CN103126983A - Emulsion prepared by difluprednate crystal form I - Google Patents
Emulsion prepared by difluprednate crystal form I Download PDFInfo
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Abstract
An emulsion prepared by a difluprednate crystal form I contains difluprednate used as active ingredients, one type or multiple types of oil, one type or multiple types of emulgator and water. The emulsion comprises, by weight, 0.01% to 0.1% of the difluprednate, 1% to 20% of the oil, and 1% to 10% of the emulgator. The emulsion prepared by the difluprednate crystal form I is characterized in that when the emulsion is prepared, the difluprednate adopted is the difluprednate crystal form I, wherein the X-ray powder diffraction of the difluprednate crystal form I has a characteristic peak when a diffraction angle 2theta is 8.9 degrees, 11.6 degrees and 17.6 degrees.
Description
Technical field
The present invention relates to a kind of steroidal 17-hydroxy-11-dehydrocorticosterone Emulsion, especially relate to a kind of difluprednate Emulsion.
Background technology
Difluprednate (CAS:23674-86-4, difluprednate) molecular formula is as follows:
Difluprednate is a kind of of steroidal 17-hydroxy-11-dehydrocorticosterone, can suppress the reaction of inflammation and allergic skin, also suppress simultaneously to add the related reaction of rapid regeneration and cause symptom with cell, for example erythema, edema, thickization of skin, coarse the going down of skin surface, and alleviate the problems such as pruritus, burning sensation and pain.Owing to having introduced 17-butyrate and 21-acetate in molecule, make the fat-soluble better of difluprednate, thereby when treating, external can reach better curative effect, existing external preparation is mainly 0.05% difluprednate ointment and ointment (trade name: MYSER, Japan Tanabe Mitsubishi Pharmaceutical Co produces)
Patent documentation US 3780177 mentions in difluprednate preparation and makees solvent with dichloromethane/ether/petroleum ether and obtain the difluprednate crystallization, we repeat to have obtained the difluprednate crystal form II to this, its X-ray diffraction in 2 θ=6.1 °, there is absworption peak (as Fig. 2) position of 13.1 °, 15.4 °, 16.9 °
Chinese patent application CN98109772.3 discloses a kind of difluprednate (being difluprednate Emulsion) and discloses employing Semen Ricini wet goods fatty glyceride dissolving difluprednate, be prepared into again oil in water emulsion, in this patent application, employing is dissolved to difluprednate and is heated to we of 70 ℃ and finds to obtain in prior art the difluprednate crystal form II, when adopting the dissolving of Semen Ricini wet goods, even Oleum Ricini is heated to 65 ℃, and the stirring of lasting long period can not be dissolved the difluprednate of whole recipe quantities.In addition, decomposition to a certain degree can occur in difluprednate when temperature is higher, thereby has influence on the quality of preparation, and the Emulsion its related substances that makes is higher, and storage stability is relatively poor.
Summary of the invention
For overcoming the problems of the prior art, the invention provides a kind of better deliquescent difluprednate crystal formation I that shows in oil, and provide further that to adopt difluprednate crystal formation I be the difluprednate ophthalmic emulsion of raw material, Emulsion provided by the invention, owing to having adopted new difluprednate crystal formation I, can be dissolved in faster in the preparation in the oil or oil and emulsifying agent of lower temperature, and the Emulsion its related substances that obtains is lower.
The invention provides a kind of difluprednate Emulsion, contain difluprednate as active component, one or more oil, the emulsifying agent of one or more, and water, described difluprednate accounts for the 0.01-0.1% of Emulsion gross weight, oil accounts for the 1%-20% of Emulsion weight, described emulsifying agent accounts for the 1-10% of Emulsion gross weight, it is characterized in that the difluprednate that adopts during Emulsion in preparation is difluprednate crystal formation I, its X-ray powder diffraction has been located characteristic peak the angle of diffraction 2 θ=8.9 °, 11.6 °, 17.6 °.
The wavelength of described X-ray powder diffraction
Described difluprednate consumption preferably accounts for 0.05% of Emulsion gross weight
Described difluprednate Emulsion, its medium oil comprises fatty glyceride.Fatty glyceride is to be selected from Oleum Ricini, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, soybean oil, olive oil and MCT Oil (medium chain triglycerides, namely 6～12 carbon atoms form the triglyceride that the fatty acid of carbochains forms) in one or more, preferred Oleum Ricini.
Described difluprednate Emulsion is characterized in that described difluprednate is dissolved in oil or oil and emulsifying agent.
Described difluprednate Emulsion is characterized in that described difluprednate crystal formation I preparation method is as follows
Get the difluprednate crude drug and entirely be dissolved in acetonitrile, cooling after crystal, filtration, drying appear in reduction vaporization, obtain difluprednate crystal formation I,
Described difluprednate Emulsion, wherein emulsifying agent is non-ionic surface active agent.Be selected from one or more in polyoxyethylene hydrogenated Oleum Ricini and polyoxyethylene sorbitan fatty acid ester.
Wherein the polyoxyethylene sorbitan fatty acid ester be selected from polyoxyethylene 20 sorbitan monooleate (tween 80), polyoxyethylene 20 sorbitan monolaurate (tween 20), polyoxyethylene 20 sorbitan monopalmitate (Tween-40) and polyoxyethylene 20 sorbitan monostearate (Tween-60) in one or more.
Described difluprednate Emulsion, can also comprise buffer agent, described buffer agent is selected from, acetate such as sodium acetate etc., phosphate such as sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate etc., 6-aminocaprolc acid, amino acid salts such as sodium glutamate etc., boric acid and salt thereof, citric acid and salt thereof etc.
Described difluprednate Emulsion can also comprise quaternary amine such as benzalkonium chloride as antibacterial, benzethonium chloride etc.; Cationic compound such as gluconic acid hibitane etc.; Nipagin ester such as methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben etc.; Alcoholic compound such as chlorobutanol (β, β, β-chlorobutanol), Bian alcohol etc.; Peracetic acid sodium; Merthiolate; Sorbic acid etc.
Described difluprednate Emulsion can also comprise osmotic pressure regulator.Described osmotic pressure regulator is one or more in sodium chloride, glycerol, glucose, mannitol, sorbitol.
The osmotic pressure of described difluprednate Emulsion is 300～500mOsm/kg.
Described difluprednate Emulsion can also comprise additive, for example one or more in emulsion stabilizer, stabilizing agent, antioxidant, intercalating agent, pH adjusting agent, thickening agent.Described antioxidant includes but are not limited to ascorbic acid and salt, tocopherol, sodium thiosulfate, sodium sulfite, acetone acid and salt thereof etc.Intercalating agent includes but are not limited to EDTA-2Na, citric acid and salt thereof etc.PH adjusting agent includes but are not limited to hydrochloric acid, phosphoric acid, acetic acid, sulphuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, ammonia etc.Described emulsion stabilizer includes but are not limited to one or more in polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof.Described difluprednate Emulsion preferably prepares aqueous compositions such as becoming oil-in-water type (o/w) emulsion, microemulsion.
Described difluprednate Emulsion is a kind of oil-in-water emulsion.Can prepare becomes eye drop, nasal drop or [Dan and skin Emulsion.
The preferred 5-0.001 μ of the oil droplet mean diameter m of described difluprednate Emulsion better is preferably 1-0.001 μ m, most preferably is 0.5-0.01 μ m, more preferably 0.5-0.1 μ m.Can measure mean diameter with the instrument of measuring particle size distribution.
Described mean diameter is volume average particle size.
Described difluprednate Emulsion pH is selected from 3-8.4-7 more preferably.
The compound method of described difluprednate Emulsion can for: difluprednate crystal formation I is dissolved in oil or oil and emulsifying agent and is heated to lower than 50 ℃, be stirred to fully and dissolve.Additive is added to the water, uses pH adjusting agent, pH is transferred to 3-8, even in order to make emulsifying, can use known instrument such as high speed shear device, dispersing emulsification machine, high pressure homogenizer, homogenizer, micro fluid device, high-pressure homogenizer etc.
Described difluprednate Emulsion is preferably used as the preparation to eye, nose or ear topical, better preferably as eye drop, nasal drop or [Dan.The present composition has stronger antiinflammatory action and anti-allergic effects. and in addition, it is a large amount of difluprednates of defeated cloth preferably, and drug distribution is even, and sense of discomfort and foreign body sensation can make administration the time are minimized.In addition, giving low dose of this compositions just is enough to tell on, thereby can reduce side effect.Therefore it can be used for prevention and treats various inflammatory diseasess and anaphylactic disease, irritated victory conjunctivitis for example, and vernal conjunctivitis, blepharitis, catarrhal conjunctivitis, uveitis etc., and effective to eye, nose, ear topical.
Described difluprednate Emulsion can be used for mammal safely (as people, Canis familiaris L., rabbit, cattle, horse, monkey, cat, sheep, Deng), consumption is according to the difference of the kind of disease, symptom, patient's age body weight and change, because eye drop approximately contains 0.01-0.1% difluprednate Emulsion, when giving adult's medication, consumption preferred according to the state of an illness is that every eyes once drop to two, and the medication number of times is sky two to four times.By the more detailed description that embodiment and experimental example carry out the present invention, should not be considered as the present invention is limited.In below embodiment and experimental example, add approximately 2ml compositions to be determined, measure mean diameter (disperse medium: water, refractive index: 1.70-0.20i) with the Shimadzu SALD-2000 laser diffraction instrument of measuring particle size distribution.
The invention provides a kind of difluprednate Emulsion, difluprednate crystal formation I is dissolved in oil or oil and emulsifying agent, be prepared into Emulsion, compare with crystal formation I and marketable material medicine, the temperature that crystal formation I needs when dissolving is lower, and dissolution velocity is faster, and the Emulsion its related substances that obtains is lower.Stable content is better, more is conducive to the storage of long period.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of crystal formation I in crystallization embodiment 1
Fig. 2 is the X-ray powder diffraction figure of crystal form II in crystallization embodiment 1
The specific embodiment
Difluprednate marketable material medicine is available from Tianjin Medicine Institute Co., Ltd.
Crystal formation determining instrument: x-ray powder diffraction instrument, the wavelength of X-ray powder diffraction
Crystallization embodiment 1
The preparation of difluprednate crystal formation I
Get the 1kg difluprednate and be dissolved in the 2L acetonitrile, be heated to molten clearly, elimination insoluble matter, more slowly add 8L water adds fashionable wanting and slowly stirs while adding, and after finishing, filtration, drying, obtains difluprednate crystal K21.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=8.9 °, 11.6 °, 17.6 °, as shown in Figure 1.
The method that provides according to US in prior art 3780177, make solvent with dichloromethane/ether/petroleum ether and obtain the difluprednate crystal form II, carry out X-ray powder diffraction, in 2 θ=6.1 °, there is absworption peak the position of 13.1 °, 15.4 °, 16.9 °, as shown in Figure 2.
Each crystal formation of difluprednate produces the impurity contrast and contrasts in dissolution characteristics and course of dissolution in oil and oil and emulsifying agent
Get respectively crystal form II, crystal formation I, be placed in the mortar porphyrize, be dissolved in respectively the mixture of Oleum Ricini or Oleum Ricini and tween 80, oil temperature is initially 40 ℃, dissolves in stirring, after stirring 15min as can not dissolve fully, heat up 5 ℃ and continue to stir 15min, by that analogy.
Grouping and dissolving situation are as follows
Difluprednate Oleum Ricini solution after dissolving is detected its related substances, and compare with its related substances before dissolving
Its related substances sees the following form
| Raw material | Experimental group 1 | |
Experimental group 3 | Experimental group 4 |
| Its related substances % before dissolving | 1.03 | 0.99 | 1.03 | 0.99 |
| Its related substances % after dissolving | 1.07 | 1.83 | 1.04 | 1.96 |
Detect by solubility test and related substance and show, as the difluprednate crystal form II that exists in prior art, when dissolving with Oleum Ricini, being heated to 70 ℃ can not dissolve fully, dissolve fully and added emulsifier tween-after 80s also to need to be heated to 70 ℃ of ability, and crystal formation I solubilized when being heated to 40 ℃ with Oleum Ricini and emulsifiers dissolve the time, and during only with Oleum Ricini when being heated to 50 ℃ solubilized, and crystal formation I all can keep stable afterwards in dissolving.
FORMULATION EXAMPLE 1
Difluprednate 0.01g (crystal formation I)
Soybean oil 10.0g
Tween 80 5.0g
Glycerol 2.2g
6-aminocaprolc acid 0.1g
Methyl hydroxybenzoate 0.02g
Propylparaben 0.01g
Sodium hydroxide is regulated pH to 5.5, and it is 350mOsm/kg that sodium chloride is regulated osmotic pressure
Purified water is to 100ml
Purified water is heated to approximately 50 ℃, adds tween 80, glycerol, 6-aminocaprolc acid and Nipagin ester and dissolving, regulate pH to 5.5 with sodium hydroxide.Soybean oil is heated to 50 ℃ in addition, adds the difluprednate dissolving to obtain oil phase.Add oil phase to obtain colostrum when stirring water with uniform mixer.At last with colostrum through the high pressure dispersing emulsification machine, then degerming obtains Emulsion after filtration.Gained Emulsion oil droplet mean diameter is 0.11 μ m.
FORMULATION EXAMPLE 2
Difluprednate 0.1g (crystal formation I)
Oleum Ricini 10.0g
Tween 80 5.0g
Glycerol 2.2g
Sodium acetate 0.1g
Benzalkonium chloride 0.01g
It is 380mOsm/kg that salt acid for adjusting pH to 5.0 sodium chloride is regulated osmotic pressure
Purified water is to 100ml
Purified water is heated to approximately 50 ℃, adds glycerol, polyvinyl alcohol, sodium acetate and benzalkonium chloride and dissolving, with salt acid for adjusting pH to 5.0.In addition Oleum Ricini and tween 80 are mixed and heated to 40 ℃, add the difluprednate dissolving to obtain oil phase.Add oil phase to obtain colostrum when shearing water with clipper.At last colostrum is processed at high pressure homogenizer, then degerming obtains Emulsion after filtration.Gained Emulsion oil droplet mean diameter is 0.46 μ m.
FORMULATION EXAMPLE 3-1
Difluprednate 0.05g (crystal formation I)
Oleum Ricini 5.0g
Tween 80 4.0g
Glycerol 2.2g
Sodium acetate 0.05g
EDTA-2Na 0.02g
Boric acid 0.1g
Sorbic acid 0.1g
It is 320mOsm/kg that sodium hydroxide is regulated pH to 5.5 sodium chloride adjusting osmotic pressure
Purified water is to 100ml
Purified water is heated to approximately 50 ℃, add tween 80, glycerol,, sodium acetate, EDTA-2Na, boric acid, sorbic acid and dissolving, regulate pH to 5.5 with sodium hydroxide.Oleum Ricini is heated to 50 ℃ in addition, adds the difluprednate dissolving to obtain oil phase.Add oil phase to obtain colostrum when shearing water with clipper.At last colostrum is processed at high pressure homogenizer, then degerming obtains Emulsion after filtration.Gained Emulsion oil droplet mean diameter is 0.21 μ m.
FORMULATION EXAMPLE 3-2
Identical with FORMULATION EXAMPLE 3-1 formula, adopt crystal form II, difluprednate is dissolved in the mixture of Oleum Ricini and tween 80 and is heated to 70 ℃ and be stirred to dissolving fully.Other techniques are identical with FORMULATION EXAMPLE 3-1.Emulsion oil droplet mean diameter is 0.20 μ m
FORMULATION EXAMPLE 4
Difluprednate 0.05g (crystal formation I)
Oleum Ricini 5.0g
Tween 80 4.0g
Glycerol 2.2g
Polyvinyl alcohol 0.02g
Sodium acetate 0.05g
EDTA-2Na 0.02g
Boric acid 0.1g
Sorbic acid 0.1g
It is 320mOsm/kg that sodium hydroxide is regulated pH to 5.5 sodium chloride adjusting osmotic pressure
Purified water is to 100ml
Purified water is heated to approximately 50 ℃, adds tween 80, glycerol, polyvinyl alcohol, sodium acetate, EDTA-2Na, boric acid, sorbic acid and dissolving, regulate pH to 5.5 with sodium hydroxide.Oleum Ricini is heated to 50 ℃ in addition, adds the difluprednate dissolving to obtain oil phase.Add oil phase to obtain colostrum when shearing water with clipper.At last colostrum is processed at high pressure homogenizer, then degerming obtains Emulsion after filtration.Gained Emulsion oil droplet mean diameter is 0.26 μ m.
Pharmacology embodiment
Independent instillation difluprednate eye suspension and and after, compared the defeated cloth (the defeated cloth of ophthalmic) in the anterior chamber who advances the people rabbit between them
Difluprednate eye suspension is a kind of steroid reagent, known it the experimental uveitis of rabbit is had obvious inhibitory action.In this experiment, compared the defeated cloth (the defeated cloth of ophthalmic) that enters anterior chamber's difluprednate between difluprednate eye suspension and Emulsion provided by the invention, in order that improve the defeated cloth of ophthalmic of difluprednate.
(1) experimental group compound
1, suspension (in 100ml)
Fill a prescription as follows: difluprednate 0.1g, sodium acetate 0.1g, hydroxypropyl emthylcellulose 0.2g, sodium chloride 0.8g, benzethonium chloride 0.005g, salt acid for adjusting pH ester 5.0 adds purified water to 100ml.
Compound method:
Recipe quantity 80% purified water is heated to approximately 70 ℃, then adds people's hydroxypropyl emthylcellulose.After disperseing, mixture is cooled to approximately 30 ℃.Then, add people's sodium acetate and benzethonium chloride and dissolving. with hydrochloric acid, pH is transferred to 5.0, refilter sterilized mixture.Add people's difluprednate and make suspension fully. supply the purification water yield, so just obtain ophthalmic suspension.Difluprednate micropowder mean diameter is 4 μ m.
2, Emulsion 1, and FORMULATION EXAMPLE 3-1 obtains Emulsion
3, Emulsion 2, and FORMULATION EXAMPLE 3-2 obtains Emulsion
(2) laboratory animal is used heavily approximately 2kg, and eye is without the male Japanese albinism rabbit of disease, and male and female are not limit, 5 every group.
(3) experimental technique splashes into experimental group compound (50 μ L) in the laboratory animal eyes, after one hour, with pentobarbital, rabbit is killed.Use immediately the front eye portion of normal saline flushing after killing, take out aqueous humor.Be DFB (6 α, 9 α-two fluprednisolones-17-butyrate) because difluprednate 21 acetates in aqueous humor take off the esterification metabolism, measure DFB with the HPLC method, meter is made anterior chamber's difluprednate CI.
Chromatographic condition: chromatographic column, TSK gel ODS-80Ts; Mobile phase, 10mMNaH
2PO
4(pH7) acetonitrile=55/44 (volume ratio) flow velocity 1.3ml/min; Sample size, 50 μ L; Column temperature, 40 ℃; Detect wavelength, UV240nm.
Splash into separately the experimental group compound after one hour the DFB concentration of rabbit camera oculi anterior as shown in the table.(X±n，n＝10)
When difluprednate is made Emulsion provided by the invention, although the drug level of Emulsion is its half in suspension, but the amount of its defeated cloth of ophthalmic is more than 2 times of suspension than same dosage (50 μ L), has significant difference (P＜0.01).The above results shows Emulsion provided by the invention, even smaller dose also has the effect stronger than suspension.In addition, Emulsion provided by the invention is compared with the Emulsion and the commercially available Emulsion that adopt crystal form II and preparation, and the defeated cloth of ophthalmic is substantially consistent.
Therefore, Emulsion provided by the invention has stronger antiinflammatory action and anti-allergic effects.
Study on the stability is got Emulsion 1-2, is packed as the eye drop packing that 5ml/ props up, and carries out the accelerated stability test of 6 months, 40 ℃ of preservation conditions, and relative humidity 75% ± 5% keeps in Dark Place, and take initial difluprednate content as 100%, investigates stability
Table 2 difluprednate emulsion stability investigation result (content) (n=50,
)
Study on the stability shows, adopt the Emulsion of crystal formation I preparation, also being better than the crystal form II that adopts the prior art preparation on storage stability is the Emulsion of raw material preparation, the Emulsion that adopts difluprednate crystal formation I preparation is described, produce impurity except avoiding causing in the preparation medicine to decompose, also have better storage stability.
Claims (10)
1. difluprednate Emulsion, contain difluprednate as active component, one or more oil, the emulsifying agent of one or more, and water, described difluprednate accounts for the 0.01-0.1% of Emulsion gross weight, oil accounts for the 1%-20% of Emulsion weight, described emulsifying agent accounts for the 1-10% of Emulsion gross weight, it is characterized in that the difluprednate that adopts during Emulsion in preparation is difluprednate crystal formation I, its X-ray powder diffraction has been located characteristic peak the angle of diffraction 2 θ=8.9 °, 11.6 °, 17.6 °.
2. Emulsion as claimed in claim 1, is characterized in that described oil comprises fatty glyceride.
3. Emulsion as claimed in claim 2, is characterized in that described fatty glyceride is one or more that are selected from Oleum Ricini, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, soybean oil, olive oil and MCT Oil.
4. Emulsion as claimed in claim 1, is characterized in that described Emulsion is a kind of oil-in-water emulsion.
5. Emulsion as claimed in claim 1, is characterized in that, also comprises buffer agent, and described buffer agent is selected from acetate, phosphate, 6-aminocaprolc acid, amino acid salts, boric acid and salt thereof, one or more in citric acid and salt thereof.
6. Emulsion as claimed in claim 1, is characterized in that described Emulsion, also comprises the quaternary amine as antibacterial, cationic compound, Nipagin ester, alcoholic compound, one or more in peracetic acid sodium, merthiolate, sorbic acid.
7. Emulsion as claimed in claim 1, is characterized in that described Emulsion, also comprises osmotic pressure regulator.
8. Emulsion as claimed in claim 1, is characterized in that described Emulsion, also comprises one or more in emulsion stabilizer, stabilizing agent, antioxidant, intercalating agent, pH adjusting agent, thickening agent.
9. described Emulsion as arbitrary in claim 1-8, the oil droplet mean diameter that it is characterized in that described Emulsion is 5-0.0001 μ m.
10. Emulsion as claimed in claim 1, is characterized in that described Emulsion pH is selected from 3-8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392060.9A CN103126983B (en) | 2011-11-30 | 2011-11-30 | Emulsion prepared by Difluprednate crystal form I |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392060.9A CN103126983B (en) | 2011-11-30 | 2011-11-30 | Emulsion prepared by Difluprednate crystal form I |
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| CN103126983A true CN103126983A (en) | 2013-06-05 |
| CN103126983B CN103126983B (en) | 2016-02-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663141A (en) * | 2016-03-24 | 2016-06-15 | 北京茗泽中和药物研究有限公司 | Ophthalmic emulsion with difluprednate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3780177A (en) * | 1967-06-16 | 1973-12-18 | Warner Lambert Co | 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use |
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
-
2011
- 2011-11-30 CN CN201110392060.9A patent/CN103126983B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3780177A (en) * | 1967-06-16 | 1973-12-18 | Warner Lambert Co | 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use |
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
Non-Patent Citations (1)
| Title |
|---|
| MASAZUMI YAMAGUCHI, ET AL.: ""Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663141A (en) * | 2016-03-24 | 2016-06-15 | 北京茗泽中和药物研究有限公司 | Ophthalmic emulsion with difluprednate |
| CN105663141B (en) * | 2016-03-24 | 2018-06-15 | 北京茗泽中和药物研究有限公司 | Difluprednate ophthalmic emulsion |
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| Publication number | Publication date |
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| CN103126983B (en) | 2016-02-03 |
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