CN101601650A - Fluticasone propionate lipidosome cream - Google Patents
Fluticasone propionate lipidosome cream Download PDFInfo
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- CN101601650A CN101601650A CNA2008100534709A CN200810053470A CN101601650A CN 101601650 A CN101601650 A CN 101601650A CN A2008100534709 A CNA2008100534709 A CN A2008100534709A CN 200810053470 A CN200810053470 A CN 200810053470A CN 101601650 A CN101601650 A CN 101601650A
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Abstract
A kind of is active component with the fluticasone propionate, the liposome vesicle diameter is less than the liposome drug combination of 800nm, said composition is as the fluticasone propionate 0.025%～0.2% of active component, phosphatidase 10 .5%～6%, lipotropy additive 0～1%, the antioxidant 0.01～1% that is used for the described pharmaceutical composition of preservation, pH value is remained on the pH buffer agent of 5-7.5, wetting agent 3%～15%, oil-phase component 20%～30%, antibiotic antiseptic 0.01%-0.1% also has the water of surplus to form, and is used for the treatment of human or animal's dermatosis.
Description
Invention field
The present invention relates to a kind of skin composition that contains fluticasone propionate lipidosome.
Background technology
Fluticasone propionate (fluticasone propionate, CAS:80474-14-2), its molecular formula is as follows:
Fluticasone propionate emulsifiable paste commodity are called CUTIVATE, are Ge Lansu company (GSK) at first exploitation listings in 1988.A kind of specification of 0.05% content is only arranged at present, and (http: // 69.20.19.211/cder/pediatric/labels/Fluticasone-Cutivate. pdf) disclosing its main component is: fluticasone propionate 0.05% in the description of CUTIVATE emulsifiable paste; Adjuvant: liquid Paraffin, microwax, propylene glycol and sorbitan sesquioleate (sorbitan sesquioleate) however this medicine also exists the Donisolone side effect of general skin, as the inhibition of hpa axis, long-term a large amount of hypercortisolisms of causing (Cushing ' s) that use are caused thinning of skin as meeting, skin shows telangiectasis, and can cause cutis laxa, bring out acne, cause hair follicle to infect, the hair undue growth, skin allergy is might cause the physiological period disorder.
Liposome (liposome) is that drug encapsulation is loaded body preparation in the formed ultra micro ball of class lipid bilayer, and possess hydrophilic property and hydrophobicity double grading can be wrapped up lipotropy, both sexes, water solublity and macromolecular drug.The similar cellularity of liposome has biocompatibility and biological degradability concurrently.And the successful key of external preparation for skin medicine treatment to be medicine must see through horny layer arrival diseased region reach effective treatment concentration and keep certain hour.As the local skin drug administration carrier, liposome has the advantages of good skin transdermal enhancing effect, the skin targeting.
Chinese patent application CN200380107482.0 discloses a kind of Liposomal formulation that comprises the water-soluble sugar 17-hydroxy-11-dehydrocorticosterone, but the technical scheme of this application only discloses and is applicable to water miscible glucocorticoid such as dexamethasone sodium phosphate etc.
Chinese patent application CN200580035942.2 discloses the liposome composition of a kind of glucocorticoid and glucocorticoid derivatives, yet the technical scheme of this application only discloses and has been applicable to amphiphilic alkalescence glucocorticoid such as Urbason Solubile, and points out hydrophobic glucocorticoid (GC) be difficult to pack into (the 6th page of description) in the liposome in this application description.We can draw from the disclosed content of this application, the liposome kind that is difficult to pack into of the hydrophobicity glucocorticoid as fluticasone propionate.
Chinese patent ZL 01812895.5 discloses a kind of Liposomal formulation that contains hydrophobicity glucocorticoid clobetasol propionate, in the technical scheme of this disclosure of the Invention, preferably be made for gel, yet in this patent in the disclosed technical scheme, as the consumption of the C/PL of lipotropy additive only than being 1: 1～1: 3, and the diameter of liposome vesicle is up to 2000-5000nm, in experimenting, we find out that, because the liposome vesicle diameter that technical scheme adopted of this disclosure of the Invention is bigger, influence the osmotic absorption of medicine, can't give full play to the advantage of external preparation for skin liposome administration.
Summary of the invention:
For overcoming the defective in the above-mentioned existing fluticasone propionate external preparation, the invention provides a kind of is active component with the fluticasone propionate, the liposome vesicle diameter is less than the liposome drug combination of 800nm, and described pharmaceutical composition is by being made of following component:
Fluticasone propionate 0.025%-～0.2% as active component, phosphatidase 10 .125%～6%, lipotropy additive 0～1%, the antioxidant 0.01～1% that is used for the described pharmaceutical composition of preservation, pH value is remained on the pH buffer agent of 5-7.5, wetting agent 3%～15%, oil-phase component 20%～30%, antibiotic antiseptic 0.01%-0.1%, the water of surplus in addition.
Above-described percentage ratio is the percentage by weight that accounts for pharmaceutical composition.
In the liposome drug combination of the present invention, the liposome vesicle diameter is less than the bilayer vesicles of 800nm or multilamellar capsule.
Phospholipid of the present invention includes but are not limited to phosphatidylcholine such as dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, phosphatidyl glycerol is as two palmityl phosphatidyl glycerols, distearyl phosphatidyl glycerol, Phosphatidylserine is as two palmityl Phosphatidylserine, distearyl Phosphatidylserine, in soybean lecithin, hydrogenated soy phosphatidyl choline, the Ovum Gallus domesticus Flavus lecithin one or more, one or more in preferably soya lecithin, hydrogenated soy phosphatidyl choline or the Ovum Gallus domesticus Flavus lecithin.The weight ratio of described phospholipid and active component is 5～30: 1, preferred 10～20: 1.
Described lipotropy additive comprises but is not limited only to cholesterol, phosphatidic acid, stearylamine, preferred cholesterol, we are unexpected to find compared with prior art, when the consumption of wherein said lipotropy additive is 0～1 with ratio with phospholipid: can make described liposome in the time of 5, preferred 1: 15～1: 8, most preferably be 1: 10.
The preferred ethylenediaminetetraacetic acid (EDTA) of described antioxidant and/or its alkali metal salt, ascorbic acid, alpha-tocopherol and 2,6-ditertbutylparacresol (BHT), sodium pyrosulfite, preferred especially ethylenediaminetetraacetic acid (EDTA) and/or its alkali metal salt and/or alpha-tocopherol, the consumption of described antioxidant is preferably 0.05%～0.3%.
Described antibiotic antiseptic can include but are not limited to benzoic acid, benzyl alcohol, p-Hydroxybenzoate (nipalgin), comprise in methyl hydroxybenzoate, ethyl hydroxybenzoate, the propylparaben one or more, preferred especially p-Hydroxybenzoate (nipalgin), described antibiotic antiseptic consumption is preferably 0.1%.
Described pH buffer agent can comprise phosphoric acid/phosphate buffer, acetic acid/acetate buffer, citric acid/citrate buffer agent, boric acid/borate buffer, preferably phosphoric acid/phosphate buffer, the phosphate buffer of preferred especially pH=6.5.
Described wetting agent includes but are not limited to glycerol, propylene glycol, sorbitol, preferred glycerol.Described wetting agent consumption preferred 4%～10%, preferred especially 5%.
The preferred distilled water of described water
Described oil-phase component is by comprising in solid in the oil-phase component, consistency modifiers, the emulsifying agent one or more.
Solid in the described oil-phase component includes but are not limited to one or more of stearic acid, paraffin, Cera Flava, higher alcohol, described higher alcohol is the monohydric alcohol of 16～22 carbon atoms, preferred hexadecanol and/or octadecanol, described oil-phase component consumption is 1%～15%.
Described consistency modifiers includes but are not limited to one or more in vaseline, liquid paraffin, the vegetable oil, preferred vaseline and/or liquid Paraffin, and the consumption of described consistency modifiers is 5%～20%.
Described emulsifying agent, include but are not limited to the derivant of soap class emulsifying agent, polyoxyethylene ether, preferably as the glyceryl monostearate of soap class emulsifying agent and/or as the peregal A-20 of polyoxy ether class emulsifying agent, total consumption of described emulsifying agent is 1～18%, preferred soap class emulsifying agent consumption is 0.5%～10%, and polyoxy ether class emulsifying agent consumption is 0.5%～8%.
Described higher alcohol also plays the effect of surfactant simultaneously in emulsifiable paste.Percentage ratio of the present invention is the percentage by weight of relative pharmaceutical composition.
It is described that the composition of described emulsifiable paste matrix is not limited only to technical solution of the present invention, also comprise any composition that can be used to prepare ointment substrate, the composition of described matrix components can be with reference to disclosed scheme in " pharmaceutics " (the 5th edition, Cui Fude published in 2003).
Pharmaceutical composition of the present invention can be prepared in order to following method:
(1) preparation of liposome solutions
Method 1. takes by weighing fluticasone propionate, phospholipid, lipotropy additive, the antioxidant of recipe quantity, be dissolved in an amount of low boiling solvent, described low boiling solvent includes but are not limited to one or more in dichloromethane, methanol, ethanol, oxolane, acetone, ether, dichloromethane, the chloroform, and preferred dichloromethane and methanol volume ratio are 1: 1 mixed solvent.With gained solution at low temperatures (30～40 ℃, preferred 37 ℃, in addition certain in case of necessity vacuum) evaporation remove solvent, form a skim on chamber wall, what add recipe quantity regulates the water of pH value with the pH buffer agent, use ultra-sonic dispersion, cross 0.8 μ m filter membrane, obtain liposome solutions.
Method 2. takes by weighing fluticasone propionate, phospholipid, lipotropy additive, the antioxidant of recipe quantity, be dissolved in an amount of lower boiling solvent, described solvent includes but are not limited to one or more in methanol, ethanol, oxolane, the acetone, in the ether, preferred alcohol or ether; This solution is slowly injected recipe quantity mix up the water of pH value,, remove solvent in 30～40 ℃ of following low-temperature evaporations (decompression in case of necessity) with the pH buffer agent.Surplus solution is handled under 1000～1500bar pressure to clarification with high pressure homogenizer, crossed 0.8 μ m film.
(2) preparation of oil phase
That gets recipe quantity is heated to fusing (60 ℃～90 ℃) as oil-phase component, and (available in case of necessity an amount of organic solvent dissolution stirs while adding to evenly promptly described antibiotic antiseptic.
(3) preparation of fluticasone propionate lipidosome cream
Liposome solutions is heated to 60～90 ℃, the wetting agent that is heated to same temperature is joined in the liposome solutions, mixing, the oil-phase component that will be heated to 60～90 ℃ again joins in the liposome solutions, stir while adding evenly to condensation promptly.
For fear of the degraded of material in the process of preparation Liposomal formulation, preferably use noble gas, all solution of helium or nitrogen purge for example, and under atmosphere of inert gases, carry out all steps.
In technical scheme provided by the invention, because compared with prior art, the ratio of lipotropy additive such as cholesterol and phospholipid consumption has been reduced to 0～1: 5 by 1: 3～1: 1 of prior art, thereby has reduced the liposome vesicle diameter that makes.After measured, the lipidosome cream envelop rate of gained of the present invention is up to 85%～90%.
The lipidosome cream agent of gained of the present invention is preferred for treating people or mammalian skin disease, by embodiment as can be seen, compare with fluticasone propionate emulsifiable paste of the prior art, the absorption of lipidosome cream effective ingredient provided by the invention is better, the dosage that needs when reaching the identical treatment effect still less, and unexpectedly we have found owing to gained lipidosome cream in the technical solution of the present invention has high envelop rate, the effect of sealing of liposome is brought into play, thereby compared with prior art stability is better for lipidosome cream provided by the present invention.
The specific embodiment:
The following specific embodiment only is the explanation that technical solution of the present invention is implemented, and can not be interpreted as the restriction to the technology of the present invention offshoot program.Below among each embodiment the amount of preparation of emulsifiable paste all in 1000g.The distilled water that added adopts according to " compound method of disclosed phosphate buffer in the Chinese pharmacopoeia 2005 editions is with the phosphate buffer of distilled water preparation becoming pH=6.5.And,, use all solution of nitrogen purge, and under atmosphere of inert gases, carry out all steps for fear of the degraded of material in the process of preparation Liposomal formulation.In the implementation process of each embodiment, be the decline of the active component content of avoiding preparing the final products that may cause in the liposome solutions process, the product activity component content that can adopt the method for conventional method such as suitable increase active component inventory that each embodiment is obtained reaches requirement.
Embodiment 1
The prescription of oil phase:
White vaseline 100g octadecanol 30g liquid Paraffin 50g glyceryl monostearate 20g peregal a-2020g methyl hydroxybenzoate 0.5g propylparaben 0.05g
The prescription of liposome solutions:
Fluticasone propionate 1g soybean lecithin 20g cholesterol 2g disodiumedetate (EDTA-2Na) 1g alpha-tocopherol 1g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Glycerol 50g
Distilled water is to 1000g (in composition total weight)
Preparation:
(1) preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, adds the nipalgin that is dissolved in an amount of organic solvent, and the wetting agent of getting recipe quantity again is heated to same temperature and slowly joins in the oil phase, stirs while adding to evenly promptly.
(2) preparation of liposome solutions
The fluticasone propionate, phospholipid, cholesterol, the alpha-tocopherol that take by weighing recipe quantity are dissolved in methylene chloride (V: V=1: 1), with gained solution at 37 ℃, solvent is removed in evaporation, on chamber wall, form a skim, the distilled water that adds recipe quantity disodiumedetate and adjusted good pH value that adds recipe quantity, use ultra-sonic dispersion, cross 0.8 μ m filter membrane, obtain liposome solutions.
(3) preparation of fluticasone propionate lipidosome cream
Liposome solutions is heated to 70 ± 10 ℃, adds the glycerol of recipe quantity, the oil-phase component that will be heated to 70 ± 10 ℃ joins in the liposome solutions, stir while adding evenly to condensation promptly.Make 0.1% fluticasone propionate lipidosome cream.
Embodiment 2
The oil phase prescription:
White vaseline 120g octadecanol 50g liquid Paraffin 50g glyceryl monostearate 40g peregal a-2020g methyl hydroxybenzoate 0.5g propylparaben 0.05g
The liposome solutions prescription is:
Fluticasone propionate 0.5g hydrogenated soy phosphatidyl choline 10g cholesterol 1g disodiumedetate 1g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Distilled water is to 1000g (in composition total weight)
Compound method as embodiment 1 makes 0.05% fluticasone propionate lipidosome cream.
Embodiment 3
The oil phase prescription:
White vaseline 60g hexadecanol 40g octadecanol 40g liquid Paraffin 90g glyceryl monostearate 20g peregal a-2040g methyl hydroxybenzoate 0.5g propylparaben 0.05g
The liposome solutions prescription
Fluticasone propionate 0.25g Ovum Gallus domesticus Flavus lecithin 3g cholesterol 0.6g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Distilled water is to 1000g (in composition total weight)
Compound method as embodiment 1 makes 0.025% fluticasone propionate lipidosome cream.
Embodiment 4
The prescription of oil phase:
White vaseline 30g octadecanol 70g liquid Paraffin 100g glyceryl monostearate 50g peregal a-2040g methyl hydroxybenzoate 0.5g propylparaben 0.05g
The liposome solutions prescription:
Fluticasone propionate 1g soybean lecithin 15g cholesterol 0g disodiumedetate 1g alpha-tocopherol 0.5g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Distilled water is to 1000g (in composition total weight)
(1) preparation of liposome solutions
Take by weighing fluticasone propionate, soybean lecithin, cholesterol, the alpha-tocopherol of recipe quantity, be dissolved in an amount of dehydrated alcohol, the recipe quantity distilled water that the slow injection of gained solution has been added recipe quantity disodiumedetate and adjusted good pH value, solvent is removed in evaporation, surplus solution is handled 2 times under 1200bar with high pressure homogenizer, cross 0.8 μ m film, and supply the distillation water yield that evaporates.
Compound method as embodiment 1 makes 0.1% fluticasone propionate lipidosome cream.
Embodiment 5
The prescription of oil phase:
White vaseline 50g octadecanol 90g liquid Paraffin 70g glyceryl monostearate 30g peregal a-2040g methyl hydroxybenzoate 0.5g propylparaben 0.05g
The liposome solutions prescription:
Fluticasone propionate 0.5g dipalmitoyl phosphatidyl choline 10g cholesterol 0g disodiumedetate 1g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Distilled water is to 1000g (in composition total weight)
Liposome solutions compound method such as embodiment 4
Compound method as embodiment 1 makes 0.05% fluticasone propionate lipidosome cream.
Embodiment 6
The liposome solutions prescription:
Fluticasone propionate 0.25g distearyl phosphatidyl glycerol 7g, cholesterol 1g disodiumedetate 1g
Liposome solutions is buffered to the phosphate buffer of pH=6.5
Distilled water is to 1000g (in composition total weight)
Liposome solutions compound method such as embodiment 5
Compound method as embodiment 1 makes 0.025% fluticasone propionate lipidosome cream.
The mensuration of embodiment 7 envelop rates
(rp-hplc determination Itraconazole liposome medicament contg and envelop rate, pharmaceutical analysis magazine, 1453～1455) disclosed methods such as employing Dong Di are measured the envelop rate that makes liposome among the embodiment 1-6,
Condition determination: equipment: HP 1084B chromatograph of liquid, HP 79850BLC terminal and UV detector
Column material: Supelcosil Lc-18,5um, 150 * 4.6mm
Detect wavelength: 245nm
Mobile phase: acetonitrile: water: oxolane=36: 64: 3
Column temperature: 25 ℃ of flow velocitys: about 0.8ml/ branch
G-50 polydextran gel granule, Switzerland Pharmacia company produces; Sephadex column (Sephadex G one 50 posts): take by weighing polydextran gel granule 10g, water for injection soaks 24h, and ultrasonic degasification is adopted wet method to fill out the post method and filled the people to make glass tubing by oneself (among the 20mm * 250mm), stand-by.
Measurement result: the envelop rate of liposome is all greater than 90% among all embodiment.
The treatment of pharmacology embodiment 1 xylol induced mice auricle edema
The foundation of auricle edema model: respectively drip 10 μ l caused by dimethylbenzene xylene inflammation with microsyringe at the mouse right ear tow sides
Laboratory animal grouping and administration: 60 of male mice in kunming, body weight 24-26g, is divided into 6 groups by 10 every group.Cause the 30min administration of scorching back, dosage is in fluticasone propionate, takes off cervical vertebra in 2 hours to put to death animal after administration.Take off with the card punch of the diameter 9mm auricle with the same position of ears, accurately weighing with left and right sides auricle weight difference is the swelling degree, calculates inhibitory rate of intumesce with following formula: inhibitory rate of intumesce=(1-swelling degree/matched group 1 swelling degree weight) * 100%
Positive controls causes emulsifiable paste matrix among the scorching laggard embodiment of giving 1, and the inhibitory rate of intumesce of relative comparison group 2 carries out the t check.
Animal grouping and administration, see the following form with swelling inhibition situation
| Group | Use medicine | Drug concentration % | Application dose (μ g/ ear) | Swelling degree (mg) | Inhibitory rate of intumesce % | ??P |
| Matched group 1 | Positive control | ??0 | ??8.8±2.6 | |||
| ?? *Matched group 2 | The CUTIVATE emulsifiable paste | ??0.05 | ??5 | ??6.2±2.1 | ??29.5 | |
| Test group 1 | Embodiment 2 | ??0.05 | ??5 | ??3.8±1.8 | ??56.8 | ?? *P＜0.01 |
| Test group 2 | Embodiment 3 | ??0.025 | ??2.5 | ??4.5±2.0 | ??46.7 | ?? *P＜0.05 |
| Test group 3 | Embodiment 5 | ??0.05 | ??5 | ??3.7±2.1 | ??58.0 | ?? *P＜0.01 |
| Test group 4 | Embodiment 6 | ??0.025 | ??2.5 | ??4.4±2.3 | ??50.0 | ?? *P＜0.05 |
Data as can be seen from table, the lipidosome cream that the embodiment of the invention provides is compared with existing 0.05% fluticasone propionate emulsifiable paste, suppressing to have significant effect when mice causes the ear swelling that inflammation causes because of xylol, the emulsifiable paste that (5 μ g/ ears are in fluticasone propionate) embodiment of institute of the present invention provides under identical application dose compare with existing 0.05% fluticasone propionate emulsifiable paste and have very significant effect (
*P＜0.01), and application dose only for the test group 2,4 of existing emulsifiable paste 50% also have significant effect (
*P＜0.05), shows that thus in the inhibition test to mice ear, technical scheme of the present invention has produced significant effect.And the prepared lipidosome cream of two kinds of different liposome preparation methoies that above-mentioned test also shows technical solution of the present invention to be adopted can produce essentially identical therapeutic effect.
The absorbefacient research of pharmacology embodiment 2 transdermal test in vitro
Carry out the radioactive label of fluticasone propionate in advance with tritium by the isotope in solid phase, catalysis and xenogenesis exchange.Obtain the specific activity of the 150mCi/mmol of 95% radiochemically pure.The fluticasone propionate of labelling is made 0.05% fluticasone propionate lipidosome cream according to embodiment 1,4 methods respectively, and prepare conventional 0.05% fluticasone propionate emulsifiable paste according to disclosed method in the pharmaceutics the 5th edition.
The human skin that is used for the research of transdermal test in vitro absorbability obtains from human plastic operation.
On skin, use behind the said preparation and from medicine-feeding part, to take a sample in 24 hours, then carry out strip step, SCD, epidermal area and skin corium.The radioactivity of measuring each sample of being got by liquid glimmer instrument is to determine the absorbance of active component.Following table has shown the absorbance of fluticasone propionate in the skin different tissues structure
| Horny layer % | Epidermal area % | Skin corium % | Total amount % in the skin | |
| Embodiment 1 | ??43.6 | ??4.8 | ??4.2 | ??52.6 |
| Embodiment 4 | ??43.4 | ??4.9 | ??4.1 | ??53.4 |
| Conventional emulsifiable paste | ??17.2 | ??6.2 | ??5.8 | ??29.2 |
Can draw from last table, the skin absorbs rate of the lipidosome cream of the employing embodiment of the invention 2,5 method gained is apparently higher than the conventional emulsifiable paste with dosage.And in the group that lipidosome cream is used, fluticasone propionate is at main therapeutic goal position---present better targeting in the horny layer and distribute.
Stability test embodiment
Lipidosome cream provided by the present invention and existing 0.1% fluticasone propionate emulsifiable paste (trade name: CUTIVATE) compare and carry out study on the stability long-term and that quicken, the plastic-aluminum combined hose packing that the canned 10g/ of going into of emulsifiable paste of embodiment 2,5 gained is propped up.Respectively get 20, compare with commercially available 20 of the CUTIVATE emulsifiable paste of date of manufacture in one month.
Get that embodiment 2,5 makes and fill is the lipidosome cream that 10g/ props up the plastic-aluminum tube packaging, carry out accelerated stability with the CUTIVATE emulsifiable paste and investigate, changes of contents result such as following table:
" the ointment regulation that Chinese pharmacopoeia version in 2005 is two ones, the active component content scope is 90%-110%.Embodiment 2,5 fluticasone propionate lipidosome cream samples that make and the contrast of CUTIVATE emulsifiable paste stability data can be found: during pro-was investigated in 3 months, compare embodiment 2 with the CUTIVATE emulsifiable paste, the content difference of 5 self-control samples is remarkable (P＞0.05) not, and compare embodiment 2 with the CUTIVATE emulsifiable paste, the its related substances difference of 5 samples is not significantly (P＞0.05) also, and all within acceptability limit, but in 3-6 month, the content of CUTIVATE emulsifiable paste sharply descends, content only 80.73% in the time of June, related substance does not meet the regulation of Chinese Pharmacopoeia up to 16.03%; And the content of embodiment 2,5 self-control samples all keeps up to about 95%, compare with content, the related substance of corresponding C UTIVATE emulsifiable paste all have significance (P＜0.01) this proved absolutely that the emulsifiable paste that makes according to the embodiment of the invention is better than CUTIVATE emulsifiable paste stability.In addition, layering, metachromatism all do not take place in the emulsifiable paste that makes by the present invention program in long-time stability are investigated.
Can find according to embodiment 2,5 homemade fluticasone propionate lipidosome cream samples and the contrast of CUTIVATE emulsifiable paste accelerated stability data: at high temperature under condition and the high light, all samples content all slightly descends in time, its related substances all slightly rises in time, and the former content and the latter generally exceed 1%～2% on year-on-year basis though embodiment 2,5 makes that the content of sample compares with the CUTIVATE emulsifiable paste that difference does not have significance (P＞0.05).Under super-humid conditions, the content of all samples and its related substances change less, illustrate under this condition, and be less for the emulsifiable paste stability influence.Accelerated stability data contrast table understands that the self-control sample is better than CUTIVATE emulsifiable paste accelerated stability outline.In addition, layering, metachromatism all do not take place in our 3 batch samples in accelerated stability is investigated.
Claims (10)
1, a kind of fluticasone propionate external-use liposome pharmaceutical composition, described pharmaceutical composition is made of following component: as the fluticasone propionate 0.025%～0.2% of active component, phosphatidase 10 .125%～6%, lipotropy additive 0～1% is used for the antioxidant 0.01～1% of the described pharmaceutical composition of preservation, pH value is remained on the pH buffer agent of 5-7.5, wetting agent 3%～15%, oil-phase component 20%～30%, antibiotic antiseptic 0.01%-0.1%, and the water of surplus.
2, pharmaceutical composition as claimed in claim 1 is characterized in that described liposome vesicle diameter is bilayer vesicles or multilamellar capsule less than 800nm.
3, pharmaceutical composition as claimed in claim 1 or 2, it is characterized in that, described phospholipid is phosphatidylcholine such as dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, phosphatidyl glycerol is as two palmityl phosphatidyl glycerols, distearyl phosphatidyl glycerol, Phosphatidylserine is as two palmityl Phosphatidylserine, distearyl Phosphatidylserine, one or more in soybean lecithin, hydrogenated soy phosphatidyl choline, the Ovum Gallus domesticus Flavus lecithin.The weight ratio of described phospholipid and active component is 5～30: 1.
4, as arbitrary described pharmaceutical composition in the claim 1 to 3, it is characterized in that the preferred cholesterol of described lipotropy additive, consumption is 0～1: 5 for the weight ratio with phospholipid.
5,, it is characterized in that described oil-phase component comprises one or more in solid in the oil-phase component, consistency modifiers, the emulsifying agent as arbitrary described pharmaceutical composition in the claim 1 to 4.
6, pharmaceutical composition as claimed in claim 5 is characterized in that solid in the described oil-phase component includes but are not limited to one or more of stearic acid, paraffin, Cera Flava, higher alcohol, and described oil-phase component consumption is 1%～15%.
7, pharmaceutical composition as claimed in claim 6 is characterized in that preferred hexadecanol of described oil-phase component and/or octadecanol.
8, as the described pharmaceutical composition of claim 5 to 7, it is characterized in that described emulsifying agent is that the consumption of one or more the described emulsifying agents in the derivant of soap class emulsifying agent, polyoxyethylene ether is 1～18%, soap class emulsifying agent consumption is 0.5～10%, and polyoxy ether class emulsifying agent consumption is 0.5%～8%.
9, as the described pharmaceutical composition of claim 6 to 8, it is characterized in that described denseness adjusting is preferably one or more in liquid Paraffin, vaseline or the vegetable oil, consumption is 5%～20%.
10,, it is characterized in that described wetting agent is one or more in glycerol, propylene glycol, the sorbitol as arbitrary described pharmaceutical composition in the claim 1 to 9.
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| CN107519177A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition using fluticasone propionate as active component |
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| CN112823009A (en) * | 2019-08-28 | 2021-05-18 | 上海谷森医药有限公司 | Fluticasone furoate liposome preparation and preparation method thereof |
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