CN103127132A - Dermal medicine composition containing fluticasone propionate and nitric oxide synthase (NOS) inhibitor - Google Patents
Dermal medicine composition containing fluticasone propionate and nitric oxide synthase (NOS) inhibitor Download PDFInfo
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Abstract
A dermal medicine composition containing fluticasone propionate and a nitric oxide synthase (NOS) inhibitor comprises the fluticasone propionate used as an active ingredient, an amino acid derivative used as the NOS inhibitor, one type or a plurality of types of medicine auxiliary materials suitable for skins and the balance water.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, a kind of dermatologic compositions that contains 17-hydroxy-11-dehydrocorticosterone and no inhibitor.
Background technology
Glucocorticoid has antiinflammatory, antiallergic, rheumatism, immunosuppressive action, is widely used in treatment anaphylaxis and autoimmune inflammation disease.As connective tissue disease, activeness rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, ulcerative colitis, acute leukemia etc., also be used for some severe infections and Comprehensive Treatment poisoning, malignant lymphoma.
scytitis such as eczema (eczema), allergic dermatitis (allergic dermatitis), atopic dermatitis (atopic dermatitis) urticaria (Urticaria) etc. is all to be caused allergy and caused scytitis by certain allergen, the allergic effect that causes skin allergic reaction is original multiple, wherein viral, fungus, the infection such as antibacterial cause one of major reason of scytitis, (detection and the clinical meaning thereof of allergy dermatitis patients serum fungus specific IgE such as Yuan Wei, Zunyi Medical College's journal, in February, 2004, 24-25) disclose in 136 routine allergic dermatitis patients and have 96 examples to be diagnosed as the merging fungal infection, the document thinks that fungal infection is important sensitizing agent in the various skin inflammation such as allergic dermatitis.Glucocorticoid is widely used in the treatment scytitis, but due to the immunosuppressive action of glucocorticoid, makes glucocorticoid not only can not reach the effect of antiinflammatory when being used for the treatment of the inflammation that the skin surface fungal infection causes, and can make on the contrary the inflammation aggravation.Affected the application of glucocorticoid when the treatment scytitis.Moreover because allergic dermatitis and noninfective allergic dermatitis that the infection such as fungus cause are quite similar on surface symptoms, be difficult to differentiate as not adopting microscopic examination, therefore easily cause clinically mistaken diagnosis, thereby delay treatment.And the dermatosis that causes for infection such as dermatophytess, although do not use glucocorticoid in treatment, but the sensitization due to microorganisms such as funguses, often be attended by the generation of allergic skin inflammation, (the impact of corticosteroid on fungus such as Jia Dongmei, foreign medical science skin cypridology fascicle, the 29th the 4th phase of volume in 2003,201-203) disclose in the cutaneous fungal infection experiment, after adopting antifungal drug treatment to infection to eliminate, animal often also has the inflammatory crust to exist, and illustrates that scytitis often more is difficult to treatment than infection itself.
NO is a kind of biological function inorganic molecules widely, participate in the metabolism of circulation, the system such as neural, immune and bone, synthetic by NOS (nitricoxide synthase) in vivo, the NO Developmental and Metabolic Disorder can cause the diseases such as rheumatic arthritis, asthma, apoplexy, presenile dementia, nitricoxide synthase (NOS) inhibitor is that a class can suppress nitric oxide synthase activity, thereby reduces the material of NO content in body.Studies have shown that multinomial thereby no inhibitor can be used for the treatment of the diseases associated with inflammation such as above-mentioned disease such as arthritis by the NO content that suppresses in NOS activity decreased body.But reducing the synthetic of NO, it may produce the main mechanism of the side reactions such as endothelial dysfunction, pain sensation sensitization, the better easing pain and diminishing inflammation effect (CN200880004081.5) that offshore company's NSAID (non-steroidal anti-inflammatory drug) is combined with nitric oxide of reporting is also arranged simultaneously, so nitric oxide, nitric oxide synthase inhibitors both which kind of can play in vivo better antiinflammation and also have larger difference, because pharmacological action is indistinct, side reaction is larger, so no inhibitor is not now also as medicament administration.The main amino acid derivativges of existing no inhibitor for research experiment such as L-N
6-(acetimidoyl)-lysine, NG-nitro-L-arginine, L-NMME, N ω, N ω-Asymmetric Dimethylarginine and S-methyl isothiourea, aminoguanidine etc.But we find S-methyl isothiourea and aminoguanidine etc. medicine, due to itself chemical property, when being used for the outer used time, exist larger zest when treatment, cause compliance not good.
Summary of the invention:
in constantly scientific research, the discovery that we are surprised, amino acid derivativges and fluticasone propionate as no inhibitor are united use as skin-use preparation, compare with alone fluticasone propionate, can significantly improve the therapeutic effect of fluticasone propionate, and, we find unexpectedly, the coupling of these two kinds of medicines can also suppress local immunity power that the application due to fluticasone propionate causes and reduce and cause side effect such as increasing the weight of infection, we also find when adopting Percutaneous absorption enhancer in addition, especially the uniting when using of ethylhexyl salicylate that accounts for the isopropyl myristate of pharmaceutical composition percentage by weight 0.1-1% and account for pharmaceutical composition percentage by weight 1-5%, the pharmaceutical composition that obtains is suppressing the fluticasone propionate side effect, and produced beyond thought raising on the raising therapeutic effect.
The invention provides a kind of dermatologic compositions, contain as the fluticasone propionate of active component with as the amino acid derivativges of no inhibitor, and one or more are applicable to excipient substance that skin uses and the water of surplus.
Described dermatologic compositions is characterized in that.Described amino acid derivativges as no inhibitor is L-N
6-(acetimidoyl)-lysine, NG-nitro-L-arginine, L-NMME, N ω, one or more of N ω-Asymmetric Dimethylarginine and ester thereof or salt.
Described dermatologic compositions, the weight proportion that it is characterized in that fluticasone propionate and no inhibitor is 1: 0.1-10.Be preferably 1: 0.5-5, more preferably 1: 0.5-2.Described dermatologic compositions, described active component content is counted 0.01-0.2% with fluticasone propionate, is preferably 0.05-0.1%.
Dermatologic compositions provided by the invention can be mixed with unguentum, gel, solution, spray, suspensoid etc., and all are applicable to the preparation that skin is used.The adjuvant that skin uses of being applicable to of described dermatologic compositions includes but are not limited to one or more in pH adjusting agent, antibiotic antiseptic, antioxidant, cosolvent, osmotic pressure regulator, viscosity modifier, surfactant, rheology control agent, oil-phase component, wetting agent, stabilizing agent.
PH adjusting agent in described adjuvant can be enumerated but be not limited only to one or more in phosphoric acid and salt, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethane etc., one or more in preferred hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
Described osmotic pressure regulator can be enumerated but be not limited only to one or more in glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, mannitol, preferred sodium chloride.
Described viscosity modifier can be enumerated but be not limited only to one or more in sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, polyvinyl pyrrolidone.
Described wetting agent is selected from one or more in glycerol, propylene glycol, sorbitol, preferred glycerol.
Described antibiotic antiseptic is selected from benzoic acid, benzyl alcohol, p-Hydroxybenzoate (nipalgin), comprises one or more in methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, particularly preferably p-Hydroxybenzoate (nipalgin).
The optional non-ionic surface active agent of described surfactant, can enumerate but be not limited only to tween 80, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, sucrose ester, polyoxyethylene alkyl ether, one or more in polyoxyethylene polyoxypropylene glycol and analog thereof, poloxamer, tyloxapol.
When dermatologic compositions of the present invention is made gel, described adjuvant contains water and is the carbomer resin as rheology control agent, be particularly preferably carbomer 934 and/or Acritamer 940 and/or Carbopol 941, consumption is 0.1%～1% of pharmaceutical composition weight, preferred 0.2% to 0.5%.
When dermal drug compositions of the present invention is made ointment, describedly be applicable to the excipient substance that skin uses and contain wetting agent 1%～15%, oil-phase component 20%～30%, described wetting agent includes but are not limited to glycerol, propylene glycol, sorbitol, preferred glycerol, described oil-phase component comprise one or more in solid in oil-phase component, consistency modifiers, emulsifying agent.
Solid in 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 solid consumption is 1%～15%.
Described consistency modifiers includes but are not limited to one or more in vaseline, liquid paraffin, vegetable oil, preferred vaseline and/or liquid Paraffin, and the consumption of described consistency modifiers is 5%～20%.
Described emulsifying agent, preferred glyceryl monostearate and/or peregal A-20, preferred glyceryl monostearate consumption is 0.5%～10%, peregal A-20 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.
Above degree is the percentage by weight of described dermatologic compositions.
The pH of dermatologic compositions provided by the invention is selected from 4-7
during described active component can adopt with the dispersion in compositions at described dermatologic and active fraction preparation be become micropowder and be scattered in compositions, or with active dissolution in organic solvent and be scattered in method in compositions, also can be prepared into cyclodextrin clathrate and be scattered in known methods such as method in compositions, preferred active fraction preparation becomes micropowder and is scattered in compositions, the method of micronization that adopts can adopt spray drying method, fluid bed supersonic jet mill method, the speed lapping method, ball-milling method, the fluid energy mill method, solvent method etc., the preferred spray drying method that adopts.
The micropowder that described fluticasone propionate preferably is prepared into, the particle diameter of described micropowder are 0.5～50 μ m, preferred 5-30 μ m.
Described no inhibitor is preferably soluble in water when preparation.
described dermatologic compositions, preferably also add Percutaneous absorption enhancer, described Percutaneous absorption enhancer is menthol, Borneolum Syntheticum, the quintessence oil class, isopropyl myristate, oleic acid, oleyl alcohol, cyclopentadecanone, dehydration sorbic acid sugar alcohol monoleate, the glycerol monoleate, PGML, polyethylene glycol monolaurate, 2-n-nonyl-1, the 3-dioxolanes, 2-(N, the N-dimethylamino)-propanoic acid-dodecyl ester or its salt derivative, 2 ethyl hexanoic acid-2-ethyl hexyl ester, Isosorbide dimethyl ether, 4-decyl oxazolidine-2 ketone, 3-methyl-4-decyl oxazolidine-2 ketone, dimethyl-para-amino benzoic acid monooctyl ester, OctMet, ethylhexyl salicylate, laurocapram.Being preferably the use of uniting for the isopropyl myristate that accounts for pharmaceutical composition percentage by weight 0.1-1% and the ethylhexyl salicylate that accounts for pharmaceutical composition percentage by weight 1-5%, is more preferably the use of uniting that accounts for isopropyl myristate with the ethylhexyl salicylate that accounts for pharmaceutical composition percentage by weight 3% of pharmaceutical composition percentage by weight 0.1-0.3%.
Particle diameter of the present invention is mass median diameter (mass mean diameter).
Dermatologic compositions provided by the invention, can be used in dermatosis particularly scytitis treatment, the scytitis that particularly infects for concurrent antibacterial, can suppress local immunity power that the side effect because of fluticasone propionate causes reduces the infection that causes and increases the weight of, can alleviate significantly the symptom of laboratory animal, produce beyond thought therapeutic effect.When special in addition when the fluticasone propionate in active component is prepared into micropowder, nos inhibitor selects when soluble in water, add Percutaneous absorption enhancer, can better promote absorption and effect that NOS suppresses, but can not increase the systemic Absorption of fluticasone propionate, thereby can better bring into play the effect that no inhibitor suppresses the fluticasone propionate side effect, produce better therapeutic effect, be specially adapted to existing the treatment as the scytitis of fungal infection.Particularly the present invention preferably unites the cutaneous permeable agent of use, compares with alone any one cutaneous permeable agent, has produced beyond thought effect, has better brought into play the therapeutic effect of 17-hydroxy-11-dehydrocorticosterone and has suppressed its side effect.
The specific embodiment
Prepared various pharmaceutical composition all need be sterilized.Fluticasone propionate all need be ground into the micropowder of 5 μ m to 30 μ m with mechanical activation comminution or other forms before preparation, the skin composition that provides in the embodiment of the present invention is all in 1000ml.Process for preparation preferably carries out under nitrogen protection.The pharmaceutical composition that embodiment prepares can be distributed into solution, also can divide to install to and make spray in aerosol container.
Embodiment 1
L-N6-(acetimidoyl)-lysine 5g, sodium chloride is appropriate, sodium carboxymethyl cellulose 2.5g, poloxamer 0.5g, fluticasone propionate 0.5g, the water for injection of surplus
Compound method: sodium carboxymethyl cellulose, the poloxamer of recipe quantity are dissolved in 500ml water for injection, stir molten clearly, add the L-N6-(acetimidoyl) of recipe quantity-lysine, transfer pH to 5.5.The fluticasone propionate micropowder that adds recipe quantity adds the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=03%, fluticasone propionate %=0.05%.
Embodiment 2 gels
L-NMME 10g, glycerol 50ml, carbomer 934 2g,
Fluticasone propionate 1g,
The carbomer 934 of getting recipe quantity adds the glycerol moistening to grind, adding 500ml purified water swelling as gel-type vehicle, the fluticasone propionate micropowder of recipe quantity is joined in gel-type vehicle stir evenly, again with the L-NMME of recipe quantity, be dissolved in suitable quantity of water, slowly join in gel-type vehicle and stir evenly, sodium hydroxide adjust pH to 5.5 with appropriate 1mol/L adds the water of surplus and get final product.Resulting composition no inhibitor %=1%, fluticasone propionate=0.1%.
Embodiment 2-1
Fill a prescription identical with embodiment 2, separately get menthol 10g, be dissolved in the recipe quantity glycerol, other compound methods are identical with embodiment 2.
Embodiment 3 ointments
N ω, N ω-Asymmetric Dimethylarginine 1g, glycerol 50g
Fluticasone propionate, 0.5g
The formula of oil phase:
White vaseline 60g octadecanol 30g liquid Paraffin 30g glyceryl monostearate 50g peregal a-2010g
Preparation:
1. the preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, then the glycerol of getting recipe quantity is heated to same temperature and slowly joins in oil phase, stirs while adding to evenly and get final product.
The preparation of emulsifiable paste
With N ω, N ω-Asymmetric Dimethylarginine is dissolved in suitable quantity of water, adds the fluticasone propionate micropowder that is scattered in water, supplementing water is heated to 65 ℃ to recipe quantity, the oil-phase component that will be heated to again 70 ℃ adds, and stirs while adding evenly to condensation and get final product.Resulting composition no inhibitor %=0.1%, fluticasone propionate %=0.05%.
Embodiment 3-1
Fill a prescription identical with embodiment 3, separately get OctMet 10g, be dissolved in the recipe quantity glycerol, compound method is identical with embodiment 3.
Embodiment 3-2 ointment
Except the fluticasone propionate consumption changes into 0.1g, other formulas, preparation method are identical with embodiment 3-1, make compositions, resulting composition no inhibitor %=0.1%, fluticasone propionate %=0.01%.
Embodiment 4
NG-nitro-L-arginine 0.2g, sodium chloride is appropriate, hydroxypropyl cellulose 2.5g, tyloxapol 1.0g
Fluticasone propionate 2g,
The water for injection of surplus
Compound method: hydroxypropyl cellulose, the tyloxapol of recipe quantity are dissolved in 500ml water for injection, stir molten clearly, add the NG-nitro-L-arginine of recipe quantity, transfer pH to 5.0.Add after recipe quantity fluticasone propionate micropowder is disperseed with water-wet, then add the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=0.02%, fluticasone propionate %=0.2%
Embodiment 4-1
Fill a prescription identical with embodiment 4, separately get laurocapram 10g, be dissolved in the recipe quantity glycerol, other compound methods are identical with embodiment 4.
Embodiment 5
L-NMME 0.4g, glycerol 50ml, carbomer 934 5g fluticasone propionate 2g
The carbomer 934 of getting recipe quantity adds the glycerol moistening to grind, adding 500ml purified water swelling as gel-type vehicle, slowly join in gel-type vehicle after the fluticasone propionate micropowder of recipe quantity is disperseed with water-wet and stir evenly, L-NMME with recipe quantity is dissolved in suitable quantity of water again, slowly join in gel-type vehicle and stir evenly, sodium hydroxide adjust pH to 5.5 with appropriate 1mol/L adds the water of surplus and get final product.Resulting composition no inhibitor %=0.04%, fluticasone propionate %=0.2%.
Embodiment 5-1
Fill a prescription identical with embodiment 5, separately get isopropyl myristate 10g, be dissolved in the recipe quantity glycerol, compound method is identical with embodiment 5.
Embodiment 6
N ω, N ω-Asymmetric Dimethylarginine 2g
Fluticasone propionate 2g, glycerol 120g
The formula of oil phase:
White vaseline 30g octadecanol 120g liquid Paraffin 10g glyceryl monostearate 20g peregal a-2050g
Preparation:
2. the preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, then the glycerol of getting recipe quantity is heated to same temperature and slowly joins in oil phase, stirs while adding to evenly and get final product.
The preparation of emulsifiable paste
With N ω, N ω-Asymmetric Dimethylarginine is dissolved in suitable quantity of water, adds the fluticasone propionate micropowder that is scattered in water, supplementing water is to recipe quantity, be heated to again 65 ℃, then will be heated to the oil-phase component of 70 ℃ and add, stir while adding evenly to condensation and get final product.Resulting composition no inhibitor %=0.2%, fluticasone propionate %=0.2%.
Embodiment 6-1
Fill a prescription identical with embodiment 6, separately get ethylhexyl salicylate 30g, be dissolved in the recipe quantity glycerol, compound method is identical with embodiment 6.
Embodiment 7
NG-nitro-L-arginine 1g, sodium chloride is appropriate, hydroxypropyl emthylcellulose 5g, the appropriate fluticasone propionate 0.5g of tyloxapol 2g sodium hydroxide,
The water for injection of surplus
Compound method: hydroxypropyl emthylcellulose, the tyloxapol of recipe quantity are dissolved in 500ml water for injection, stir molten clearly, add the NG-nitro-L-arginine of recipe quantity, transfer pH to 5.5 with sodium hydroxide.Add after recipe quantity fluticasone propionate micropowder is disperseed with water-wet, add the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=0.1%, fluticasone propionate %=0.05%.
Embodiment 8
L-N
6-(acetimidoyl)-lysine 1g, glycerol 150g
Fluticasone propionate 0.2g
The formula of oil phase:
White vaseline 90g octadecanol 60g liquid Paraffin 60g glyceryl monostearate 10g peregal a-2030g
Preparation:
1. the preparation of oil phase
The oil-phase component of getting recipe quantity is heated to 70 ℃, then the glycerol of getting recipe quantity is heated to same temperature and slowly joins in oil phase, stirs while adding to evenly and get final product.
2. the preparation of emulsifiable paste
With L-N
6-(acetimidoyl)-lysine is dissolved in suitable quantity of water, adds the fluticasone propionate micropowder that is scattered in water, and supplementing water is to recipe quantity, then is heated to 65 ℃, then will be heated to the oil-phase component of 70 ℃ and add, and stirs while adding evenly to condensation and get final product.Resulting composition no inhibitor %=0.1%, fluticasone propionate %=0.02%.
Embodiment 8-1
Fill a prescription identical with embodiment 8, separately get ethylhexyl salicylate 30g, be dissolved in the recipe quantity glycerol, other compound methods are identical with embodiment 8.
Embodiment 8-2
Fill a prescription identical with embodiment 8, separately get and separately get ethylhexyl salicylate 30g and 1g IPM, be dissolved in the recipe quantity glycerol, other compound methods are identical with embodiment 8.
Embodiment 8-3
Fill a prescription identical with embodiment 8, separately get and separately get ethylhexyl salicylate 30g and 3g IPM, be dissolved in the recipe quantity glycerol, other compound methods are identical with embodiment 8.
Embodiment 9
L-NMME 2g, sodium chloride is appropriate, hydroxypropyl emthylcellulose 2g, tyloxapol 2g, fluticasone propionate 1g,
The water for injection of surplus
Compound method: with recipe quantity, hydroxypropyl emthylcellulose, tyloxapol be dissolved in 500ml water for injection, stirs molten clearly, adds the L-NMME dissolving of recipe quantity, transfers pH to 6.0.Add the fluticasone propionate micropowder that is scattered in water, add the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=0.2%, fluticasone propionate %=0.1%.
Embodiment 10
N ω, N ω-Asymmetric Dimethylarginine 1g
Sodium chloride is appropriate, carboxymethyl cellulose 2g, poloxamer 2g
Fluticasone propionate 1g, the water for injection of surplus
Compound method: carboxymethyl cellulose, the poloxamer of recipe quantity are dissolved in 500ml water for injection, stir molten clearly, add the N ω of recipe quantity, N ω-Asymmetric Dimethylarginine is transferred pH to 6.0.Add the fluticasone propionate that is scattered in water, add the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=0.1%, fluticasone propionate %=0.1%
Embodiment 11
L-NMME 0.2g sodium chloride is appropriate, polyvinylpyrrolidone 1g, poloxamer 2g, fluticasone propionate 0.2g, the water for injection of surplus
Compound method: polyvinylpyrrolidone, the poloxamer of recipe quantity are dissolved in 500ml water for injection, stir molten clearly, add the L-NMME of recipe quantity, transfer pH to 6.0 with sodium hydroxide.The fluticasone propionate that adds recipe quantity adds the water for injection of surplus.Transfer to etc. with sodium chloride and ooze, packing.Resulting composition no inhibitor %=0.02%, fluticasone propionate %=0.02%
Pharmacology embodiment
Laboratory animal: albino guinea-pig, one-level, male and female half and half, body weight 200-250g plant in Britain
Fungal infection: alpha fungus (bacterium T
5cT.men-tagrophyte, trichophyton), provided by China Committee for Culture Collection of Microorganisms's medical mycology center, recover its pathogenicity inoculation sub husky fort agar (Sabrouraud dextrose agar SDA) slant tube before experiment, 26 ℃ of cultivations, careful scraping bacterium colony after 10d is made with normal saline and is contained spore count 10
5/ ml suspension
Get Cavia porcellus, electricity consumption pushes away one side depilation 3cm * 8cm area at its back, after 24h, with the central skin of the broken depilation face of aseptic fine sandpaper sassafras, take slight oozing of blood as degree, causing area is 2cm * 6cm rectangle wound face, evenly inoculate again above-mentioned bacterial strains suspension, every 1cm on wound face
2Inoculation 1ml.Room temperature keeps 30 ℃, after 10d the animal inoculation fungus go out skin occur erythra, squama or or crust, scraping erythra, squama or crust microscopy can be seen alpha fungus mycelia and spore., representing lesion degree with " 0,1,2,3,4 " classification, criterion is: expression in 0 minute is without skin lesion, and 1 is divided into the point-like erythema, and 2 are divided into the gamut erythema, and 3 are divided into redness, squama, and 4 are divided into erythema, the incrustation that overruns.Getting scoring is Cavia porcellus more than 3 minutes, random packet, and every group of 10 administration and grouping see the following form:
| Numbering | Administration |
| Experimental group 1 | Embodiment 1 makes compositions, fluticasone propionate %=0.05%, no inhibitor %=0.5% |
| Experimental group 2 | Embodiment 2 makes compositions, fluticasone propionate %=0.1%, no inhibitor %=1% |
| Experimental group 2-1 | Embodiment 2-1 makes compositions |
| Experimental group 3 | Embodiment 3 makes compositions, fluticasone propionate %=0.05%, no inhibitor %=0.1% |
| Experimental group 3-1 | Embodiment 3-1 makes compositions |
| Experimental group 3-2 | Embodiment 3-2 makes compositions, fluticasone propionate %=0.01%, no inhibitor %=0.1% |
| Experimental group 4 | Embodiment 4 makes compositions, fluticasone propionate %=0.2%, no inhibitor %=0.02% |
| Experimental group 4-1 | Embodiment 4-1 makes compositions |
| Experimental group 5 | Embodiment 5 makes compositions, fluticasone propionate %=0.2%, no inhibitor %=0.04% |
| Experimental group 5-1 | Embodiment 5-1 makes compositions |
| Experimental group 6 | Embodiment 6 makes compositions, no inhibitor %=0.2%, fluticasone propionate %=0.2%. |
| Experimental group 6-1 | Embodiment 6-1 makes compositions |
| Experimental group 7 | Embodiment 7 makes compositions, no inhibitor %=0.1%, fluticasone propionate %=0.05%. |
| Experimental group 8 | Embodiment 8 makes compositions, no inhibitor %=0.1%, fluticasone propionate %=0.02%. |
| Experimental group 8-1 | Embodiment 8-1 makes compositions |
| Experimental group 8-2 | Embodiment 8-2 makes compositions |
| Experimental group 8-3 | Embodiment 8-3 makes compositions |
| Experimental group 9 | Embodiment 9 makes compositions, no inhibitor %=0.2%, fluticasone propionate %=0.1%. |
| Experimental group 10 | Embodiment 10 makes compositions, no inhibitor %=0.1%, fluticasone propionate %=0.1% |
| Experimental group 11 | Embodiment 11 makes compositions, no inhibitor %=0.02%, fluticasone propionate %=0.02% |
| Matched group 1-matched group 11 | Adopt respectively the formula of the compositions of experimental group 1-11, do not add no inhibitor. |
| Matched group 12 | Adopt the formula of the compositions of experimental group 6-1, do not add no inhibitor |
| Matched group 13 | Positive controls adopts normal saline |
Experimental technique, each experimental group is administered once every day, evenly smears Experimental agents once in the laboratory animal affected part at every turn, and it is identical that each organizes each administration emulsifiable paste amount, and 3d, 7d after administration mark to the laboratory animal affected part respectively
Show by pharmacological evaluation, compare with the matched group 13 as negative control, so significant therapeutic effect that the laboratory animal of experimental group all produces, and use merely the matched group 1-11 of fluticasone propionate external curing, and added Percutaneous absorption enhancer, the simple treatment of control group effect of fluticasone propionate of using is relatively poor, does not especially obviously improve through the treatment symptom of 7 days, and what have deterioration even occurred.Pharmaceutical composition provided by the invention is described, by adding no inhibitor, has suppressed fluticasone propionate in antiinflammatory, thereby reduce the side effect that skin surface immunity causes that infection increases the weight of.Particularly in each experimental group, used experimental group 2-1,3-1,4-1,5-1,6-1, the 8-1 of the pharmaceutical composition with Percutaneous absorption enhancer to compare with experimental group 2-6,8 respectively, therapeutic effect has also produced obvious raising, especially 8-2,8-3 group curative effect is compared with experimental group 2-1,3-1,4-1,5-1,6-1,8-1, the raising of therapeutic effect is more obvious, illustrates in Percutaneous absorption enhancer as according to ratio provided by the invention, ethylhexyl salicylate and isopropyl myristate coupling successful are better than other cutaneous permeable agents to use separately.And add each experimental group of cutaneous permeable agent, therapeutic effect is also significantly better than the experimental group that does not use cutaneous permeable agent of same dosage, the effect that can improve no inhibitor that adds of Percutaneous absorption enhancer is described, better suppress the side effect of fluticasone propionate, improve the therapeutic effect of medicine.
Pharmacology embodiment 3, transdermal permeation in vitro
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 the pH7.4 phosphate buffer to make release medium in receiving chamber, keep endodermis and solution close contact.Get the 0.1ml medicinal liquid and be coated on skin, regulate water-bath and make outer jacket layer temperature constant in (37 ± 1) degree, mixing speed is 100rpm, respectively at 0,0.15,0.5,0.75,1,1.5,2 hour absorption release medium 4ml, adds simultaneously equivalent PBS liquid.Discharge liquid and determine concentration C i with the method for Chinese Pharmacopoeia version in 2010, try to achieve drug per unit area accumulation transit dose Q:Q=CiV/A according to following formula.In formula, Q is drug per unit area accumulation transit dose, and Ci is the drug level in release medium in the t time, and V is the receiving chamber volume, and A is the skin diffusion area.With Q and C, the time is carried out linear regression respectively, try to achieve permeability (J/ μ gh
-1)
The preparation of Experimental agents: momestasone furoate, methylprednisolone aceponate, hydrocortisone butyrate with same dose replace fluticasone propionate as the glucocorticoid in active component, nos inhibitor and other adjuvants are according to the formula of embodiment 8-2 or 8-3, preparation becomes Comparative Examples 1-6, formula and active component such as following table
Get the pharmaceutical composition that makes of embodiment 8 and 8-1～8-3 and reference examples 1-6 group, carry out the body outer osmotic test, Experimental agents sugar cortex micropowder mean diameter all between 15-18 μ m, can think in this experiment particle diameter on permeability without impact.Result is as follows:
| Numbering | Glucocorticoid J (μ gh -1) | Numbering | Glucocorticoid J (μ gh -1) |
| Embodiment 8 | 1.56 | Comparative Examples 2 | 5.72 |
| Embodiment 8-1 | 5.51 | Comparative Examples 3 | 5.61 |
| Embodiment 8-2 | 7.13 | Comparative Examples 4 | 5.57 |
| Embodiment 8-3 | 7.85 | Comparative Examples 5 | 5.62 |
| Comparative Examples 1 | 5.64 | Comparative Examples 6 | 5.73 |
Test shows, as the embodiment 8-1～8-3 that adopts Percutaneous absorption enhancer, its drug osmotic rate is apparently higher than the embodiment 8 that is not used in Percutaneous absorption enhancer.But used particularly preferred embodiment 8-2, the 8-3 that unites the cutaneous permeable agent of use of the present invention, the permeability of fluticasone propionate is apparently higher than embodiment 8-1, and we find unexpectedly simultaneously, same dose and formula, but adopt the reference examples 1-6 of the glucocorticoid of other kinds, the permeability of its glucocorticoid and embodiment 8-1 are substantially suitable, thereby illustrate that preferably uniting the permeability of using Percutaneous absorption enhancer can specifically increase fluticasone propionate improves its therapeutic effect.
Claims (10)
1. dermatologic compositions contains as the fluticasone propionate of active component with as the L-N of no inhibitor
6-(acetimidoyl)-lysine, as the isopropyl myristate that accounts for pharmaceutical composition percentage by weight 0.1-1% of Percutaneous absorption enhancer with account for the ethylhexyl salicylate of pharmaceutical composition percentage by weight 1-5%, and one or more are applicable to excipient substance that skin uses and the water of surplus.
2. dermatologic compositions as claimed in claim 1 is characterized in that described fluticasone propionate and is 1 as the mass ratio of no inhibitor: 0.1-10.
3. dermatologic compositions as claimed in claim 1 is characterized in that described active component content counts 0.01-0.2% with fluticasone propionate.
4. dermatologic compositions as described in as arbitrary in claim 1-3 is characterized in that being mixed with unguentum, gel, solution, spray, suspensoid.
5. dermatologic compositions as claimed in claim 5 is characterized in that describedly being applicable to adjuvant that skin uses and including but are not limited to one or more in pH adjusting agent, antibiotic antiseptic, antioxidant, cosolvent, osmotic pressure regulator, viscosity modifier, surfactant, rheology control agent, oil-phase component, wetting agent, stabilizing agent.
6. dermatologic compositions as claimed in claim 5, when it is characterized in that described dermatologic compositions is made gel, described adjuvant contains water and is the carbomer resin as rheology control agent.
7. dermatologic compositions as claimed in claim 6, is characterized in that described carbomer resin is preferably carbomer 934 and/or Acritamer 940 and/or Carbopol 941, and consumption is 0.1%～1% of dermatologic compositions weight.
8. dermatologic compositions as claimed in claim 5 when it is characterized in that described dermatologic compositions is made ointment, describedly is applicable to the excipient substance that skin uses and contains wetting agent 1%～15%, oil-phase component 20%～30%.
9. dermatologic compositions as claimed in claim 7, is characterized in that described described wetting agent includes but are not limited to glycerol, propylene glycol, sorbitol.
10. dermatologic compositions as claimed in claim 1, is characterized in that the micropowder that described fluticasone propionate preferably is prepared into, and the particle diameter of described micropowder is 0.5～50 μ m.
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| CN 201110391664 CN103127132A (en) | 2011-11-30 | 2011-11-30 | Dermal medicine composition containing fluticasone propionate and nitric oxide synthase (NOS) inhibitor |
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| CN 201110391664 CN103127132A (en) | 2011-11-30 | 2011-11-30 | Dermal medicine composition containing fluticasone propionate and nitric oxide synthase (NOS) inhibitor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Application publication date: 20130605 |