CN103127139B - Difluprednate topical external preparation - Google Patents
Difluprednate topical external preparation Download PDFInfo
- Publication number
- CN103127139B CN103127139B CN201110392104.8A CN201110392104A CN103127139B CN 103127139 B CN103127139 B CN 103127139B CN 201110392104 A CN201110392104 A CN 201110392104A CN 103127139 B CN103127139 B CN 103127139B
- Authority
- CN
- China
- Prior art keywords
- difluprednate
- preparation
- preparations
- agent
- micropowder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
Difluprednate topical external preparation, contain the difluprednate micropowder as active component and one or more pharmaceutic adjuvants comprising water, it is characterized in that described difluprednate micropowder is scattered in pharmaceutic adjuvant with suspension, difluprednate is crystal formation I, its X-ray powder diffraction in the angle of diffraction 2 θ=8.9,11.6, there is characteristic peak at 17.6 places.
Description
Technical field
The present invention relates to a kind of steroidal 17-hydroxy-11-dehydrocorticosterone local topical formulation, especially relate to a kind of difluprednate topical external preparation.
Background technology
Difluprednate (CAS:23674-86-4, difluprednate) molecular formula is as follows:
Difluprednate is the one of steroidal 17-hydroxy-11-dehydrocorticosterone, the reaction of inflammation and allergic skin can be suppressed, also suppress add the related reaction of rapid regeneration with cell and cause symptom simultaneously, such as erythema, edema, skin thickization, coarse the going down of skin surface, and alleviate the problems such as pruritus, burning sensation and pain.Owing to introducing 17-butyrate and 21-acetate in the molecule, make the better fat-soluble of difluprednate, thus better curative effect can be reached when external curing, existing external preparation is mainly 0.05% difluprednate ointment and emulsifiable paste (trade name: MYSER, Tanabe Mitsubishi Pharmaceutical Co of Japan produces), in the description (http://di.mt-pharma.co.jp/file/if/f_mys.pdf) of difluprednate emulsifiable paste, disclose its adjuvant used is, propylene glycol, cera alba, Myrj 45, this emulsifiable paste is suspension type emulsifiable paste, crude drug is dispersed in emulsifiable paste matrix with micropowder form.
Through overtesting, we find, commercially available difluprednate emulsifiable paste, and the emulsifiable paste adopting existing difluprednate crude drug to prepare, and along with the storage of emulsifiable paste, original is that agglomeration has appearred in the difluprednate micropowder of suspended particles distributions in mastic.Thus make the particle diameter of drug powder become large, although present drug standard is not made stipulations to this situation of ointment, we test discovery, and the change of drug powder particle diameter greatly directly has influence on the bioavailability of medicine thus has influence on curative effect.
Summary of the invention
For overcoming the problems of the prior art, the invention provides a kind of new Difluprednate crystal form I, and further provide a kind of containing Difluprednate crystal form I micropowder with suspension be scattered in adjuvant aqueous compositions, difluprednate preparation provided by the invention, even if store under the room temperature environment colded and heat succeed each other, also can avoid the reunion of micropowder, thus keep higher bioavailability.Stable content when simultaneously storing is also better
The invention provides a kind of difluprednate preparation, contain the difluprednate micropowder as active component and one or more pharmaceutic adjuvants comprising water, it is characterized in that described difluprednate micropowder is scattered in pharmaceutic adjuvant with suspension, difluprednate is crystal formation I, its X-ray powder diffraction in the angle of diffraction 2 θ=8.9,11.6, there is characteristic peak at 17.6 places.
The wavelength of described X-ray powder diffraction
Described difluprednate preparation, the difluprednate as active component containing 0.01-0.1%, preferably contains the difluprednate of 0.05%.
Described difluprednate preparation, preferably preparation becomes ointment, gel, suspensoid.
Described difluprednate preparation, make ointment, by the Difluprednate crystal form I micropowder as active component, the pharmaceutically useful adjuvant such as water as the solid of oil-phase component, consistency modifiers, wetting agent, emulsifying agent, pH buffer agent, antiseptic and surplus is formed.
Solid 3% ~ 20% containing oil-phase component in described ointment, be selected from one or more in higher alcohol (monohydric alcohol of 16-22 carbon atom), described higher alcohol selects excellent hexadecanol and/or octadecanol;
Containing consistency modifiers 5% ~ 20% in described ointment.Be selected from one or more in vaseline, liquid paraffin, vegetable oil.
Containing wetting agent 3% ~ 10% in described ointment, being selected from multicomponent alcoholics compound, is glycerol and/or propylene glycol;
Containing emulsifying agent 1-10% in described ointment, optional selfpolyoxyethylene fatty alcohol ether is peregal A-20;
Containing 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%; Preferably but be not limited only to Calcium Disodium Versenate.
Ointment provided by the invention, its formula is preferably made up of the raw material of following percentage by weight: Difluprednate crystal form I0.05%, white vaseline 3-10%, octadecanol 3-10%, liquid paraffin 3-10%, peregal A-201% ~ 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 used 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 accounting for emulsifiable paste weight.
Described higher alcohol also plays the effect of surfactant in emulsifiable paste simultaneously.
The compound method that the invention provides a kind of difluprednate emulsifiable paste is as follows:
(1) oil phase preparation: get the solid of oil-phase component, consistency modifiers, emulsifying agent heating and melting, temperature remains on 70-90 DEG C;
(2) aqueous phase preparation: will regulate the water mixing of pH value, heating, the temperature that stirs remains on 70-90 DEG C; Add antiseptic and stirring and dissolving
(3) close phase: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 70-90 DEG C, stir 10-30min, obtain substrate be cooled to 45-50 DEG C for subsequent use
(4) difluprednate micropowder is even with aqueous dispersion, adding in substrate stirs is cooled to cream.
Described difluprednate preparation, when making suspensoid, contains the Difluprednate crystal form I micropowder as active component and water.
Described suspensoid, also containing one or more in suspending agent, buffer agent, antibiotic antiseptic, osmotic pressure regulator.
Described suspending agent includes but are not limited to the one 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 as sodium acetate etc., phosphate as sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate etc., 6-aminocaprolc acid, amino acid salts as sodium glutamate etc., boric acid and salt thereof, citric acid and salt etc. thereof.
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 as benzalkonium chloride, benzethonium chloride etc.; Cationic compound is as gluconic acid hibitane etc.; Nipagin ester is as methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben etc.; Alcoholic compound is 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, containing as the Difluprednate crystal form I micropowder of active component, water and gellant.
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 the one 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 as benzalkonium chloride, benzethonium chloride etc.; Cationic compound is as gluconic acid hibitane etc.; Nipagin ester is as methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben etc.; Alcoholic compound is 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 is selected from one or more in polyoxyethylene sorbitan monooleate dehydration (tween 80), polyoxyethylene sorbitan monolaurate (tween 20), polyethenoxy sorbitan monopalmitate (Tween-40) and polyethenoxy sorbitan monostearate (Tween-60).
Described pH adjusting agent includes but are not limited in acetate as sodium acetate etc., phosphate is as sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate etc., 6-aminocaprolc acid, amino acid salts is as sodium glutamate etc., boric acid and salt thereof, citric acid and salt and sodium hydroxide, carbonic acid, sodium bicarbonate, hydrochloric acid, acetic acid etc.
In technical scheme provided by the invention, described percentage ratio is all weight percentage.
Difluprednate preparation provided by the invention as the preparation of topical treatment, as the preparation to skin, eye, nose or ear topical, preferably as percutaneous drug delivery preparation.
The difluprednate preparation prepared for raw material with Difluprednate crystal form I micropowder provided by the invention and the difluprednate preparation adopting commercially available difluprednate raw material to prepare are compared, when storing, the difluprednate micropowder be suspended in drug matrices is less likely to occur to reunite, avoid and store the drug powder granule that causes and become large, thus the Transdermal absorption characteristic avoiding medicine declines, thus avoid the curative effect affecting medicine.
Detecting instrument: Japanese Shimadzu LC-IOA high performance liquid chromatograph; SPD-10A UV-detector
Accompanying drawing explanation
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 the X-ray diffraction absorption figure of difluprednate crude drug commercially available in raw material preparation example 1
Accompanying drawing 3 is the X-ray diffraction absorption figure of the crude drug in raw material preparation example 1 in commercially available difluprednate emulsifiable paste
Detailed description of the invention
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Commercially available difluprednate crude drug, purchased from Tianjin Medicine Institute Co., Ltd.
Commercially available difluprednate emulsifiable paste, content 0.05%, trade name: MYSER, purchased from Japanese Tanabe Mitsubishi Pharmaceutical Co
The emulsifiable paste that all embodiments obtain all divides with the PAP that 10g/ props up and packages spare.Difluprednate used is the micropowder of mean diameter 5-10 μm, 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 10g difluprednate to be dissolved in 20mL acetonitrile, be heated to clearly molten, elimination insoluble matter, then reduction vaporization, occur cooling after crystal, filter, dry, obtain Difluprednate crystal form I.
X-ray powder diffraction mensuration is carried out to crystal after drying, record characteristic peak positions 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 mensuration, record characteristic peak positions 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, measure 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in water for injection, principal agent are 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 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 80 DEG C, stir 30min, be cooled to cream, obtain 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 μm
Embodiment 2-1
Difluprednate 0.5g (crystal formation I), white vaseline 30g, octadecanol 100g, liquid paraffin 100g, peregal A-2010g, 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in water for injection, principal agent are 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 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 90 DEG C, stir 30min, be cooled to cream, obtain 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 μm
Embodiment 3-1
Difluprednate 0.5g (crystal formation I), white vaseline 30g, octadecanol 100g, liquid paraffin 30g,
Peregal A-2030g, 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, propylene glycol, adds the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 80 DEG C, stir 30min, be cooled to cream, obtain 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 μm
Embodiment 4-1
Difluprednate crystal form 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, propylene glycol, adds the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 75 DEG C, stir 30min, be cooled to cream, obtain 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 μm
Embodiment 5-1
Difluprednate 1g (crystal formation I), white vaseline 150g, octadecanol 30g, liquid paraffin 80g,
Peregal A-2080g, 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent are dispersed in glycerol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 90 DEG C, stir 30min, be cooled to cream, obtain 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 μm
Embodiment 5-3
According to the composition and engineering of embodiment 5-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.2 μm
Embodiment 6-1
Difluprednate 0.2g (crystal formation I), white vaseline 30g, hexadecanol 150g, liquid paraffin 30g, peregal A-2010g, 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 μm
By above proportioning accurate weighing, 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 DEG C;
(2) aqueous phase preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent are dispersed in propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 DEG C;
(3) phase is closed: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 70 DEG C, stir 15min, be cooled to cream, obtain 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 μm
Embodiment 6-3
According to the composition and engineering of embodiment 6-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.0 μm
The preparation of embodiment 7-1 gel
Difluprednate (crystal formation I) 1g mean diameter 8.9 μm, Acritamer 940 2g, glycerol 50g, tween 80 2g
Benzalkonium chloride 1g distilled water adds to 1000ml
0.1M sodium hydroxide solution, adjusts pH to 5.5
Mixed with tween 80, benzalkonium chloride and 300ml distilled water by carbomer, be heated to 50-60 DEG C, add gradually and stir evenly, use, 0.1M sodium hydroxide solution after the aqueous dispersion of difluprednate micropowder, adjust pH to 5.5, the water supplying surplus stirs evenly and obtains 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 μm
Embodiment 7-3
According to the composition and engineering of embodiment 7-1, adopt commercially available difluprednate raw material micropowder, mean diameter 8.7 μm
The preparation of embodiment 8-1 gel
The preparation of gel
Difluprednate (crystal formation I) 1g mean diameter 6.8 μm, carbomer 934 5g, glycerol 50g, tween 80 5g
Benzalkonium chloride 1g sodium hydroxide 4g distilled water adds to 1000g
Mixed with tween 80, benzalkonium chloride and 300ml distilled water by carbomer, be heated to 50-60 DEG C, add gradually and stir evenly, use, 0.1M sodium hydroxide solution after the aqueous dispersion of difluprednate micropowder, adjust pH to 5.5, the water supplying surplus stirs evenly and obtains 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 μm
Embodiment 9-1 suspensoid
Formula is as follows: difluprednate (crystal formation I) 1g, and 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 about 70 DEG C, then adds people's hydroxypropyl emthylcellulose.After dispersion, mixture is cooled to about 30 DEG C.Then, add people's sodium acetate and benzethonium chloride and dissolve. with hydrochloric acid, pH is adjusted to 5.0, refilters sterilized mixture.Add people's difluprednate to make to suspend completely. supply the purification water yield, so just obtain ophthalmic suspension.Difluprednate micropowder mean diameter is 5.2 μm.
Embodiment 9-2
According to the composition and engineering of embodiment 9-1, adopt commercially available difluprednate raw material micropowder, mean diameter 5.7 μm
Pharmacological Examples
Adopt preparation prepared by the difluprednate of different crystal forms, under hot and humid condition, store 3 months, storage condition is relative humidity 75% ± 5%, temperature 40 DEG C ± 5 DEG C.It is the routine packaging that 10g/ props up by the drugs packaging prepared according to embodiment method.Detect the change of transdermal test in vitro assimilation effect before and after storing
After getting the healthy rat anesthesia execution of 3 monthly ages, belly wool is eliminated with shears, take off undamaged skin, removing subcutaneous tissue, the liberation port of Franz diffusion cell is individually fixed in after cleaning, add pH7.4 phosphate buffer (PBS liquid) in receiving chamber and make release medium, keep endodermis and solution close contact.Suspension group is got 0.2ml medicinal liquid and is coated on skin, and emulsifiable paste and gel component not precision measure sample 0.200g, and be spread evenly across on test skin, release area is 2.5cm
2.Regulate water-bath to make outer jacket layer temperature constant in (37 ± 1) DEG C, mixing speed is 100rpm, precision takes different emulsifiable paste sample 1.000g respectively, is spread evenly across on test skin.Drew release medium 4ml in 2 hours, with the method determination concentration C i of Chinese Pharmacopoeia version in 2010, and calculate 24h accumulation infiltration capacity and calculate 24h cumulative release permeability,
Following table shows 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, the cumulative release permeability of the preparation adopting Difluprednate crystal form I to prepare is apparently higher than the embodiment sample adopting marketable material preparation and adopt crystal form II to prepare.
Droplet measurement, respectively each 10 of the sample of Example 1-1 ~ 9-2, at 0 month and survey the volume average particle size of difluprednate micropowder after 3 months respectively by above-mentioned condition storage, separately gets 10 market milk paste formulations (i.e. " commercially available " group), test equally, result following (
n=10, unit μm)
| 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 |
Droplet measurement shows, adopt each experimental group of Difluprednate crystal form I, active component micropowder in pharmaceutical preparation is after the storage of 3 months, particle diameter is not significantly increased, and the preparation adopting marketable material micropowder to prepare and commercially available difluprednate emulsifiable paste, there is agglomeration in active component micropowder after storing, and significant increase (P < 0.01) has appearred in particle diameter.
Tested by Transdermal Absorption, compared with the preparation adopting marketable material to prepare, the preparation prepared owing to adopting Difluprednate crystal form I is at medicine after storing, and drug powder can not produce reunion, and therefore the Transdermal absorption performance of medicine also can not decline.
Claims (26)
1. a difluprednate preparation, containing 0.01-0.1% as the difluprednate micropowder of active component and one or more pharmaceutic adjuvants comprising water, it is characterized in that described difluprednate micropowder is scattered in pharmaceutic adjuvant with suspension, difluprednate is crystal formation I, its X-ray powder diffraction in the angle of diffraction 2 θ=8.9,11.6, there is characteristic peak at 17.6 places.
2. difluprednate preparation as claimed in claim 1, its feature contains the difluprednate of 0.05%.
3. the difluprednate preparation as described in as arbitrary in claim 1-2, preparation becomes ointment, gel, suspensoid.
4. difluprednate preparation as claimed in claim 3, it is characterized in that making ointment, by the Difluprednate crystal form I micropowder as active component, the water as the solid of oil-phase component, consistency modifiers, wetting agent, emulsifying agent, pH buffer agent, antiseptic and surplus is formed.
5. difluprednate preparation as claimed in claim 4, is characterized in that described ointment contains the solid 3% ~ 20% of oil-phase component, containing consistency modifiers 5% ~ 20%, containing wetting agent 3% ~ 10%, is selected from multicomponent alcoholics compound; Containing emulsifying agent 1-10%, containing antiseptic 0.01-0.2%.
6. difluprednate preparation as claimed in claim 5, is characterized in that the solid of described oil-phase component is selected from one or more of the monohydric alcohol of 16-22 carbon atom.
7. difluprednate preparation as claimed in claim 6, is characterized in that the solid of described oil-phase component is selected from hexadecanol and/or octadecanol.
8. difluprednate preparation as claimed in claim 5, is characterized in that one or more that described consistency modifiers is selected from vaseline, liquid paraffin, vegetable oil.
9. difluprednate preparation as claimed in claim 5, is characterized in that described wetting agent is selected from multicomponent alcoholics compound.
10. difluprednate preparation as claimed in claim 9, is characterized in that described wetting agent is glycerol and/or propylene glycol.
11. difluprednate preparations as claimed in claim 5, is characterized in that described emulsifying agent is selected from polyoxyethylene aliphatic alcohol ether.
12. difluprednate preparations as claimed in claim 11, is characterized in that described emulsifying agent is selected from peregal A-20.
13. difluprednate preparations as claimed in claim 5, is characterized in that described antiseptic is selected from parabens.
14. difluprednate preparations as claimed in claim 13, is characterized in that described antiseptic is selected from ethyl hydroxybenzoate.
15. difluprednate preparations as claimed in claim 4, is characterized in that described pH adjusting agent is selected from citric acid/sodium citrate buffer agent.
16. difluprednate preparations as claimed in claim 4, is characterized in that also adding stabilizing agent, and the consumption of stabilizing agent is 0.05%-0.3%.
17. difluprednate preparations as claimed in claim 16, is characterized in that described stabilizing agent is Calcium Disodium Versenate.
18. as arbitrary in claim 4-15 as described in difluprednate preparation, described in its feature, ointment formula is preferably made up of the raw material of following percentage by weight: Difluprednate crystal form I0.05%, white vaseline 3-10%, octadecanol 3-10%, liquid paraffin 3-10%, peregal A-201% ~ 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, and the weight ratio of citric acid and sodium citrate is 1:0.5 ~ 1:1.5.
19. difluprednate preparations as claimed in claim 4, is characterized in that the compound method of described ointment is as follows: (1) oil phase is prepared: get the solid of oil-phase component, consistency modifiers, emulsifying agent heating and melting, temperature remains on 70-90 DEG C; (2) aqueous phase preparation: will regulate the water mixing of pH value, heating, the temperature that stirs remains on 70-90 DEG C; Add antiseptic and stirring and dissolving (3) closes phase: slowly added by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 70-90 DEG C, stir 10-30min, obtain substrate and be cooled to 45-50 DEG C (4) for subsequent use by the aqueous dispersion of Difluprednate crystal form I micropowder evenly, adding in substrate stirs is cooled to cream.
20. difluprednate preparations as claimed in claim 3, is characterized in that being prepared into gel, containing as the Difluprednate crystal form I micropowder of active component, water and gellant.
21. difluprednate preparations as claimed in claim 20, 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.
22. difluprednate preparations as claimed in claim 21, the cellulose derivative described in its feature includes but are not limited to the one in hydroxyethyl-cellulose, ethylhydroxyethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof.
23. difluprednate preparations as claimed in claim 20, is characterized in that also comprising one or more in wetting agent, antibiotic antiseptic, emulsifying agent, pH adjusting agent.
24. difluprednate preparations as claimed in claim 3, is characterized in that being prepared into suspensoid, contain the Difluprednate crystal form I micropowder as active component and water.
25. difluprednate preparations as claimed in claim 24, is characterized in that described suspensoid, also containing one or more in suspending agent, buffer agent, antibiotic antiseptic, osmotic pressure regulator.
26. difluprednate preparations as claimed in claim 25, is characterized in that described suspending agent includes but are not limited to the one in polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392104.8A CN103127139B (en) | 2011-11-30 | 2011-11-30 | Difluprednate topical external preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110392104.8A CN103127139B (en) | 2011-11-30 | 2011-11-30 | Difluprednate topical external preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103127139A CN103127139A (en) | 2013-06-05 |
| CN103127139B true CN103127139B (en) | 2016-01-20 |
Family
ID=48488011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110392104.8A Active CN103127139B (en) | 2011-11-30 | 2011-11-30 | Difluprednate topical external preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103127139B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109200014B (en) * | 2018-09-18 | 2019-07-12 | 珠海安生凤凰制药有限公司 | A kind of triamcinolone acetonide acetate emulsifiable paste and preparation method thereof |
| CA3148362C (en) * | 2019-08-18 | 2024-02-13 | Bo Liang | 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 |
-
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 |
|---|
| Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug,difluprednate;Masazumi Yamaguchi, et al.;《International Journal of Pharmaceutics》;20050714;第301卷;121-128 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103127139A (en) | 2013-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5345937B2 (en) | Antifungal composition | |
| JP5589130B1 (en) | Crystal and pharmaceutical preparation containing the crystal | |
| TWI645852B (en) | Bioadhesive compositions for intranasal administration of granisetron | |
| CN101401783A (en) | Percutaneous absorption agent containing Ailamode, preparation method and medical uses thereof | |
| EP2056809A1 (en) | Ophthalmic percutaneous absorption type preparation | |
| JP5936544B2 (en) | Stable rasagiline composition | |
| JP2022500362A (en) | New compositions and methods | |
| CN103127139B (en) | Difluprednate topical external preparation | |
| CN102186474A (en) | Uchida hiroshi [jp]; fukuda mamoru [jp]; aritomi seigo | |
| CN103130860B (en) | The local topical preparation of a kind of Diflucortolone valerate novel crystal forms and preparation thereof | |
| CN110139641B (en) | External composition | |
| CN115475152A (en) | External preparation of flurbiprofen and preparation method thereof | |
| CN102233130B (en) | Stable pharmaceutical preparation containing thymosin 1 derivatives | |
| TWI805601B (en) | Pharmaceutical composition and method for inhibiting the formation of crystals thereof | |
| CN106560175B (en) | Menthol-camphor eutectic nanoemulsion in-situ gel preparation | |
| EP1482942A2 (en) | Stabilized pharmaceutical compositions of halofuginone and other quinazolinone derivatives | |
| CN103126983B (en) | Emulsion prepared by Difluprednate crystal form I | |
| CN103228283A (en) | Oil-in-water emulsion composition containing difluprednate and tobramycin | |
| CN111440086A (en) | Salt of tranilast | |
| JP2015091890A (en) | Crystal and pharmaceutical formulation comprising the crystal | |
| EP3441068A1 (en) | Transdermal preparation | |
| CN101921264A (en) | Candesartan organic amine salt and preparation method and application thereof | |
| CN110876713B (en) | Estradiol gel | |
| CN116919888A (en) | Pharmaceutical composition of glibenclamide for nasal administration and preparation method thereof | |
| JP2024518225A (en) | Pharmaceutical composition, aprepitant injection solution and freeze-dried powder injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20130605 Assignee: Tianjin Pharmaceutical Industry Group Corp., Ltd. Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2015120000052 Denomination of invention: Difluprednate topical external preparation 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.: 2015120000069 Denomination of invention: Difluprednate topical external preparation License type: Fen Xuke Record date: 20150929 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Tianjin Pharmaceutical Industry Group Corp., Ltd. Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2015120000052 Date of cancellation: 20170113 Assignee: Pharmaceutical Co., Ltd. Tianjin Jin Yao Assignor: Tianjin Pharmaceutical Industry Group Corp., Ltd. Contract record no.: 2015120000069 Date of cancellation: 20170113 |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20130605 Assignee: Pharmaceutical Co., Ltd. Tianjin Jin Yao Assignor: Tianjin Jinyao Group Co., Ltd. Contract record no.: 2017120000026 Denomination of invention: Difluprednate topical external preparation Granted publication date: 20160120 License type: Common License Record date: 20170116 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |