lightly after applying, therefore it shows good sense of use and skin sensitivity without stickiness. CONSTITUTION: The pharmaceutical composition for external use is comprised of: one or two kind of pharmaceutically active material as main ingredients selected from lidocaine, benzocaine, dibucaine, cojic acid, urea, hydroquinone, triamcinolone, prednisolone or hydrocortisone; dimethicone, cyclomethicone or copolymer thereof as a base; dimethiconepolyolcrosspolymer dimethicone as a base; hydrophilic oil selected from natural oil, glycerides, propylene glycol or any other oils as a base; one of polymer compound selected from poloxamers, polyethylene glycols, polyethylene oxides as a base; and water.

Description

Topical pharmaceutical composition {EPIDERMAL PREPARATIONS}

The present invention relates to a pharmaceutical composition for the skin, more specifically, a silicone oil (silicon) to form water droplets on the skin when applied to the skin in a high water-based emulsion using a three-dimensional cross-linking agent (high water emulsion emulsion) It is a gelled oil preparation, which is a local anesthetic used as a premature improvement agent, lidocaine and its hydrochloride, benzocaine and its hydrochloride, dibucaine and its hydrochloride, and melanin Kojic acid inhibits production, urea, hydroquinone, and corticosteroids, triamcinolone, prednisolone, or hydrocortisone One or two main ingredients selected from hydrocortisone are contained inside the silicone oil to improve the stability of the main ingredients from low temperature (0 ℃) to high temperature (60 ℃). Stable in water and then applied such that is not sticky, relates to a composition for the outer covering of the gel formulation characterized in that it has a light and refreshing feeling.

Conventional gel preparations have a discomfort, such as stickiness when applied to the skin, so many difficulties in use have been required to develop new formulations.

Conventional emulsifiers adsorb on the interface between water and oil to reduce interfacial energy and emulsify water by forming aggregates of pseudomolecules in micelle formation or liquid crystal formation. Therefore, the size of the emulsified particles is usually several μm or less. However, since the base of the present invention is a fine particulate polymer dispersion and does not lower the interfacial tension so much, water-in-oil (w / o) emulsions of large particles are formed. Therefore, despite these large emulsified particles, it is stable that the polyether moiety is oriented around the water particles, and the silicone chain is the outer silicone oil and the mutually integrated network. It is believed that silicone oil loses its fluidity and becomes gel. Nevertheless, this gel has a low viscosity change against temperature change because of its basic skeleton is a silicone chain, and maintains a stable structure. Stability can be maintained.

By crosslinking the silicone chain to a hydrophilic polyether chain, a silicone three-dimensional crosslinked polymer having both gel formation ability and functionality for low viscosity silicone oil is used. It is made by the dispersion of polymer and is insoluble to water and liquid oil such as silicone oil and water. Since the dispersion has hydrophilic component and hydrophobic part together, it is oriented on the interface of liquid oil and water so that the interfacial film is formed efficiently. Water-in-oil (w / o) emulsion prepared by using is designed to contain a large amount of dispersed water particles, a large amount of water.

Accordingly, the present invention has led to the development of a new, non-sticky formulation that is different from the conventional silicone-based water-in-oil (w / o) emulsifiers.

1 is a graphy of the stability of lidocaine gel,

2 is an in vitro flux analysis of lidocaine gel.

The present invention relates to a skin medicament composition that produces water droplets and is non-sticky when applied to the skin as described above. The skin medicament composition of the present invention is a lidocaine (lidocaine), a hydrochloride salt thereof, and benzocaine (benzocaine) as a local anesthetic component. ) And its hydrochloride, dibucaine and its hydrochloride, kojic acid, which inhibits melanin production, urea, hydroquinone, and triamcinolone, an adrenal cortex hormone One or two pharmacologically active substances 1-10 selected from prednisolone or hydrocortisone, and as a base 1) silicone oil to increase viscosity and stabilize drug structure. Dimethicone, cyclomethicone, or a copolymer having a basic structure of dimethicone having a low viscosity (6 cps) to a high viscosity (1000 cps) 2 types of silicone oils each selected from 3.0 to 15.0, and 2) one kind of oil selected from methylhydrogen polysiloxane, polyoxyethylene ether, dimethyl polysiloxane, and divinyl ether under addition of a platinum catalyst to react with a silicone chain. Dimethiconocopolyol crosspolymer dimeth, a type of synthetic-derived silicone oil that forms a three-dimensional cross-linked structure formed by a hydrophilic polyether chain and enables high water-soluble emulsions. 3.5-15.0 of dimethiconecopolyol crosspolymerdimethicone; and 3) two hydrophilic oils each selected from natural oils (coconut oil, soybean oil, etc.), glycerides, propylene glycol or other oils to improve skin sensitivity. And 4) poloxamers, polyethyleneglycols, and polyethylene oxides. It is designed to contain 0.5 to 5.0 of one polymer compound and water, and to improve the stiff feeling as a gel with a high water content while having a viscosity.

The pharmaceutical composition for the skin of the present invention configured as described above is used as a gel formulation for premature ejaculation improvement treatment, melanin production inhibition, skin keratosis or various skin inflammations, and the like is applied to the skin appropriately. In the formulation of the present invention, when applied to the skin, lightly rubbed, water droplets were formed and the skin sensitivity was very good without stickiness.

Hereinafter will be described for the preparation examples and experimental examples of the present invention. In the formulation examples, "" means "weight" unless otherwise specified.

Formulation Example 1

Premature ejaculation improvement gel containing lidocaine.

(Prescription)

Lidocaine 9.6

Dimethicone Copolyol Crosspolymer Dimethicone 8.0

(Dimethiconecopolyol Crosspolymerdimethicone)

Cyclomethicone 4.0

Dimethicone 5.0

Glycerin 3.0

Propylene Glycol 7.0

Poloxamer # 407 0.5

Water quantity

-----------

100

(Manufacturing method)

A gel containing 9.6 lidocaine per gram of gel, wherein according to the prescription, lidocaine is suspended in glycerin and propylene glycol at room temperature, and then the suspension is dimethicone copolyol crosspolymer dimethicone and cyclomethicone silicone oil (silicone). It is added to the oil phase and homogenized so that the main particles of the main component are covered by the silicone oil and the crosslinked body, and the water is slowly added to the paddle and stirred with a paddle at a speed of 50 to 100 rpm to allow the emulsion particles of the water to be water-in-oil ( To prepare a gel that enters the w / o) region. At this time, the hardness varies depending on the stirring speed, so pay attention. When the formulation is applied to the skin, rub gently after application to see the formation of water droplets.

Formulation Example 2

A high water-resistant emulsion type premature improvement gel containing benzocaine.

(Prescription)

Benzocaine 3.8

Dimethicone Copolyol Crosspolymer Dimethicone 8.0

(Dimethiconecopolyol Crosspolymerdimethicone)

Cyclodimethicone 4.0

Dimethicone 5.0

Glycerin 3.0

Propylene Glycol 5.0

Ploxamer # 407 1.0

Water quantity

-----------

100

(Manufacturing method)

A gel containing 3.8 benzocaine per gram of gel, wherein benzocaine is suspended in glycerin and propylene glycol at room temperature according to the above-mentioned prescription, and then the suspension is silicone oil of dimethicone copolyol crosspolymer dimethicone. The phase particles of the main component are encapsulated by the silicone oil and the crosslinked product, and the matrix prepared by poloxamer is swelled in the water phase and slowly introduced into the water phase, and then slowly added into the paddle at 50 to 100 rpm. Stirring at a speed of to prepare a gel agent in which the emulsified particles of water enter the water-in-oil (w / o) type region. At this time, the hardness varies depending on the stirring speed, so pay attention.

Formulation Example 3

Highly water-resistant gel containing lidocaine hydrochloride

(Prescription)

Lidocaine Hydrochloride 2.0

Dimethicone Copolyol Crosspolymer Dimethicone 5.0

(Dimethiconecopolyol Crosspolymerdimethicone)

Cyclodimethicone 3.0

Dimethicone 4.0

Glycerin 3.0

Propylene Glycol 5.0

Ploxamer # 407 1.0

(Or Carbopol, PEO)

Water quantity

-----------

100

(Manufacturing method)

A gel containing 2.0 lidocaine hydrochloride per gram of gel, which is dissolved in an aqueous phase at room temperature according to the above-mentioned prescription, and then glycerin and propylene glycol are added, followed by dimethicone copolyol crosspolymer dimethicone, cyclomethicone, and dimethicone silicone. It is added to the oil (silicone oil), the main component particles to wrap the silicone oil and the crosslinked body, separately swelling the matrix (martrix) in the water phase and slowly added while stirring with a paddle (paddle) at a speed of 50 ~ 100 rpm A gel agent is prepared in which emulsion particles of water enter a water-in-oil (w / o) type region.

Formulation Example 4

Silicone oil high water-resistant gel containing kojic acid.

(Prescription)

Kojic acid 1.0

Dimethicone Copolyol Crosspolymer Dimethicone 3.5

(Dimethiconecopolyol Crosspolymerdimethicone)

Cyclodimethicone 4.0

Dimethicone 6.0

Glycerin 2.0

Propylene Glycol 5.0

Ploxamer # 407 2.5

(Or Carbopol, PEO)

EDTA-2Na 0.1

Ascorbic Acid 0.5

Water quantity

-----------

100

(Manufacturing method)

A gel containing 1.0 kojic acid per gram of gel, wherein kojic acid is dissolved in an aqueous phase at room temperature according to the above-mentioned prescription, and then EDTA-2Na and ascorbic acid are dissolved, and glycerin and propylene glycol are added thereto. After homogenization, the mixture was placed on a dimethicone copolyol crosspolymer dimethicone, a cyclomethicone and a dimethicone on a silicone oil, so that the phase particles of the main component were encapsulated by the silicone oil and a crosslinked body, and then prepared separately. matrix) is prepared by swelling in an aqueous phase, and slowly adding it to a paddle, and stirring at a speed of 50 to 100 rpm to prepare a gel in which emulsion particles of water enter a water-in-oil (w / o) type region.

Formulation Example 5

Highly water-resistant gel containing urea, hydrocortisone and lactic acid.

(Prescription)

Urea 10.0

Lactic acid 5.0

Hydrocortisone 1.0

Dimethicone Copolyol Crosspolymer Dimethicone 3.5

(Dimethiconecopolyol Crosspolymerdimethicone)

Cyclodimethicone 4.0

Dimethicone 6.0

Glycerin 5.0

Propylene Glycol 5.0

Appropriate amount of polyethylene glycol

Butylhydroxyanisole 0.03

EDTA-2Na 0.1

Ascorbic Acid 0.5

Water quantity

-----------

100

(Manufacturing method)

A gel containing 10 urea, 5.0 lactic acid and 1.0 hydrocortisone per 1 g of gel, wherein the urea and lactic acid are dissolved in water according to the above prescription, and then hydrocortisone is added and homogenized by the addition of glycerin and propylene glycol. Methicone Copolyol Crosspolymer Dimethicone, cyclomethicone and dimethicone are injected onto the silicone oil (silicone oil) so that the phase particles of the main component are wrapped around the silicone oil and the crosslinked material, and the paddle speeds 50 to 100 rpm. Stirring to prepare a gel in which the emulsified particles of water enter the water-in-oil (w / o) type region.

Experimental Example 1

Stability Test of Formulations

1) Summary

As a result of the stability test conducted at 40 ° C. and 75 RH with the Lidocaine gel of the present invention, no deterioration of the content was observed for 6 months, and thus, it was considered to be a very stable formulation. do.

2) Test method

About 10 g of Lidocaine gel preparation (96 mg equivalent as Lidocaine) according to Formulation Example 1 of the present invention is taken, 0.5 ml of 1 mol / L hydrochloric acid solution and 30 ml of 0.001 mol / L hydrochloric acid solution are added, and 10 ml of internal standard solution is precisely added, followed by filtration. After that, adjust 50 ml mark with 0.001 mol / L hydrochloric acid solution to make the sample solution. Separately, quantitative lidocaine is dried in a desiccator (reduced pressure, silica gel) for 24 hours, and then about 96 mg of it is precisely taken and treated in the same manner as the sample solution below to make a standard solution.

(Internal standard solution: Methanol solution of benzophenone (1 → 4000)

Operation condition

Detector: UV 254 nm

Column: C ₁₈ (4 × 150, 10 ㎛), Column temperature: Constant temperature around 25 ℃

Mobile phase: Dissolve 2.88 g of sodium lauryl sulfate in 1 L of 0.02 mol / L phosphate buffer (pH 3.0) and acetonitrile mixture (11: 9).

Flow rate: Adjust the retention time of Lidocaine to about 6 minutes.

3) Experiment result

As a result of performing the above experiment, no decrease in content was found for 6 months and the experimental value is shown in FIG. 1 (see FIG. 1).

4) Separately, Lidocaine cream was observed every week under the harsh conditions of 4 ℃ refrigeration, but no significant deformation on the gel was observed. Therefore, it was maintained at a very stable state at low temperatures, whereby the formulation of the present invention proved to be a very stable formulation with temperature changes.

Experimental Example 2

Skin irritation test

1) Summary

Skin irritation test on rabbits with Lidocaine gel was carried out in accordance with the toxicity test standard (enacted on June 16, 1986) of Food and Drug Administration No. 96-8 up to 72 hours after administration with 6 male New Zealand White rabbits. The following results were obtained.

(1) No abnormalities in clinical symptoms, weight changes, and autopsy findings that were recognized by the test substance throughout the pre-test period were observed in all animals.

(2) No irritation such as erythema, dermal formation and edema of the test substance application site was recognized. The primary skin irritation rate was calculated as "0" by Draize's P.I.I (Primary Irritation Index) calculation.

As a result, Lidocaine gel is considered to be a "non-irritant" in New Zealand White rabbits.

2) Test substance

(1) Name: Lidocaine gel

(2) Chemical Name: Lidocaine 9.6

(3) Properties: Milky white cream (Formulation Example 1 of the present invention)

(4) Stability and homogeneity of test substance: It maintains stable and homogeneous state without change of appearance under room temperature shading.

(5) Storage condition: Store in a shaded condition at room temperature.

3) Materials and Methods

(1) Test system

① Type and system

New Zealand White Rabbit

② Reason for selection of test system

This strain is a commonly used species for topical skin stimulation tests. It has accumulated abundant basic experimental results to compare with this strain and was selected for the interpretation, comparison and evaluation of test results.

③ Month of purchase and number of animals

8 male rabbits 3 to 4 months old

④ Purification and Quarantine

Purified in animal room for about 1 week after animal acquisition. Only healthy animals were selected by observing the general condition during the acclimatization period, and the animals after hair removal were checked for abnormalities of the skin, and then only animals without abnormalities were used for the test.

(2) Breeding environment

① Environmental conditions

The test was carried out in a laboratory animal laboratory set at a temperature of 23 ± 2 ° C, a relative humidity of 50 ± 10, a ventilation number of 10-12 times / hr, an illumination time (07: 00-17: 00), and an illuminance of 150-300 Lux.

② Identification of breeding box, breeding density and breeding box

During the acclimatization and testing periods, rabbits were housed individually in stainless cages (420 W × 500 D × 310 Hmm) arranged in three stage cages.

③ Feed and negative salary method

Feed was free to feed the rabbit solid feed, negative water was freely ingested.

④ Confirm pollutant of water column

For water, pollutants were inspected by the Food Water Company's Drinking Water Standard Test, and no factor affecting the test was found.

(3) Dose and composition of test group

① Dosage setting

According to the Food and Drug Administration Notification No. 96-8, "Toxicological Standards for Drugs (enacted on June 16, 1993), 0.5 g of the sample was applied to the skin of the back of the hair.

② Group separation and animal identification

Rabbits were weighed by selecting only animals determined to be healthy during the acclimation period, and the individuals were identified by numbering them with oily magic on their heads.

(4) Administration of test substance

① Preparation and frequency of administration

The sample solution to be used in this test was used as is without dilution of Lidocaine gel.

② How to administer

Twenty four hours before application of the test substance, the skin of the back is shaved and the skin is divided into left and right, the left is the control compartment, the right is the control compartment, or the left is the control zone, the healthy skin of the administration zone and the control zone. Skins) or abrasions were divided diagonally to each other, divided into two healthy skins of 2.5 × 2.5 cm and applied to all four skins. The abrasions and skins were scratched to the extent that the epidermis was damaged, but the dermis was intact and bleeding, using the opposite side of the micro knife.

In the administration method, 1 g of the stock solution per animal was applied once to the administration site, and sterile physiological saline injection was applied to the untreated control section. After application, it was covered with gauze, fixed with a non-irritating tape, and applied for 24 hours. After the end of the application period, the application part was lightly washed with distilled water for injection.

(5) Observation and Inspection Items

① Clinical symptoms and inspection items

The appearance, feed, drinking water consumption and clinical symptoms were observed every day until 7 days after administration of the test substance.

② Weight measurement

It was measured at the time of administration and at 72 hours, respectively.

③ After application of the test substance, the tape was removed at 24 hours and 72 hours after administration to observe irritation such as erythema, skin formation, and edema formation.

(6) Evaluation of skin reaction and determination of irritation

Evaluation of skin reactions was made using the Food and Drug Administration Notice No. 96-8, "Toxicological Standards for Drugs, etc.". The determination of skin irritation was followed by the commonly used method of Draize's Primary Irritation Index (P.I.I).

※ Evaluation of skin reaction

① erythema and skin formation

· No erythema at all 0

Very light erythema (only visible to the naked eye) 1

Clear erythema 2

About severe severe erythema 3

Severe erythema (blush redness) and mild crust 4

Total possible erythema score 4

② Edema formation

No edema at all 0

Very mild edema (only visible to the naked eye) 1

Mild edema (if swollen clearly and the margins are clearly distinguished) 2

Normal edema (when swelling about 1 mm) 3

Severe edema (swelling more than 1 mm and extending beyond the exposed area) 4

Total possible edema score 4

From the test results, P.I.I (Primary Irritation Index) was evaluated as follows.

0 ~ 2: weak irritant, 3 ~ 5: moderate irritant, 6 ~ 8: strong irritant

A + B + C + D + E + F + G + H

* P.I.I = -----------------------------------

4

Erythema and crust

A: Score of normal skin at 24 hours B: Score of normal skin at 72 hours

C: Score of damaged skin at 24 hours D: Score of damaged skin at 72 hours

edema

E: Normal skin score at 24 hours F: Normal skin score at 72 hours

G: Score of damaged skin at 24 hours H: Score of damaged skin at 72 hours

Table 1

P.I.I. of Draize

Accuracy (P.I.I) division 0.0 to 0.5 Non-irritant 0.6 to 2.0 Weak irritant 2.1 to 5.0 Moderate irritant 5.1 and above Strong irritant

* P.I.I. : Primary Irritation Index

4) Result

(1) mortality

No mortality was observed in rabbits throughout the test period (see Table 2).

(2) Clinical symptoms

No clinical symptoms were observed in rabbits throughout the study (see Table 2).

(3) weight change

In all rabbits, body weight on day 3 after application showed an average weight gain of about 50 g compared to the body weight at the start of application, which is a general rabbit weight gain that is recognized by changes such as weight gain or loss in relation to the test substance. (See Table 3).

(4) Observation of the coating site

1) erythema and skin

① Normal skin: 6/6 of "no erythema at all" at 24 hours and 72 hours after administration. No abnormalities due to the stimulation of the sample were observed.

② Damaged skin: 6/6 of “no erythema at all” at 24 and 72 hours after administration. No abnormalities due to stimulation of the sample were observed. (See Table 4)

2) Edema

① Normal skin: 6/6 of “no edema” at 24 hours and 72 hours after administration. No abnormality caused by stimulation of the sample was observed.

② Damaged skin: 6/6 of “no edema” at 24 hours and 72 hours after administration. No abnormalities due to the stimulation of the sample were observed. (See Table 4)

Table 2

Mortality and clinical signs

* NAD: No Abnormalities Detected

Sex No. ofrabbits clinical signs Mortality 0 24 48 72 (hr) Male One NAD NAD NAD NAD 0/6 2 NAD NAD NAD NAD 0/6 3 NAD NAD NAD NAD 0/6 4 NAD NAD NAD NAD 0/6 5 NAD NAD NAD NAD 0/6 6 NAD NAD NAD NAD 0/6

Table 3

Changes of Body Weight in Rabbits

(unit: G)

Sex No. ofrabbits Day of application Weight gains 0 day 72 hr Male One 2,390 2,440 +50 2 2,500 2,560 +60 3 2,480 2,550 +70 4 2,380 2,440 +60 5 2,610 2,670 +60 6 2,510 2,570 +60 Mean 2,478.3 2,538.3 60 S.D. ± 85.2 ± 87.5 ± 6.3 N 6 6 6

Table 4

Score of Skin Irritation Study in Rabbits Treated with Lidocaine gel

AnimalNo. Erythema and Eschar Edema Total P.I.I. Intact site Abraded site Intact site Abraded site 24 hrs 72 hrs 24 hrs 72 hrs 24 hrs 72 hrs 24 hrs 72 hrs One 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 0 Total 0 0 0 0 0 0 0 0 0 0

(Pyunggun 0/0)

(Saline)

AnimalNo. Erythema and Eschar Edema Total P.I.I. Intact site Abraded site Intact site Abraded site 24 hrs 72 hrs 24 hrs 72 hrs 24 hrs 72 hrs 24 hrs 72 hrs One 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 0 Total 0 0 0 0 0 0 0 0 0 0

(Pyunggun 0/0)

5) Conclusion

The skin irritation test on Lidocaine gel in this study was carried out using 6 male rabbits under percutaneous application at 1 g / head (0.5 g / site) in accordance with the Korea Food and Drug Administration's Notice of Toxicology. In the general symptoms, weight change, autopsy findings, no specific lesions thought to be caused by this agent were observed. Skin irritation reactions such as erythema, skin, and edema were determined as "zero" and "non-irritant". .

As a result of calculating the skin irritation rate (P.I.I) in order to evaluate the results of the skin reaction as described above, the Lidocaine gel according to the present invention is considered to have a very high safety against skin irritation.

Experimental Example 3

In vitro Flux Studies of Lidocaine Gels

This study fixed the hairless mouse skin at 36.5 ℃ by using side-by-side diffusion cell and hairless mouse, applying a certain amount of Lidocaine gel as donor, and filling HEPES buffer saline (pH 7.4) as receptor solution. Sampling was performed. The sample obtained was analyzed using HPLC / UV system. The analysis results are shown in FIG. 2 (see FIG. 2).

From the above analysis results, it was confirmed that the gel formulation of the present invention is a very stable formulation.

The outer skin pharmaceutical agent according to the present invention is a gel of a high water content, and after rubbing lightly on the skin, water droplets are generated, and the formulation is designed to have a light texture without stickiness of the drug. The pharmaceutical composition of the present invention has lidocaine as a main component, It contains one or two pharmacologically active substances selected from benzocaine, dibucaine and the like, hydrochloride, kojic acid, urea, hydroquinone, triamcinolone, purenedisolone, or hydrocortisone, and as a base 1) dimethicone, cyclo Two kinds of silicone oil components selected from methicone or copolymers thereof, 2) dimethicone copolyol crosspolymer dimethicone, and 3) two hydrophilic selected from natural oils, glycerides, propylene glycol or other oils. 1 type of polymer selected from oil, 4) poloxamers, polyethylene glycols, and polyethylene oxides It is a gel agent comprised of a compound.

The pharmaceutical composition of the present invention as described above has a feature that the water droplets are formed when applied to the skin, there is no stickiness and the use feeling is good and the skin sensitivity is excellent.

Claims (2)

1 to 10 pharmacologically active substances selected from lidocaine or its hydrochloride, benzocaine or its hydrochloride, dibucaine or its hydrochloride, kojic acid, urea, hydroquinone, triamcinolone, purenedisolone or hydrocortisone, and base As 1) dimethicone, cyclomethicone, or copolymers of two kinds of silicone oils selected from their copolymers, 3.0 to 15.0 each; 2) dimethicone copolyol crosspolymer dimethicone 3.5 to 15.0; and 3) natural oil glycerides. Two hydrophilic oils selected from among propylene glycol, propylene glycol or other oils, each containing 3.0 to 7.0 and 4) a high water-soluble phase containing 0.5 to 5.0 of a polymer compound selected from poloxamers, polyethylene glycols and polyethylene oxides, and water. Outer shell pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the outer pharmaceutical formulation is a gel.