CN103127139A - Difluprednate topical external preparation - Google Patents
Difluprednate topical external preparation Download PDFInfo
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- CN103127139A CN103127139A CN2011103921048A CN201110392104A CN103127139A CN 103127139 A CN103127139 A CN 103127139A CN 2011103921048 A CN2011103921048 A CN 2011103921048A CN 201110392104 A CN201110392104 A CN 201110392104A CN 103127139 A CN103127139 A CN 103127139A
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Abstract
Difluprednate topical external preparation comprises difluprednate micro powder used as active ingredients and one type or multiple types of pharmaceutic adjuvants, wherein the pharmaceutic adjuvants comprise water. The difluprednate topical external preparation is characterized in that the difluprednate micro powder is scattered in the pharmaceutic adjuvants in a suspended mode, the difluprednate is difluprednate crystal form I, and 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 local topical preparation, especially relate to a kind of difluprednate local topical preparation.
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 emulsifiable paste (trade name: MYSER, Japan Tanabe Mitsubishi Pharmaceutical Co produces), the adjuvant that discloses its use in the description (http://di.mt-pharma.co.jp/file/if/f_mys.pdf) of difluprednate emulsifiable paste is, propylene glycol, cera alba, Myrj 45, this emulsifiable paste is the suspension type emulsifiable paste, crude drug is dispersed in emulsifiable paste matrix with the micropowder form.
Through overtesting, we find, commercially available difluprednate emulsifiable paste, and the emulsifiable paste that adopts existing difluprednate crude drug preparation along with the storage of emulsifiable paste, originally were the difluprednate micropowder of suspended particles distributions in mastic and agglomeration occurred.Thereby the particle diameter that makes drug powder becomes large, although present drug standard is not made stipulations to this situation of ointment, we test discovery, have influence on curative effect thereby the change of drug powder particle diameter greatly directly has influence on the bioavailability of medicine.
Summary of the invention
For overcoming the problems of the prior art, the invention provides a kind of new difluprednate crystal formation I, and further provide a kind of contain difluprednate crystal formation I micropowder with suspension be scattered in adjuvant aqueous compositions, difluprednate preparation provided by the invention, even store under the room temperature environment that colds and heat succeed each other, also can avoid the reunion of micropowder, thereby keep higher bioavailability.Stable content when storing simultaneously is also better
The invention provides a kind of difluprednate preparation, contain difluprednate micropowder and one or more pharmaceutic adjuvants that comprise water as active component, it is characterized in that described difluprednate micropowder is scattered in pharmaceutic adjuvant with suspension, difluprednate is crystal formation I, and its X-ray powder diffraction has characteristic peak at the angle of diffraction 2 θ=8.9,11.6,17.6 places.
The wavelength of described X-ray powder diffraction
Described difluprednate preparation contains the difluprednate as active component of 0.01-0.1%, preferably contains 0.05% difluprednate.
Described difluprednate preparation, preferred preparation becomes ointment, gel, suspensoid.
Described difluprednate preparation, make ointment, by the difluprednate crystal formation I micropowder as active component, consist of as the pharmaceutically useful adjuvants such as water of solid, consistency modifiers, wetting agent, emulsifying agent, pH buffer agent, antiseptic and the surplus of oil-phase component.
The solid 3%～20% that contains oil-phase component in described ointment is selected from one or more in higher alcohol (monohydric alcohol of 16-22 carbon atom), and described higher alcohol selects excellent hexadecanol and/or octadecanol;
Contain consistency modifiers 5%～20% in described ointment.Be selected from one or more in vaseline, liquid paraffin, vegetable oil.
Contain wetting agent 3%～10% in described ointment, be selected from multicomponent alcoholics compound, be glycerol and/or propylene glycol;
Contain emulsifying agent 1-10% in described ointment, optional selfpolyoxyethylene fatty alcohol ether is peregal A-20;
Contain antiseptic 0.01-0.2% in described ointment, be selected from parabens (p-Hydroxybenzoate) antiseptic, preferred ethyl hydroxybenzoate,
Described pH adjusting agent optimization citric acid/sodium citrate buffer agent;
Can also add stabilizing agent in described emulsifiable paste, the consumption of stabilizing agent is 0.05%～0.3%; Preferred but be not limited only to Calcium Disodium Versenate.
Ointment provided by the invention, its formula optimization is comprised of the raw material of following percentage by weight: difluprednate crystal formation I0.05%, white vaseline 3-10%, octadecanol 3-10%, liquid paraffin 3-10%, peregal A-20 1%～5%, glycerol 1-5%, propylene glycol 1-5%, ethyl hydroxybenzoate 0.1%, citric acid and sodium citrate amount to 0.2-1%, and surplus is water, citric acid (C
6H
8O
7H
2O) with sodium citrate (Na
3C
6H
5O
72H
2O) weight ratio is 1: 0.5～1: 1.5.
The citric acid that uses in technical solution of the present invention is C
6H
8O
7H
2O, sodium citrate Na
3C
6H
5O
72H
2O
Percentage ratio in technical solution of the present invention is the percentage by weight that accounts for emulsifiable paste weight.
Described higher alcohol also plays the effect of surfactant simultaneously in emulsifiable paste.
The compound method that the invention provides a kind of difluprednate emulsifiable paste is as follows:
(1) oil phase preparation: get solid, consistency modifiers, the emulsifying agent heating and melting of oil-phase component, temperature remains on 70-90 ℃;
(2) water preparation: the water that will regulate pH value mixes, heating, and the temperature that stirs remains on 70-90 ℃; Add antiseptic and stirring and dissolving
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stirs, maintain the temperature at 70-90 ℃, stir 10-30min, obtain substrate be cooled to 45-50 ℃ standby
(4) difluprednate micropowder water is uniformly dispersed, adding stirs in substrate is cooled to cream.
Described difluprednate preparation when making suspensoid, contains difluprednate crystal formation I micropowder and water as active component.
Described suspensoid also contains one or more in suspending agent, buffer agent, antibiotic antiseptic, osmotic pressure regulator.
Described suspending agent includes but are not limited to a kind of in polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof.
Described buffer agent includes but are not limited to 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 antibiotic antiseptic comprises one or more in quaternary amine, cationic compound, Nipagin ester, alcoholic compound, peracetic acid sodium, merthiolate, sorbic acid.Described 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 osmotic pressure regulator includes but are not limited to one or more in sodium chloride, glycerol, glucose, mannitol, sorbitol.
Described difluprednate preparation when making gel, contains difluprednate crystal formation I micropowder, water and gellant as active component.
Described gel is characterized in that described gellant includes but are not limited to carbomer, deacetylation gellan gum, carrageenan, xanthan gum, tragakanta, gelatin, carbopol, sodium alginate, cellulose derivative, poloxamer188, PLURONICS F87, polyethylene glycol-polylactic acid block copolymer (PEG-PLGA); One or more in NIPA (NiPAAM) copolymer or xylan.
Described cellulose derivative includes but are not limited to a kind of in hydroxyethyl-cellulose, ethylhydroxyethylcellulose hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof.
Described gel is characterized in that also comprising one or more in wetting agent, antibiotic antiseptic, emulsifying agent, pH adjusting agent.
Described wetting agent is selected from multicomponent alcoholics compound, preferably glycerine and/or propylene glycol.
Described antibiotic antiseptic comprises one or more in quaternary amine, cationic compound, Nipagin ester, alcoholic compound, peracetic acid sodium, merthiolate, sorbic acid.Described 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 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 polyoxyethylene sorbitan fatty acid ester be selected from polyoxyethylene sorbitan monooleate dehydration (tween 80), polyoxyethylene sorbitan monolaurate (tween 20), polyethenoxy sorbitan monopalmitate (Tween-40) and polyethenoxy sorbitan monostearate (Tween-60) in one or more.
Described pH adjusting agent includes but are not limited in 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 and sodium hydroxide, carbonic acid, sodium bicarbonate, hydrochloric acid, acetic acid etc.
In technical scheme provided by the invention, described percentage ratio all is weight percentage.
Difluprednate preparation provided by the invention is as the preparation of topical treatment, as the preparation to skin, eye, nose or ear topical, preferably as the percutaneous drug delivery preparation.
The difluprednate preparation of the preparation take difluprednate crystal formation I micropowder as raw material provided by the invention and the difluprednate preparation that adopts commercially available difluprednate raw material to prepare are compared, when storage, the difluprednate micropowder that is suspended in drug matrices is not easy to reunite, the drug powder granule of having avoided storage to cause becomes large, thereby avoided the Transdermal absorption characteristic of medicine to descend, thereby avoided affecting the curative effect of medicine.
Detecting instrument: Japanese Shimadzu LC-IOA high performance liquid chromatograph; The SPD-10A UV-detector
Description of drawings
Accompanying drawing 1 is that the X-ray diffraction of crystal formation I in raw material preparation example 1 absorbs figure
Accompanying drawing 2 is that the X-ray diffraction of difluprednate crude drug commercially available in raw material preparation example 1 absorbs figure
Accompanying drawing 3 is that the X-ray diffraction of the crude drug in commercially available difluprednate emulsifiable paste in raw material preparation example 1 absorbs figure
The specific embodiment
The below will the invention will be further described by embodiment, and these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, within still belonging to protection scope of the present invention.
Commercially available difluprednate crude drug is available from Tianjin Medicine Institute Co., Ltd.
Commercially available difluprednate emulsifiable paste, content 0.05%, trade name: MYSER is available from Japanese Tanabe Mitsubishi Pharmaceutical Co
The PAP that the emulsifiable paste that all embodiment make all props up with 10g/ divides and packages spare.Difluprednate used is the micropowder of mean diameter 5-10 μ m, and described mean diameter is volume average particle size.
The wavelength of X-ray powder diffraction
The preparation of raw material preparation example 1 crystal formation I
Get the 10g difluprednate and be dissolved in the 20mL acetonitrile, be heated to molten clear, the elimination insoluble matter, cooling after crystal, filtration, drying appear in reduction vaporization then, obtain difluprednate crystal formation I.
Crystal after drying is carried out X-ray powder diffraction measure, record characteristic peak positions and be 2 θ=8.9 °, 11.6 °, 17.6 °, as shown in Figure 1.
Get commercially available difluprednate crude drug and carry out X-ray powder diffraction and measure, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.As shown in Figure 2.
Get commercially available Diflucortolone valerate ointment, heating and filtering obtains its Raw micropowder, mensuration X-ray powder diffraction 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, as shown in Figure 3, illustrate that the crude drug that commercially available difluprednate emulsifiable paste adopts is identical with commercially available difluprednate raw material crystal formation.
Embodiment 1-1
Difluprednate 0.5g (crystal formation I), white vaseline 100g, octadecanol 30g, liquid paraffin 30g,
Peregal A-2050g, glycerol 50g, propylene glycol 20g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 3g,
Sodium citrate (Na
3C
6H
5O
72H
2O) 6g water for injection adds to 1000g, difluprednate crystal form II micropowder mean diameter 8.2 μ m
By above proportioning accurate weighing, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation: get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 90 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in water for injection, principal agent is dispersed in glycerol, propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 80 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.05%.
Embodiment 1-2
According to the composition and engineering of embodiment 1-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.1 μ m
Embodiment 2-1
Difluprednate 0.5g (crystal formation I), white vaseline 30g, octadecanol 100g, liquid paraffin 100g, peregal A-20 10g, glycerol 10g, propylene glycol 50g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 4g, sodium citrate (Na
3C
6H
5O
72H
2O) 6g water for injection is to 1000g difluprednate crystal form II micropowder mean diameter 8.5 μ m
By above proportioning accurate weighing, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in water for injection, principal agent is dispersed in glycerol, propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 90 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.05%.
Embodiment 2-2
According to the composition and engineering of embodiment 2-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.4 μ m
Embodiment 3-1
Difluprednate 0.5g (crystal formation I), white vaseline 30g, octadecanol 100g, liquid paraffin 30g,
Peregal A-20 30g, glycerol 50g, propylene glycol 50g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 0.2g,
Sodium citrate (Na
3C
6H
5O
72H
2O) 0.4g
Water for injection is to 1000g difluprednate crystal form II micropowder mean diameter 7.5 μ m
By above proportioning accurate weighing, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 85 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 80 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.05%.
Embodiment 3-2
According to the composition and engineering of embodiment 3-1, adopt commercially available difluprednate raw material micropowder, mean diameter 7.7 μ m
Embodiment 4-1
Difluprednate crystal formation 0.1g (crystal formation I), white vaseline 100g, octadecanol 60g, liquid paraffin 100g,
Peregal A-2010g, glycerol 10g, propylene glycol 10g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 3g,
Sodium citrate (Na
3C
6H
5O
72H
2O) 5g water for injection is to 1000g difluprednate crystal form II micropowder mean diameter 7.7 μ m
By above proportioning accurate weighing, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation: get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 75 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.01%.
Embodiment 4-2
According to the composition and engineering of embodiment 4-1, adopt commercially available difluprednate raw material micropowder, mean diameter 7.3 μ m
Embodiment 5-1
Difluprednate 1g (crystal formation I), white vaseline 150g, octadecanol 30g, liquid paraffin 80g,
Peregal A-20 80g, glycerol 80g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 2g,
Sodium citrate (Na
3C
6H
5O
72H
2O) 3g water for injection is to 1000g difluprednate crystal form II micropowder mean diameter 8.1 μ m
By above proportioning accurate weighing, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 90 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 90 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.1%.
Embodiment 5-2
According to the composition and engineering of embodiment 5-1, adopt difluprednate crystal form II micropowder, mean diameter 7.9 μ m
Embodiment 5-3
According to the composition and engineering of embodiment 5-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.2 μ m
Embodiment 6-1
Difluprednate 0.2g (crystal formation I), white vaseline 30g, hexadecanol 150g, liquid paraffin 30g, peregal A-20 10g, propylene glycol 30g, citric acid (C
6H
8O
7H
2O) 2.5g, sodium citrate (Na
3C
6H
5O
72H
2O) 5g water for injection is to 1000g difluprednate crystal form II micropowder mean diameter 7.9 μ m
By above proportioning accurate weighing,, the emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 is placed in container, is heated to melting, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase of step (2) preparation, stir, maintain the temperature at 70 ℃, stir 15min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.02%.
Embodiment 6-2
According to the composition and engineering of embodiment 6-1, adopt difluprednate crystal form II micropowder, mean diameter 7.9 μ m
Embodiment 6-3
According to the composition and engineering of embodiment 6-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.0 μ m
The preparation of embodiment 7-1 gel
Difluprednate (crystal formation I) 1g mean diameter 8.9 μ m, Acritamer 940 2g, glycerol 50g, tween 80 2g
Benzalkonium chloride 1g distilled water adds to 1000ml
0.1M sodium hydroxide solution is transferred pH to 5.5
Carbomer is mixed with tween 80, benzalkonium chloride and 300ml distilled water, be heated to 50-60 ℃, the difluprednate micropowder adds gradually after with aqueous dispersion and stirs evenly, use, and the 0.1M sodium hydroxide solution is transferred pH to 5.5, and the water of supplying surplus stirs evenly and namely gets clear gel.
Embodiment 7-2
According to the composition and engineering of embodiment 7-1, adopt difluprednate crystal form II micropowder, mean diameter 8.6 μ m
Embodiment 7-3
According to the composition and engineering of embodiment 7-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.7 μ m
The preparation of embodiment 8-1 gel
The preparation of gel
Difluprednate (crystal formation I) 1g mean diameter 6.8 μ m, carbomer 934 5g, glycerol 50g, tween 80 5g
Benzalkonium chloride 1g sodium hydroxide 4g distilled water adds to 1000g
Carbomer is mixed with tween 80, benzalkonium chloride and 300ml distilled water, be heated to 50-60 ℃, the difluprednate micropowder adds gradually after with aqueous dispersion and stirs evenly, use, and the 0.1M sodium hydroxide solution is transferred pH to 5.5, and the water of supplying surplus stirs evenly and namely gets clear gel.
Embodiment 8-2
According to the composition and engineering of embodiment 8-1, adopt commercially available difluprednate raw material micropowder, mean diameter 6.7 μ m
Embodiment 9-1 suspensoid
Fill a prescription as follows: difluprednate (crystal formation I) 1g, sodium acetate 1g, hydroxypropyl emthylcellulose 2g, sodium chloride 8g, benzethonium chloride 0.05g, salt acid for adjusting pH to 5.0 adds purified water to 1000ml.
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 5.2 μ m.
Embodiment 9-2
According to the composition and engineering of embodiment 9-1, adopt commercially available difluprednate raw material micropowder, mean diameter 5.7 μ m
Pharmacology embodiment
Adopt the preparation of the difluprednate preparation of different crystal forms, store 3 months under hot and humid condition, storage condition is relative humidity 75% ± 5%, 40 ℃ ± 5 ℃ of temperature.It will be the routine packing that 10g/ props up according to the drugs packaging of embodiment method preparation.The variation of transdermal test in vitro assimilation effect before and after detection of stored
After getting the healthy rat anesthesia execution of 3 monthly ages, eliminate belly wool with shears, take off undamaged skin, remove subcutaneous tissue, be individually fixed in the liberation port of Franz diffusion cell after cleaning, add pH7.4 phosphate buffer (PBS liquid) to make release medium in receiving chamber, keep endodermis and solution close contact.The suspension group is got the 0.2ml medicinal liquid and is coated on skin, and emulsifiable paste and gel component not precision measure sample 0.200g, evenly coats on test skin, and the release area is 2.5cm
2Regulate water-bath and make outer jacket layer temperature constant in (37 ± 1) ℃, mixing speed is 100rpm,, precision takes different emulsifiable paste sample 1.000g respectively, evenly coats on test skin.Drew release medium 4ml in 2 hours, determine concentration C i with the method for Chinese Pharmacopoeia version in 2010, and calculate 24h accumulation infiltration capacity and calculate 24h cumulative release permeability,
Following table has shown the 24h cumulative release permeability that preparation detects in different storing time intervals
| Numbering | 1-1 | 1-2 | 1-3 | 2-1 | 2-2 | 2-3 | 3-1 | 3-2 | 3-3 | 4-1 | 4-2 | 4-3 | 5-1 |
| 0 month % | 17.5 | 17.5 | 17.6 | 18.1 | 17.9 | 18.0 | 17.3 | 16.9 | 17.5 | 19.2 | 18.9 | 19.0 | 18.1 |
| 3 months % | 17.4 | 13.2 | 14.1 | 18.0 | 13.9 | 14.5 | 17.3 | 13.2 | 13.5 | 19.0 | 15.2 | 15.6 | 18.0 |
| Numbering | 5-2 | 5-3 | 6-1 | 6-2 | 6-3 | 7-1 | 7-2 | 7-3 | 8-1 | 8-2 | 8-3 | 9-1 | 9-2 |
| 0 month % | 18.3 | 18.5 | 17.9 | 17.8 | 18.0 | 16.9 | 17.1 | 17.0 | 17.3 | 17.5 | 17.4 | 14.5 | 14.3 |
| 3 months % | 14.6 | 15.0 | 18.0 | 14.2 | 14.6 | 16.8 | 13.5 | 13.8 | 17.2 | 14.6 | 15.1 | 14.4 | 11.1 |
Can draw from upper table, after the storage of 3 months, adopt the cumulative release permeability of the preparation of difluprednate crystal formation I preparation to prepare and adopt the embodiment sample of crystal form II preparation apparently higher than the employing marketable material.
Particle diameter detects, get respectively each 10, the sample of embodiment 1-1～9-2,0 month and store 3 months by above-mentioned condition after survey respectively the volume average particle size of difluprednate micropowder, separately get 10 market milk paste formulations (namely " commercially available " organized), test equally, result following (
N=10, the μ m of unit)
| Numbering | 1-1 | 1-2 | 2-1 | 2-2 | 3-1 | 3-2 | 4-1 | 4-2 | 5-1 | 5-2 |
| 0 month % | 8.2±1.3 | 7.8±1.2 | 8.5±1.0 | 8.6±0.9 | 7.5±0.9 | 7.6±1.0 | 7.7±1.2 | 7.6±1.1 | 8.7±1.0 | 7.9±1.1 |
| 3 months % | 9.4±1.5 | 33.6±2.4 | 9.0±1.1 | 36.9±2.4 | 8.3±1.5 | 38.2±2.0 | 9.0±1.2 | 35.2±2.5 | 10.0±1.4 | 34.6±3.1 |
| Numbering | 6-1 | 6-2 | 7-1 | 7-2 | 8-1 | 8-2 | 9-1 | 9-2 | Commercially available | |
| 0 month % | 7.9±1.5 | 7.9±1.2 | 8.9±1.2 | 8.6±1.0 | 6.8±0.8 | 7.0±1.0 | 5.2±0.8 | 5.6±0.7 | 13.7±0.7 | |
| 3 months % | 9.0±1.3 | 34.2±3.1 | 9.9±1.2 | 48.8±2.8 | 7.2±1.0 | 44.6±2.6 | 6.4±0.9 | 51.1±3.5 | 57.2±4.2 |
Particle diameter detects and shows, adopt each experimental group of difluprednate crystal formation I, active component micropowder in pharmaceutical preparation is after through the storage of 3 months, particle diameter does not obviously increase, and the preparation of employing marketable material micropowder preparation and commercially available difluprednate emulsifiable paste, agglomeration has appearred in the active component micropowder after storage, and significant increase (P＜0.01) has appearred in particle diameter.
Test by Transdermal Absorption, compare with the preparation that adopts the marketable material preparation, after the medicine process stored, drug powder can not produce reunion, so the Transdermal absorption performance of medicine can not descend yet due to the preparation that adopts difluprednate crystal formation I preparation.
Claims (10)
1. difluprednate preparation, contain difluprednate micropowder and one or more pharmaceutic adjuvants that comprise water as active component, it is characterized in that described difluprednate micropowder is scattered in pharmaceutic adjuvant with suspension, difluprednate is crystal formation I, and its X-ray powder diffraction has characteristic peak at the angle of diffraction 2 θ=8.9,11.6,17.6 places.
2. difluprednate preparation as claimed in claim 1 is characterized in that containing the difluprednate as active component of 0.01-0.1%.
3. difluprednate as claimed in claim 1, its feature contains 0.05% difluprednate.
4. described difluprednate preparation as arbitrary in claim 1-3, preparation becomes ointment, gel, suspensoid.
5. difluprednate preparation as claimed in claim 4, it is characterized in that making ointment, by the difluprednate crystal formation I micropowder as active component, consist of as the pharmaceutically useful adjuvants such as water of solid, consistency modifiers, wetting agent, emulsifying agent, pH buffer agent, antiseptic and the surplus of oil-phase component.
6. difluprednate preparation as claimed in claim 5, is characterized in that described ointment contains the solid 3%～20% of oil-phase component, contains consistency modifiers 5%～20%, contains wetting agent 3%～10%, is selected from multicomponent alcoholics compound; Contain emulsifying agent 1-10%, contain antiseptic 0.01-0.2%.
7. difluprednate preparation as claimed in claim 5, is characterized in that described pH adjusting agent is selected from the citric acid/sodium citrate buffer agent.
8. described difluprednate preparation as arbitrary in claim 5-7,, the described ointment formula optimization of its feature is comprised of the raw material of following percentage by weight: difluprednate crystal formation I 0.05%, white vaseline 3-10%, octadecanol 3-10%, liquid paraffin 3-10%, peregal A-20 1%～5%, glycerol 1-5%, propylene glycol 1-5%, ethyl hydroxybenzoate 0.1%, citric acid and sodium citrate amount to 0.2-1%, surplus is water, and the weight ratio of citric acid and sodium citrate is 1: 0.5～-1: 1.5.
9. difluprednate preparation as claimed in claim 4, is characterized in that being prepared into gel, contains difluprednate crystal formation I micropowder, water and gellant as active component.
10. difluprednate preparation as claimed in claim 4, is characterized in that being prepared into suspensoid, contains difluprednate crystal formation I micropowder and water as active component.
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| CN201110392104.8A CN103127139B (en) | 2011-11-30 | 2011-11-30 | Difluprednate topical external preparation |
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| CN201110392104.8A CN103127139B (en) | 2011-11-30 | 2011-11-30 | Difluprednate topical external preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109200014A (en) * | 2018-09-18 | 2019-01-15 | 珠海安生凤凰制药有限公司 | A kind of triamcinolone acetonide acetate emulsifiable paste and preparation method thereof |
| EP4013423A4 (en) * | 2019-08-18 | 2023-08-16 | IVIEW Therapeutics, Inc. | In-situ gel forming ophthalmic formulations containing difluprednate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612115A (en) * | 2008-06-23 | 2009-12-30 | 广东肇庆星湖生物科技股份有限公司 | A kind of compound difluprednate ointment |
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2011
- 2011-11-30 CN CN201110392104.8A patent/CN103127139B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612115A (en) * | 2008-06-23 | 2009-12-30 | 广东肇庆星湖生物科技股份有限公司 | A kind of compound difluprednate ointment |
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 |
|---|---|---|---|---|
| CN109200014A (en) * | 2018-09-18 | 2019-01-15 | 珠海安生凤凰制药有限公司 | A kind of triamcinolone acetonide acetate emulsifiable paste and preparation method thereof |
| EP4013423A4 (en) * | 2019-08-18 | 2023-08-16 | IVIEW Therapeutics, Inc. | In-situ gel forming ophthalmic formulations containing difluprednate |
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| CN103127139B (en) | 2016-01-20 |
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