JP3410364B2 - Difluprednate-containing composition - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a liquid composition containing difluprednate, oil, water, and an emulsifier. More specifically, the present invention relates to a liquid composition of difluprednate having good transferability of difluprednate to an affected area, uniform drug distribution, and less discomfort or foreign body sensation.

[0002]

2. Description of the Related Art Difluprednate (6α, 9α-difluoroprednisolone 17-butyrate 21-acetate) is a steroidal anti-inflammatory drug and is known to exhibit an excellent anti-inflammatory effect by transdermal administration ( JP-B-45-28370 and JP-B-45-28371). Difluprednate has also been reported to show superior anti-inflammatory and anti-allergic effects by transdermal and subcutaneous administration (Applied Pharmacology (1985) 29 (3).
343-353, Applied Pharmacology (1985) 29 (3) 355-362). Therefore, difluprednate is mainly used as a therapeutic agent for skin diseases in the form of ointments, creams and the like. On the other hand, when the difluprednate is administered locally to the eye, nose, ear, etc., it is desired to be in a liquid form such as eye drops, nasal drops, ear drops. However, since difluprednate has a very low solubility in water, it is difficult to prepare stable eye drops, nasal drops, ear drops, etc. containing a therapeutically effective concentration. Has proposed a form of a suspension aqueous preparation (JP-A-8-217678).

However, for example, when a difluprednate suspension aqueous solution is used as an eye drop, a common problem with the suspension aqueous eye drop, that is, it is difficult to maintain uniform drug distribution at the time of instillation Or, a sense of discomfort that a solid gets into your eyes,
It has been pointed out that the feeling of foreign matter cannot be completely removed. Further, since difluprednate is a steroidal anti-inflammatory drug, it has been pointed out that it has sufficient side effects for the treatment of inflammatory diseases and allergic diseases, but also has side effects. Therefore, in consideration of the case where there is inflammation in the part (inner part of the eye) away from the instilled part (outer part of the eye), an effective dosage will be rapidly and uniformly transferred to the affected part, and development of a dosage form that can suppress side effects Is desired.

As mentioned above, since difluprednate has excellent anti-inflammatory and antiallergic effects,
It is useful for the prevention and treatment of various inflammatory diseases and allergic diseases. For the treatment of local diseases such as eyes, nose, and ears, it is necessary to formulate into a dosage form capable of instillation, nose, ear, etc., but difluprednate is required for the treatment of these local diseases. When used in the form of a turbid aqueous formulation, there are problems in terms of transferability of the drug to the affected area, uniformity of drug distribution, and feeling of use such as discomfort and foreign body sensation as described above.

[0005]

Therefore, the object of the present invention is to have good transferability to the affected area, uniform drug distribution during administration, less discomfort during administration, less foreign body sensation, and reduced side effects. To provide a difluprednate-containing composition.

[0006]

As a result of intensive studies to solve the above problems, the present inventors have prepared a liquid composition containing difluprednate, oil, water, and an emulsifier. When used topically, the transfer of difluprednate is rapid even when administered locally to the eyes, nose, ears, etc., the transfer amount is large, the distribution amount is uniform, and discomfort and foreign body sensation during use are extremely high. I found that there are few. Further, they have found that, because difluprednate has a good migration property, the drug effect is sufficiently exerted even at a low dose, and side effects can be suppressed, and the present invention was completed.

That is, the present invention relates to (1) difluprednate liquid composition characterized by containing difluprednate, oil, water, and an emulsifier, and (2) 1 part by weight of difluprednate, Oil 10-100,000 parts by weight, water 100-100,000 parts by weight and emulsifier 10
The composition of (1) above, containing 100,000 parts by weight,
(3) Oil 10 to 10 parts by weight of difluprednate
10000 parts by weight of water, 100 to 50000 parts by weight of water, and 10 to 10000 parts by weight of an emulsifier, (4) 1 part by weight of difluprednate,
The composition of the above (1) containing 10 to 5,000 parts by weight of oil, 500 to 50,000 parts by weight of water and 10 to 5,000 parts by weight of an emulsifier, (5) The above (1) wherein the oil is an oil containing a fatty acid ester of glycerin. (6) The composition of (5) above, wherein the fatty acid ester of glycerin is selected from the group consisting of castor oil, peanut oil, cottonseed oil, soybean oil, olive oil, and medium chain fatty acid triglyceride, (7)
The composition according to (1) above, wherein the emulsifier contains a surfactant,
(8) The composition according to (7) above, wherein the surfactant is a nonionic surfactant, and (9) the nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester. The composition (8), wherein the polyoxyethylene sorbitan fatty acid ester (10) is selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate. The composition of (9) above selected from the group consisting of: (11)
The above (1), (2), which is an oil-in-water emulsion,
(3) or (4) composition, and (12) eye drops,
The above (1), (2) in the form of nasal drops or ear drops,
It relates to the composition of (3) or (4).

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The composition of the present invention contains difluprednate, oil, water, and an emulsifier. The type of oil that can be used in the present invention may be one that can be applied to the eyes of low toxicity and low irritation, and preferably those containing a fatty acid ester of glycerin, such as castor oil, peanut oil, and cottonseed oil. , Soybean oil, olive oil, medium-chain fatty acid triglyceride [eg, Miglyol (trade name, Mitsuba Trading Co., Ltd.)] and the like. More preferred are castor oil and medium-chain fatty acid triglyceride (for example, migliol) having high solubility of difluprednate, and the like.

In the present invention, as an emulsifier, a surfactant, for example, a nonionic surfactant having surface active ability can be blended. Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, preferably polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoester. Examples thereof include palmitates and polyoxyethylene sorbitan monostearates.

The blending ratio of each of the above components in the composition of the present invention is not particularly limited, but for example, 10 parts by weight to 100,000 parts by weight of oil and 10 parts by weight of water to 1 part by weight of difluprednate.
0 to 100,000 parts by weight, emulsifier 10 to 100,000 parts by weight, preferably 1 part by weight of difluprednate,
The oil is mixed in an amount of 10 to 10000 parts by weight, water 100 to 50000 parts by weight, and an emulsifier 10 to 10000 parts by weight. Particularly preferably, the oil is mixed in an amount of 10 to 5000 parts by weight, water in an amount of 500 to 50,000 parts by weight, and an emulsifier in an amount of 10 to 5,000 parts by weight with respect to 1 part by weight of difluprednate. In particular, the weight ratio of oil to water as the medium is 1: 4 to 1:
It is preferably 99.

A water-soluble polymer can be added to the composition of the present invention in order to improve the emulsion stability. Examples of the water-soluble polymer include povidone (polyvinylpyrrolidone), polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof.

A buffer may be added to the composition of the present invention. Examples of the buffer include acetate such as sodium acetate, monosodium dihydrogen phosphate, disodium monohydrogen phosphate, monopotassium dihydrogen phosphate, phosphate such as dipotassium monohydrogen phosphate, epsilon aminocaproic acid. Amino acid salts such as sodium glutamate, boric acid and its salts, citric acid and its salts, and the like.

A preservative can be added to the composition of the present invention. Examples of preservatives include benzalkonium chloride, quaternary ammonium salts such as benzethonium chloride, cationic compounds such as chlorhexidine gluconate, methyl paraoxybenzoate, paraoxybenzoic acid esters such as propyl paraoxybenzoate, chlorobutanol, and the like. Examples thereof include alcohol compounds such as benzyl alcohol, sodium dehydroacetate, thimerosal, sorbic acid and the like.

A tonicity agent may be added to the composition of the present invention. Examples of the tonicity agent include sodium chloride, glycerin, glucose, mannitol, sorbitol and the like.

In addition to the composition of the present invention, various additives such as stabilizers, antioxidants, chelating agents, pH adjusters and thickeners can be added. Examples of antioxidants include ascorbic acid and salts thereof, tocopherol, sodium thiosulfate, sodium bisulfite, pyruvic acid and salts thereof, and the like. Examples of chelating agents include sodium edetate, citric acid and salts thereof. Examples of pH adjusters include hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, aqueous ammonia and the like.

The composition of the present invention is an oil-in-water type (O / W
Type) emulsions, microemulsions, and other aqueous preparations.

The median diameter of oil droplets of the composition of the present invention is preferably 5 to 0.0001 μm, and more preferably 1 to 0.
001 μm is more preferable, and 1 to 0.01 μm is particularly preferable. The median diameter can be measured using a particle size distribution measuring device.

The pH of the composition of the present invention is preferably 3-8. A more preferable pH is 4 to 7, which further improves the stability of difluprednate.

The composition of the present invention is prepared by a known method.
It is prepared by emulsifying oil and water in which difluprednate is dissolved with an emulsifier. For example, an emulsifier may be prepared by adding an emulsifier and, if necessary, the above-mentioned additive to water and adjusting the pH to 3 to 8 using a pH adjuster, and then adding an oil in which difluprednate is dissolved. it can.
Known means such as a homomixer, a homogenizer, a microfluidizer, and a high-pressure homogenizer can be used for uniform emulsification.

The composition of the present invention is preferably used as a preparation for topical administration to the eye, nose or ear, and further preferably used as eye drops, nasal drops and ear drops.

The composition of the present invention has excellent anti-inflammatory and anti-allergic effects. In addition, the migration of difluprednate is good, the migration is large, the distribution is uniform, and the discomfort and foreign body sensation upon administration are extremely small. Furthermore, since the drug effect is sufficiently exerted at the administration of a low dose, side effects can be suppressed. Therefore, it is useful for the prevention and treatment of various inflammatory diseases and allergic diseases such as allergic conjunctivitis, spring catarrhal, blepharitis, catarrhal conjunctivitis, uveitis, and also for the eyes, nose, ears, etc. It can also be used advantageously when administered topically.

The composition of the present invention can be safely administered to mammals (humans, dogs, rabbits, cows, horses, monkeys, cats, sheep, etc.).

The dose of the composition of the present invention depends on the type of disease,
Although it varies depending on symptoms, age of the patient, weight, etc., when used as an eye drop for adults, for example, as an eye drop containing about 0.005 to 0.1% of difluprednate per eye per patient, Depending on the symptom, it is desirable to administer a single dose of 1 to 2 drops to the eye drop about 2 to 4 times a day.

[0024]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. In the following examples and test examples,
The median diameter is Shimadzu laser diffraction type particle size distribution measuring device S
ALD-2000 (dispersion medium: water, refractive index: 1.70-
To 0.20i), about 2 mL of the composition to be measured was added and measured.

[0025] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, boric acid, sodium edetate, and sorbic acid are added and dissolved, and the pH is adjusted to 6.0 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.

Example 2 Difluprednate 0.005 g Castor oil 1.0 g Polysorbate 80 0.5 g Concentrated glycerin 2.2 g Hydroxypropylmethylcellulose 0.1 g Sodium acetate 0.05 g Chlorobutanol 0.3 g Hydrochloric acid qs Sterile purified water Total volume 100 mL (pH 4.0) Sterile purified water is heated to about 70 ° C., polysorbate 80, concentrated glycerin, hydroxypropylmethylcellulose, sodium acetate and chlorobutanol of the above formulation are added and dissolved, and pH is adjusted to 4 with hydrochloric acid. The water phase was adjusted to 0.0. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.12 μm.

[0027] Sterile purified water was heated to about 70 ° C., polysorbate 80, concentrated glycerin, ε-aminocaproic acid, and chlorhexidine gluconate of the above formulation were added and dissolved, and the pH was adjusted to 5.5 with sodium hydroxide to obtain an aqueous phase. . Separately, Miglyol was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.21 μm.

[0028] Sterile purified water is heated to about 70 ° C., polyoxyethylene hydrogenated castor oil 60, concentrated glycerin, sodium glutamate, methyl paraoxybenzoate and propyl paraoxybenzoate of the above formulation are added and dissolved, and the pH is adjusted to 5 with sodium hydroxide. The water phase was adjusted to 0.0. Castor oil about 7
The mixture was heated to 0 ° C., difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention is 0.06μ.
It was m.

[0029] Sterile purified water was heated to about 70 ° C., polysorbate 80, polyvinyl alcohol, concentrated glycerin, sodium acetate and benzalkonium chloride of the above formulation were added and dissolved, and the pH was adjusted to 5.0 with hydrochloric acid to form an aqueous phase. . Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention is 0.
It was 06 μm.

[0030] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium hydrogen phosphate, sodium edetate, and benzalkonium chloride are added and dissolved, and the pH is adjusted to 7.0 with sodium hydroxide. The water phase was used. Separately, Miglyol was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.

[0031] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.

[0032] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.

[0033] Sterile purified water is heated to about 70 ° C., polysorbate 80 of the above formulation, concentrated glycerin, sodium acetate, sodium edetate, boric acid and sorbic acid are added and dissolved, and the pH is adjusted to 5.5 with sodium hydroxide. The water phase was used. Separately, castor oil was heated to about 70 ° C., and difluprednate was added and dissolved to obtain an oil phase. The oil phase was added while stirring the aqueous phase with a homomixer to obtain a crude emulsion. This crude emulsion was made into fine particles with a microfluidizer and sterilized by filtration to obtain the composition of the present invention. The median diameter of oil droplets in the composition of the present invention was 0.06 μm.

Test Example 1 Difluprednate suspension ophthalmic solution and the composition of the present invention were compared and examined for the transferability in rabbit anterior chamber (intraocular transferability) after a single instillation. The steroid drug difluprednate suspension ophthalmic solution has already been reported to have a significant inhibitory effect on experimental uveitis in rabbits. In this study, for the purpose of improving the intraocular translocation of difluprednate, the composition of the present invention and difluprednate suspension ophthalmic solution were compared and examined for the intracameral translocation of difluprednate (intraocular translocation). did. (1) Test composition The composition of the present invention having the formulation shown in Table 1 and a suspension ophthalmic solution were prepared as follows. [Inventive Composition] 800 mL of sterile purified water is heated to about 70 ° C., 40 g of polysorbate 80 and concentrated glycerin 2 are added.
6 g was added and dissolved to obtain an aqueous phase. Separately, castor oil 50
g was heated to about 70 ° C., 0.5 g of difluprednate was added and dissolved to obtain an oil phase. While stirring the aqueous phase with a homomixer, the oil phase was added to make a crude emulsion, and sterilized purified water was added to make 1000 mL. This crude emulsion was made into fine particles using a microfluidizer and then sterilized by filtration to obtain the composition of the present invention. [Suspension eye drop] 800 mL of sterilized purified water is heated to about 70 ° C., 2 g of hydroxypropylmethyl cellulose is added,
After being sufficiently dispersed, the mixture was cooled to about 30 ° C. to dissolve hydroxypropylmethyl cellulose. To this solution, 1 g of sodium acetate, 8 g of sodium chloride and 0.5 mL of a benzalkonium chloride solution (10 W / V%) were added and dissolved. After adjusting the pH to 5.0 with hydrochloric acid, the solution was sterilized by filtration, 1 g of difluprednate was added and sufficiently suspended, and sterile purified water was added to 1000 mL to obtain a suspension ophthalmic solution.

[0035]

[Table 1]

(2) Test Animal A Japanese White Male Rabbit having a body weight of about 2 kg with no abnormalities in the eyes was used. These rabbits have a room temperature of 23 ± 3 ° C,
The animals were bred one by one in a breeding room set at a relative humidity of 55 ± 10%, and were fed solid feed (Lab RG-RO, Japanese agricultural products) 10 times a day.
0 g was given and tap water was freely taken.

(3) Test method Rabbits were instilled with 50 μL of the test composition, and 1 hour later, the animals were sacrificed with pentobarbital. Immediately after the sacrifice, the anterior ocular segment was washed with physiological saline, and the anterior chamber water was collected. Difluprednate was deesterified at the 21st position in aqueous humor etc.
Since it is metabolized to α, 9α-difluoroprednisolone 17-butyrate), DFB was measured by high performance liquid chromatography as an index of the concentration of difluprednate in the anterior chamber. The high performance liquid chromatographic conditions are as follows.

High-performance liquid chromatographic conditions Column: TSK gel ODS-80Ts Mobile phase: 10 mM NaH ₂ PO ₄ .2H ₂ O (pH 7) / CH ₃ CN = 55/45 Column temperature: 40 ° C Flow rate: 1.3 mL / min Wavelength: 240 nm Injection volume: 50 μL

Table 2 shows the DFB concentration in the rabbit anterior chamber 1 hour after the first instillation of the test composition.

[0040]

[Table 2]

By preparing difluprednate in the composition of the present invention, the amount transferred into the eye showed a value of 42.95 ng / mL, even though the concentration of the drug contained was half that of the suspension. This value was about 2.2 times the intraocular amount of the suspension, and a significant difference was observed. From the above results, it was revealed that the composition of the present invention exerts the drug effect more than that of the suspension even if the dose is lower than that of the suspension.

[0042]

The composition of the present invention has excellent anti-inflammatory and anti-allergic effects. Further, the composition of the present invention, compared to the conventional difluprednate-containing formulation, has good transferability to the affected area, and since the drug distribution during administration is uniform, the drug effect is sufficiently exerted at low dose administration. It Further, compared to the conventional preparation containing difluprednate, the discomfort and foreign body sensation during administration are extremely small, and the preparation can be easily administered locally to the eyes, nose, ears and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 37/08 A61P 37/08 (72) Inventor Masazumi Yamaguchi 1 KCC House No. 101, 4-366, Minamibeppu, Nishi-ku, Kobe City, Hyogo Prefecture (72) Inventor Katsuhiro Inada, No. 1-3401, 1-2-2, Ibukidaihigashi-cho, Nishi-ku, Kobe-shi, Hyogo (56) References JP-A-5-43465 (JP, A) JP-A-8-217678 (JP, A) Japanese Patent Publication No. 45-28370 (JP, B1) Japanese Patent Publication No. 45-28371 (JP, B1) US Patent 3780177 (US, A) US Patent 4427670 (US, A) International Publication 98/30221 (WO, A1) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 31/575 A61K 9/107 A61P 11/02 A61P 27/14 A61P 27/16 A61P 37/08 CA (STN)

Claims (10)

(57) [Claims] 1. (a) Difluprednate, (b) Castor
Oil, peanut oil, cottonseed oil, soybean oil, olive oil and medium
An oil selected from the group consisting of chain fatty acid triglycerides ,
(C) Water and (d) Emulsifier-containing eye drops, spots
Emul containing difluprednate which is nasal or ear drops
John composition. 2. With respect to 1 part by weight of difluprednate,
Oil 10-100,000 parts by weight, water 100-100,000
A composition according to claim 1 which comprises parts by weight and 10 to 100,000 parts by weight of emulsifier. 3. With respect to 1 part by weight of difluprednate,
The composition according to claim 1, which comprises 10 to 10000 parts by weight of oil, 100 to 50000 parts by weight of water, and 10 to 10000 parts by weight of an emulsifier. 4. With respect to 1 part by weight of difluprednate,
An oil containing 10 to 5000 parts by weight, 500 to 50000 parts by weight of water and 10 to 5000 parts by weight of an emulsifier.
The composition as described. 5. The emulsifier contains a surfactant.
The composition as described. 6. The composition according to claim 5 , wherein the surfactant is a nonionic surfactant. 7. The composition according to claim 6, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid ester. 8. The polyoxyethylene sorbitan fatty acid ester is selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monostearate. Item 7. The composition according to Item 7 . 9. The composition according to claim 1, which is an oil-in-water emulsion. 10. Difluprednate, castor oil, water,
And polyoxyethylene (20) sorbitan monoole
Containing benzoate, eye drops, nasal solutions or are ear drops
An emulsion composition containing difluprednate.