CN103126984A - Difluprednate emulsion - Google Patents
Difluprednate emulsion Download PDFInfo
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- CN103126984A CN103126984A CN2011103921029A CN201110392102A CN103126984A CN 103126984 A CN103126984 A CN 103126984A CN 2011103921029 A CN2011103921029 A CN 2011103921029A CN 201110392102 A CN201110392102 A CN 201110392102A CN 103126984 A CN103126984 A CN 103126984A
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- emulsion
- difluprednate
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Abstract
A difluprednate emulsion comprises 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 difluprednate, 1% to 20% of oil, and 1% to 10% of emulgator. The difluprednate dissolves in the oil and the emulgator.
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, Japanese Tanabe Mitsubishi Pharmaceutical Co produces).
As the steroidal 17-hydroxy-11-dehydrocorticosterone that is insoluble in water, when being used for the treatment of eye inflammation, preparation becomes the eye drop of suspensoid form mostly, a kind of Fluor-Op is disclosed as Chinese patent CN99802317.5, adopt hydroxypropyl emthylcellulose as suspending agent, and added non-ionic surface active agent to promote the dispersion of drug microparticles.yet when adopting this suspensoid technique to prepare the difluprednate eye to use suspensoid, we find owing to limit by existing micropowder technology, in suspension, active component micropowder mean diameter is only 1-10 μ m left and right, exist in use foreign body sensation and granular sensation, poor compliance, in addition, we find, when adopting suspensoid to be, it is relatively poor that the preparation that obtains enters the defeated cloth (the defeated cloth of ophthalmic) of anterior chamber's difluprednate, thereby cause the bioavailability of medicine, for reaching same curative effect, to have to adopt higher drug level, thereby increased the probability that has side effects.
Summary of the invention
For overcoming the problems of the prior art, the invention provides a kind of difluprednate Emulsion, difluprednate is dissolved in oil and emulsifying agent, be prepared into Emulsion, can obtain the emulsion droplet particle diameter less, compliance is better, the better preparation of the defeated cloth of ophthalmic.
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, and described difluprednate is dissolved in oil and emulsifying agent.
Described difluprednate consumption preferably accounts for 0.05% of Emulsion 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, 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.
Described difluprednate Emulsion is a kind of oil-in-water emulsion.Can prepare becomes eye drop, nasal drop or [Dan and skin Emulsion.
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, 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; 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 the quaternary amine as antibacterial, cationic compound, Nipagin ester, alcoholic compound, one or more in peracetic acid sodium, merthiolate, sorbic acid.Quaternary amine such as benzalkonium chloride, 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.
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 preferably 300～500mOsm/kg.
Described difluprednate Emulsion can also comprise additive, for example one or more in 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 difluprednate Emulsion preferably prepares aqueous compositions such as becoming oil-in-water type (o/w) emulsion, microemulsion.
The preferred 5-0.0001 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 is: additive is added to the water, with pH adjusting agent, pH is transferred to 3-8, adding oil and the emulsifying agent that has dissolved active component.In order to make emulsifying even, 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.
when preparation Emulsion, we find, difluprednate dissolubility in oil is lower, even be heated to 70 ℃, the principal agent of recipe quantity also can't all be dissolved in the oil of recipe quantity, for this reason, the invention provides a kind of difluprednate Emulsion, improved preparation technology, difluprednate is dissolved in oil and emulsifying agent, be prepared into Emulsion, and the preferred osmotic pressure of Emulsion, compare with suspensoid, the emulsion droplet particle diameter of Emulsion is less, compliance is better in use, and embodiment shows according to pharmacology, the defeated cloth of the ophthalmic of Emulsion is better than existing mixed suspension form far away, adopt Emulsion to realize the defeated cloth of better ophthalmic with less active component content, thereby can reduce the concentration of effective ingredient, the side effect of avoiding glucocorticoid to bring.
The specific embodiment
The difluprednate crude drug is available from Tianjin Medicine Institute Co., Ltd.
The principal agent solubility experiment
Respectively the difluprednate micropowder is dissolved in different oil, is heated to 70 ℃, after stirring 30min, difluprednate all can not dissolve fully, illustrates that difluprednate dissolubility in oil is lower, can't directly be dissolved in oil and prepare Emulsion, and the grouping situation is as follows
| Experimental group 1 | Experimental group 2 | Experimental group 3 | Experimental group 4 | |
| Crude drug/g | 0.1 | 0.5 | 0.1 | 0.5 |
| Oleum Ricini/g | 100 | 50 | ||
| Soybean oil/g | 50 | 100 |
Embodiment 1
Difluprednate 0.01g
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 70 ℃, and glycerol, 6-aminocaprolc acid and Nipagin ester and dissolving are regulated pH to 5.5 with sodium hydroxide.In addition soybean oil and tween 80 are mixed and heated to 70 ℃, add 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 0.48 μ m.
Embodiment 2
Difluprednate 0.05g
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 70 ℃, adds glycerol, 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 70, add 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 0.12 μ m.
Embodiment 3
Difluprednate 0.05g
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 70 ℃, adds glycerol, sodium acetate, EDTA-2Na, boric acid, sorbic acid and dissolving, regulate pH to 5.5 with sodium hydroxide.In addition Oleum Ricini and tween 80 are mixed and heated to 70 ℃, 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, filtration sterilization obtains Emulsion.Gained Emulsion oil droplet mean diameter is 0.18 μ m.
Pharmacology embodiment
After independent instillation difluprednate eye suspension and the present composition, 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 aseptic powder 0.1g, sodium acetate 0.1g, hydroxypropyl emthylcellulose 0.2g, sodium chloride 0.8g, benzethonium chloride 0.005g, salt acid for adjusting pH to 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, filtration sterilization.Add people's difluprednate aseptic powder and make suspension fully. supply the purification water yield, so just obtain the eye suspension.Difluprednate micropowder mean diameter is 4 μ m.
2, Emulsion is the Emulsion of peace according to embodiment 3 method preparations.The emulsion droplet mean diameter is 0.24 μ m.
(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.
Therefore, Emulsion provided by the invention has stronger antiinflammatory action and anti-allergic effects.
In addition, Emulsion provided by the invention is compared with the conventional formulation that contains difluprednate, and it can be distributed to the injury preferably, and drug distribution is even during administration, like this, as long as smaller dose it just can bring into play enough effects.And compare with conventional formulations such as suspensoids, when also having administration without sense of discomfort, the better characteristics of compliance, easier of topicals such as eye, nose, ears.
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, and described difluprednate is dissolved in oil and/or emulsifying agent.
2. Emulsion as claimed in claim 1, is characterized in that described grease separation is from Oleum Ricini.
3. Emulsion as claimed in claim 1, is characterized in that described Emulsion is a kind of oil-in-water emulsion.
4. Emulsion as claimed in claim 1, is characterized in that described emulsifying agent is selected from one or more in tween 80, Tween-60, Tween-40, tween 20.
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, citric acid and salt thereof.
6. Emulsion as claimed in claim 1, is characterized in that described Emulsion, also comprises osmotic pressure regulator, and described osmotic pressure regulator is selected from one or more in sodium chloride, glycerol, glucose, mannitol, sorbitol.
7. 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.
8. Emulsion as claimed in claim 7, the oil droplet mean diameter that it is characterized in that described Emulsion is 1-0.001 μ m.
9. Emulsion as claimed in claim 8, the oil droplet mean diameter that it is characterized in that described Emulsion is 0.5-0.01 μ m.
10. Emulsion as claimed in claim 1, is characterized in that described Emulsion pH is selected from 3-8.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011103921029A CN103126984A (en) | 2011-11-30 | 2011-11-30 | Difluprednate emulsion |
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| CN2011103921029A CN103126984A (en) | 2011-11-30 | 2011-11-30 | Difluprednate emulsion |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103364502A (en) * | 2013-07-04 | 2013-10-23 | 山东省医药工业研究所 | High performance liquid chromatography (HPLC) determination method for related substances in difluprednate |
| CN105213310A (en) * | 2015-10-16 | 2016-01-06 | 广州仁恒医药科技有限公司 | A kind of pharmaceutical composition containing difluprednate and preparation method thereof |
| CN105496955A (en) * | 2015-12-11 | 2016-04-20 | 北京蓝丹医药科技有限公司 | Difluprednate ophthalmic emulsion and preparation method thereof |
| 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 |
-
2011
- 2011-11-30 CN CN2011103921029A patent/CN103126984A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| INTERNATIONAL JOURNAL OF PHARMACEUTICS: "Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103364502A (en) * | 2013-07-04 | 2013-10-23 | 山东省医药工业研究所 | High performance liquid chromatography (HPLC) determination method for related substances in difluprednate |
| CN103364502B (en) * | 2013-07-04 | 2015-04-22 | 山东省医药工业研究所 | High performance liquid chromatography (HPLC) determination method for related substances in difluprednate |
| CN105213310A (en) * | 2015-10-16 | 2016-01-06 | 广州仁恒医药科技有限公司 | A kind of pharmaceutical composition containing difluprednate and preparation method thereof |
| CN105496955A (en) * | 2015-12-11 | 2016-04-20 | 北京蓝丹医药科技有限公司 | Difluprednate ophthalmic emulsion and preparation method thereof |
| 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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Application publication date: 20130605 Assignee: Tianjin Pharmaceutical Industry Group Corp., Ltd. Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2015120000051 Denomination of invention: Difluprednate emulsion License type: Common License Record date: 20150916 Application publication date: 20130605 Assignee: Pharmaceutical Co., Ltd. Tianjin Jin Yao Assignor: Tianjin Pharmaceutical Industry Group Corp., Ltd. Contract record no.: 2015120000070 Denomination of invention: Difluprednate emulsion License type: Fen Xuke Record date: 20150929 |
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Application publication date: 20130605 |