CN103705922B - Using glucocorticoid as the externally-applied medicinal composition of active constituent - Google Patents
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Abstract
Using glucocorticoid as the externally-applied medicinal composition of active constituent, contains the glucocorticoid as active constituent and one or more excipient substances, contain natrium adetate or mosatil in the excipient substance.
Description
Technical field
The present invention relates to the externally-applied medicinal compositions that an a kind of glucocorticoid is active constituent.
Background technology
Glucocorticoids medicine, external application can be such that dermal capillary shrinks, and inhibit epidermal cell proliferation or regeneration, inhibit knot
The new life for forming fibrocyte in tissue stablizes intracellular lysosome membrane, the tissue damage for preventing lysosomal enzyme release caused, tool
There are stronger anti-inflammatory and anti-allergic effects.For allergic dermatitis, atopic dermatitis, contact dermatitis, seborrhea, wet
Rash, cutaneous pruritus, psoriasis, neurodermatitis etc..But long-term or large-area applications, atrophoderma and blood capillary can be caused
Enlargement of pipe, occurs acne sample dermatitis and epifolliculitis, and Perioral Dermatitis increases the infectibility etc. to infection.Can occasionally it cause abnormal anti-
Answering property contact dermatitis.What is more important long-time service can also cause pigmentation, i.e. skin darkening, and this variation is often
It is irreversible.Li Li journeys et al. are reported（The clinical observation of Fluocinonide liniment treated neurodermatitis, Tianjin pharmacy,
The 2nd phase of volume 18 in April, 2006, page 28）75 patients are treated with Fluocinonide liniment, main adverse reaction is just
It is that 5 patients pigmentation occur.
Mosatil（Disodium Edetate（Ethylenediaminetetra acetic AcidDisodium
Calcium Salt, Ethylenediaminetetraacetic Acid Calcium Salt, Ethylenediaminetetraacetic Acid Calcium Salt）Stable and soluble network can be combined into various metals
Close object, by being drained in urinating, therefore be mainly used for the poisoning of some metals, be mainly used for treat lead poisoning, can also treat cadmium, manganese, chromium,
Nickel, cobalt and copper poisoning, and it is used as the lead nigration of diagnosis.It is seldom used in excipient substance.
Natrium adetate（EDTA2Na）Make heavy metal detoxification medicine, complexing agent, antioxidant synergist, stabilizer and softening agent etc.,
The chelating agent for being widely used as injection in excipient substance simultaneously uses, such as《Pharmacy》（5th edition, Cui Defu chief editors, people
People's health publishing house publishes, 2006）One column of chelating agent only has natrium adetate in 61 page table 3-4 injection conventional additives.
Mosatil natrium adetate
Both natrium adetate and mosatils title is approximate, and effect is also similar, but due in mosatil by
In the presence of calcium ion, effect produces larger difference.
Both natrium adetate exists in use with mosatil obscures sunken phenomenon, and certain people think structure proximate,
Effect is approximate, can exchange use.But《Misapplying natrium adetate may be lethal》（《Adverse drug reaction magazine》2008
01 phase）In point out on January 16th, 2008, U.S. FDA issues important safety information about natrium adetate, warns patient and doctor
Raw miss may be lethal for chelation therapy and other usages that do not ratified by FDA by natrium adetate replacement mosatil.According to
Ground acid disodium (edetate disodium, Na2EDTA) and mosatil (edetate calcium disodium,
CaNa2EDTA) nomenclature of drug is similar, and usually abbreviation is indicated with EDTA.Therefore, in prescription, dispensing and drug administration process easily
It mixes up.Existing two medicines be used to that internal heavy metal or minerals be complexed, external with urine ejection to form soluble complex.It is real
On border, it is for different therapeutic purposes that FDA ratified both drugs originally, and the effect of two medicines is extremely different.Edetic acid(EDTA) two
Sodium is approved for treatment hypercalcinemia and digitalis poisoning institute proarrhythmia because that can reduce calcium level, is cyclic system
System medication；Mosatil can be combined with lead ion strength, the drive lead treatment of serious Lead Poisoning Patients is approved for, for a huge sum of money
Belong to antidote.With time duration, two medicines gradually derive many other usages, such as:Drive away other heavy metals in vivo, or uses
In treatment coronary heart disease, and largely used in clinic.But this treatment for being referred to as " chelation therapy ", safety and validity
Not yet approved by FDA.In particular, it should be pointed out that the Lead Poisoning Patients of mosatil treatment, especially children should be given, by
In misuse natrium adetate, may result in blood calcium, seriously reduction causes twitch even dead.
Due to the effect and adverse reaction of glucocorticoid itself, in external preparation for skin in use, according to state food drug
The regulation of Surveillance Authority, the pharmaceutical packing that cannot have used plastic tube to be in direct contact as paste, at present outside skin
It is packed by taking paste as an example with what pharmaceutical preparation was in direct contact in preparation, state approval use is in direct contact the packaging material of drug only
For aluminum pipe or medicinal polyethylene/compound ointment tube of aluminium/polyethylene（Lower abbreviation compound aluminum tube）, aluminium soft tube, compound aluminum tube all contain
There is aluminium, although the inside and outside wall of composite soft tube is plastics, centre is aluminium, and composite soft tube different materials weld stitching portion leakage
Possibility, the longitudinal seam of pipe shaft welding, the note of pipe shaft and two kinds of different materials of pipe shoulder connect, and aluminium therein is very likely to and medicine
Product are in direct contact.
There are more active groups on glucocorticoid molecular structure, by taking Fluocinonide as an example, that is, there is ester bond, contracting
The groups such as ketone, ketone group, hydroxyl, double bond, so fluocinolone acetonide and its ester is caused to there is the possibility degraded in acid, alkalinity, from
And cause the decline of content.Especially after directly being packed using aluminum pipe, trace meter particle such as alumina particles will become
The catalyst that fluocinolone acetonide and its ester decompose carries out the decline that storage will result in product content.
Invention content：
In constantly scientific research, it has been found that contain addition edetic acid(EDTA) two in glucocorticoid skin external preparation
Sodium or mosatil, can significantly improve preparation stability, also, it has been surprisingly found that compared with natrium adetate,
Pigmentation caused by can also inhibiting glucocorticoid using mosatil promotes the recovery of skin, improves therapeutic effect.
The present invention provides a kind of pharmaceutical composition, contains glucocorticoid as active constituent and one or more
Excipient substance, natrium adetate or mosatil are contained in the excipient substance, edetic acid(EDTA) is preferably comprised in excipient substance
Calcium sodium and do not contain natrium adetate, the content of mosatil is preferably 0.025-1%.
The glucocorticoid be selected from fluocinolone acetonide, Triamcinolone acetonide, Halcinonide, budesonide, cortisone, hydrogenation can
Pine, fluorometholone, dexamethasone, betamethasone, prednisolone, prednisone, hydrocortisone, Rimexolone（Rimexolone）、
Loteprednol, ciclesonide, alclometasone, beclomethasone, betamethasone, Chloroprednisone, clobetasol, clobetasone, chlorine can
Hold in the palm dragon, chlorine wave Buddhist nun alcohol, deflazacort, desonide, Desoximetasone, diflorasone, diflucortolone, Difluprednate, Flucloronide,
Flumethasone, flunisolide, fluocortolone, fluperolone, Fluprednidene, fluprednisolone, fludroxycortide, Halcinonide, Buprofein,
Halometasone, Halopredone, Hydrocortamate, medrysone, meprednisone, methylprednisolone, Mometasone, paramethasone, prednicarbate, wave
Prednylidene 21-diethylaminoacetatte, triamcinolone, Triamcinolone acetonide, Amcinonide, fluticasone, desonide, mazipredone, Tixocortol and its pharmaceutically acceptable
Salt or one or more of ester.
The glucocorticoid can obtain loose, butyric acid hydrogen selected from Fluocinonide, fluocinolone acetonide, triamcinolone acetonide acetate, hydrogenation
Change cortisone, dexamethasone, dexamethasone acetate.Beclomeasone propionate, clobetasol propionate, prednicarbate, Triamcinolone acetonide, vinegar
Sour Triamcinolone acetonide, halobetasol propionate, clobetasol propionate, Halometasone, fluticasone propionate, momestasone furoate, Halcinonide,
One or more of Methylprednisolone Aceponate, prednisone acetate, Econopred.
The content of described pharmaceutical composition, natrium adetate or mosatil is 0.01-2%, preferably 0.025-1%.
The content of the pharmaceutical composition, the glucocorticoid as active constituent is 0.01%~2%, preferably
0.02%~1%.
The pharmaceutical composition can prepare paste making agent, gelling agent, solution, spray, suspension.
The pharmaceutical composition, the pharmaceutic adjuvant include pH adjusting agent, antibiotic antiseptic, antioxidant, help
Solvent, osmotic pressure regulator, viscosity modifier, surfactant, rheology control agent, moisturizer, skin penetration enhancer, base
It is one or more of the alcohol of liquid under matter, water, room temperature.
The pH adjusting agent be phosphoric acid and its salt, boric acid and its salt, citric acid and its salt, acetic acid and its salt, tartaric acid and
Its salt, hydrochloric acid and its salt, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, tromethamine
One or more of.Preferably phosphoric acid and its salt, citric acid and its salt, acetic acid and its salt, hydrochloric acid and its salt, sodium hydroxide,
One or more of potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus.
The osmotic pressure regulator be glycerine, propylene glycol, sodium chloride, potassium chloride, D-sorbite, one kind in mannitol or
It is several.
The viscosity modifier is sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl fibre
One or more of element, polyvinyl alcohol, carboxy vinyl polymer, polyvinylpyrrolidone are tieed up, dosage is 0.1%~2%.
The surfactant is nonionic surfactant or lauryl sodium sulfate.
The nonionic surfactant is Tween-80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol-stearic acid
Ester, Macrogol 4000, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol and the like,
One or more of poloxamer, tyloxapol, peregal A, dosage are 0.1%~2%.
The moisturizer is one or more of glycerine, propylene glycol, sorbierite.Preferably in propylene glycol, glycerine
It is one or more of.
The skin penetration enhancer is menthol, borneol, essential oil class, isopropyl myristate, oleic acid, oleyl alcohol, ring ten
Five alkanones, anhydrosorbitol acid Sorbitane monooleate, Monoolein, propylene glycol monolaurate, polyethylene glycol mono laurate
Ester, 2- n-nonyls -1,3-dioxolane, 2-（N, N- dimethylamino）Propionic acid-dodecyl ester or its salt derivative, 2- second
Base caproic acid -2- ethylhexyls, Isosorbide dimethyl ether, -2 ketone of 4- decyls oxazolidine, -2 ketone of 3- methyl -4- decyls oxazolidine,
One or more of dimethyl-p-aminobenzoate monooctyl ester, OctMet, octyl salicylate.
Be the alcohol of liquid under the room temperature it is the one or more of monohydric alcohol, polyalcohol.It is preferred that monohydric alcohol is mixed with polyalcohol
Close object.The monohydric alcohol is ethyl alcohol, isopropanol, and polyalcohol is propylene glycol, glycerine.The monohydric alcohol be ethyl alcohol, isopropanol, it is more
First alcohol is glycerine.
The antioxidant is one or more of vitamin C, sodium pyrosulfite.
The antibiotic antiseptic is benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, methyl p-hydroxybenzoate, right
One or more of nipagin A, propylparaben, chlorobutanol.
The matrix is vaseline, lanolin, dimethicone, atoleine, beeswax, spermaceti, stearic acid, plant
One or more of oil, octadecyl alcolol, hexadecanol, carbomer.
The rheology control agent is carbomer.
The pharmaceutical composition, when preparing paste making agent, the excipient substance suitable for skin contains moisturizer
1%~15%, oil-phase component 20%~30%., the oil-phase component includes solid in oil-phase component, consistency modifiers, emulsification
One or more of agent.
Solid in the oil-phase component includes one or more of octadecyl alcolol, solid paraffin, beeswax, stearic acid.Institute
It is 1%~15% to state oil-phase component solid dosage.
The consistency modifiers are selected from one or more of vaseline, lanolin, dimethicone, atoleine.
The dosage of the consistency modifiers is 5%~20%.The preferred albolene of vaseline.
The emulsifier is selected from one or more of lauryl sodium sulfate, peregal A-20, the use of the emulsifier
Amount is 0.5-5%.
The moisturizer is selected from one or more of glycerine, propylene glycol, dosage 3%-10%.
Described pharmaceutical composition, when gelling agent is made, the auxiliary material contains water and is carbomer as rheology control agent
Resin, particularly preferably carbomer 934 and/or Acritamer 940 and/or Carbopol 941, dosage are pharmaceutical composition weight
0.1%~1%, preferably 0.2% to 0.5%.
The above degree is the weight percent of the dennophannaceutical compositions.
The pH of dennophannaceutical compositions provided by the invention is selected from 4-7.
The pharmaceutical composition, the packaging material for being in direct contact pharmaceutical composition contain metal.Preferably aluminium.
The Pharmaceutical composition, it is characterized in that the packaging material for being in direct contact pharmaceutical composition contains metal.The metal
For aluminium.
The active constituent the dermatologic may be used with the dispersion in composition active constituent is prepared into it is micro-
Powder is simultaneously scattered in composition, or active dissolution in organic solvent and is scattered in the method in composition, can also be prepared
At cyclodextrin inclusion compound and the known methods such as the method in composition are scattered in, preferably active constituent is prepared into micro mist and is scattered in
In composition, spray drying process, fluid bed supersonic jet mill method, high speed grinding may be used in the method for micronization of use
Method, ball-milling method, fluid energy mill method, solvent method etc..
Grain size of the present invention is mass median diameter（mass mean diameter）.
Specific implementation mode
Obtained various pharmaceutical compositions are both needed to sterilize.Glucocorticoid before preparation need use mechanical crushing or its
His form is ground into 10 μm of micro mist.
Embodiment 1-1
Dexamethasone acetate 1g, albolene 100g, octadecyl alcolol 30g, atoleine 30g,
Peregal A-20 50g, glycerine 50g, propylene glycol 20g, ethyl-para-hydroxybenzoate 1g,
Natrium adetate 0.1g waters for injection add to 1000g,
By the above proportioning accurate weighing, emulsifiable paste process for preparation is as follows：
（1）Oil phase is prepared：Take albolene, octadecyl alcolol, atoleine, peregal A-20 is placed in container, is heated to melting
Melt, temperature is maintained at 90 DEG C；
（2）Water phase is prepared：Natrium adetate is dissolved in water for injection, main ingredient is dispersed in glycerine, propylene glycol,
The aqueous solution of natrium adetate, ethyl-para-hydroxybenzoate is added, heating stirs evenly temperature and is maintained at 90 DEG C；
（3）Close phase：By step（1）The oil phase of preparation is slowly added into step（2）In the water phase of preparation, stirring keeps temperature
At 80 DEG C, 30min is stirred, cream is cooled to, obtains 1000g emulsifiable pastes, content 0.1%.
Embodiment 1-2
It is 0.25g by the quantitative change of natrium adetate according to the formula and technique of embodiment 1-1.
Embodiment 1-3
It is 1g by the quantitative change of natrium adetate according to the formula and technique of embodiment 1-1.
Embodiment 1-4
It is 5g by the quantitative change of natrium adetate according to the formula and technique of embodiment 1-1.
Embodiment 1-5
It is 10g by the quantitative change of natrium adetate according to the formula and technique of embodiment 1-1.
Embodiment 1-6
It is 25g by the quantitative change of natrium adetate according to the formula and technique of embodiment 1-1.
Embodiment 1-7
According to the formula and technique of embodiment 1-1, it is added without natrium adetate.
Embodiment 2-1 to embodiment 2-6
According to the formula and technique of embodiment 1-1 to embodiment 1-6, corresponding natrium adetate is replaced with into Ca-EDTA
Sodium, amount are constant.
Embodiment 3-1
Methylprednisolone Aceponate 0.5g, albolene 30g, octadecyl alcolol 120g, atoleine 50g,
Lauryl sodium sulfate 10g, glycerine 10g, propylene glycol 50g, ethyl-para-hydroxybenzoate 1g,
Natrium adetate 1g waters for injection are to 1000g
By the above proportioning accurate weighing, emulsifiable paste process for preparation is as follows：
（1）Oil phase is prepared：, take albolene, octadecyl alcolol, atoleine to be placed in container, be heated to melting, temperature is protected
It holds at 75 DEG C；
（2）Water phase is prepared：General, lauryl sodium sulfate, natrium adetate are dissolved in water for injection, and main ingredient is evenly dispersed
In glycerine, propylene glycol, the aqueous solution of natrium adetate, ethyl-para-hydroxybenzoate is added, heating stirs evenly temperature holding
At 90 DEG C；
（3）Close phase：By step（1）The oil phase of preparation is slowly added into step（2）In the water phase of preparation, stirring keeps temperature
At 90 DEG C, 30min is stirred, cream is cooled to, obtains 1000g emulsifiable pastes, content 0.05%.
Embodiment 3-2
According to the formula and technique of embodiment 3-1, natrium adetate is replaced with into mosatil.
Embodiment 3-3
According to the formula and technique of embodiment 3-1, it is added without natrium adetate.
Embodiment 4-1
Fluticasone propionate 0.1g, albolene 80g, octadecyl alcolol 120g, atoleine 40g,
Peregal A-20 5g, glycerine 40g, ethyl-para-hydroxybenzoate 0.5g,
Natrium adetate 2g
Water for injection is to 1000g
By the above proportioning accurate weighing, emulsifiable paste process for preparation is as follows：
（1）Oil phase is prepared：Take albolene, octadecyl alcolol, atoleine, peregal A-20 is placed in container, is heated to melting
Melt, temperature is maintained at 75 DEG C；
（2）Water phase is prepared：Natrium adetate is dissolved in the water for injection of recipe quantity, by main ingredient be dispersed in glycerine,
In propylene glycol, the aqueous solution of natrium adetate, ethyl-para-hydroxybenzoate is added, heating stirs evenly temperature and is maintained at 90 DEG C；
（3）Close phase：By step（1）The oil phase of preparation is slowly added into step（2）In the water phase of preparation, stirring keeps temperature
At 75 DEG C, 30min is stirred, cream is cooled to, obtains 1000g emulsifiable pastes, content 0.01%.
Emulsifiable paste fluticasone propionate content 0.01%
Embodiment 4-2
According to the formula and technique of embodiment 4-1, natrium adetate is replaced with into mosatil.
Embodiment 4-3
According to the formula and technique of embodiment 4-1, it is added without natrium adetate.
Embodiment 5-1
Hydrocortisone 10g, albolene 100g, octadecyl alcolol 60g, atoleine 100g,
Peregal A-20 10g, glycerine 10g, propylene glycol 10g, ethyl-para-hydroxybenzoate 1g, citric acid（C6H8O7·
H2O）3g, sodium citrate（Na3C6H5O7·2H2O）5g natrium adetates 1g
Water for injection is to 1000g
By the above proportioning accurate weighing, emulsifiable paste process for preparation is as follows：
（1）Oil phase is prepared：Take albolene, octadecyl alcolol, atoleine, peregal A-20 is placed in container, is heated to melting
Melt, temperature is maintained at 75 DEG C；
（2）Water phase is prepared：Natrium adetate is dissolved in the water for injection of recipe quantity, by main ingredient be dispersed in glycerine,
In propylene glycol, the aqueous solution of natrium adetate, ethyl-para-hydroxybenzoate is added, heating stirs evenly temperature and is maintained at 90 DEG C；
（3）Close phase：By step（1）The oil phase of preparation is slowly added into step（2）In the water phase of preparation, stirring keeps temperature
At 75 DEG C, 30min is stirred, cream is cooled to, obtains 1000g emulsifiable pastes, content 1%.
Embodiment 5-2
According to the formula and technique of embodiment 5-1, natrium adetate is replaced with into mosatil.
Embodiment 5-3
According to the formula and technique of embodiment 5-1, it is added without natrium adetate.
Embodiment 6-1 suspensions
Formula is as follows：Momestasone furoate 0.25g, sodium acetate 1g, hydroxypropyl methyl cellulose 2g, sodium chloride 8g,
Benzethonium chloride 0.05g, salt acid for adjusting pH to 6.0, natrium adetate 1g natrium adetates 1g add purified water extremely
1000ml。
Preparation method：
80% purified water of recipe quantity is heated to about 70 DEG C, then adds people's hydroxypropyl methyl cellulose.After being dispersed through, it will mix
It closes object and is cooled to about 30 DEG C,.Then, add people's sodium acetate, natrium adetate and benzethonium chloride and dissolve and be adjusted to pH with hydrochloric acid
5.0, refilter sterilized mixture.Active constituent, which is added, makes complete suspension supply purifying water, just obtains suspension in this way.It is living
Property ingredient micro mist average grain diameter be 5.2 μm.Content is 0.025%
Embodiment 6-2
According to the formula and technique of embodiment 6-1, natrium adetate is replaced with into mosatil.
Embodiment 6-3
According to the formula and technique of embodiment 6-1, it is added without natrium adetate.
The preparation of embodiment 7-1 gelling agents
8.9 μm, Acritamer 940 2g, glycerine 50g of 0.5 g average grain diameters of prednicarbate, Tween-80 2g
Benzalkonium chloride 1g natrium adetate 1g distilled water adds to 1000ml
0.1M sodium hydroxide solutions adjust pH to 5.5
Carbomer is mixed with Tween-80, benzalkonium chloride, natrium adetate and 300ml distilled water, is heated to 50-60
DEG C, it is gradually added into and stirs evenly after active constituent micro mist is water-dispersible, use, 0.1M sodium hydroxide solutions, adjust pH to 5.5, supply surplus
Water stir evenly up to clear gel.Content is 0.05%
Embodiment 7-2
According to the formula and technique of embodiment 7-1, natrium adetate is replaced with into mosatil.
Embodiment 7-3
According to the formula and technique of embodiment 7-1, it is added without natrium adetate.
The preparation of embodiment 8-1 gelling agents
The preparation of gelling agent
6.8 μm, carbomer 934 5g, glycerine 50g of clobetasol propionate 1g average grain diameters, Tween-80 5g
Benzalkonium chloride 1g sodium hydroxide 4g distilled water natrium adetates 1g adds to 1000g
Carbomer is mixed with Tween-80, benzalkonium chloride, natrium adetate and 300ml distilled water, is heated to 50-60
DEG C, it is gradually added into and stirs evenly after active constituent micro mist is water-dispersible, use, 0.1M sodium hydroxide solutions, adjust pH to 5.5, supply surplus
Water stir evenly up to clear gel.Content 0.1%
Embodiment 8-2
According to the formula and technique of embodiment 8-1, natrium adetate is replaced with into mosatil.
Embodiment 8-3
According to the formula and technique of embodiment 8-1, it is added without natrium adetate.
Embodiment 9-1
Beclomeasone propionate 0.25g, albolene 100g, octadecyl alcolol 30g, atoleine 30g,
Peregal A-20 50g, glycerine 50g, propylene glycol 20g, ethyl-para-hydroxybenzoate 1g,
Natrium adetate 1g waters for injection add to 1000g,
By the above proportioning accurate weighing, emulsifiable paste process for preparation is as follows：
（1）Oil phase is prepared：Take albolene, octadecyl alcolol, atoleine, peregal A-20 is placed in container, is heated to melting
Melt, temperature is maintained at 90 DEG C；
（2）Water phase is prepared：Natrium adetate is dissolved in water for injection, main ingredient is dispersed in glycerine, propylene glycol,
The aqueous solution of natrium adetate, ethyl-para-hydroxybenzoate is added, heating stirs evenly temperature and is maintained at 90 DEG C；
（3）Close phase：By step（1）The oil phase of preparation is slowly added into step（2）In the water phase of preparation, stirring keeps temperature
At 80 DEG C, 30min is stirred, cream is cooled to, obtains 1000g emulsifiable pastes, content 0.025%.
Embodiment 9-2
According to the formula and technique of embodiment 9-1, natrium adetate is replaced with into mosatil.
Embodiment 9-3
According to the formula and technique of embodiment 9-1, it is added without natrium adetate.
1 stability test of Pharmacological Examples
By above-described embodiment in addition to the preservation of 6-1,6-2 extra is all made of aluminum pipe, two kinds of compound aluminum tube is in direct contact drug
Packaging material is packed, and 6-1,6-2 embodiment take aluminum pipe, compound aluminum tube, low borosilicate glass ampoule to preserve.Aluminum pipe
The product of packing Co., Ltd. is raised using Changzhou hundred, compound aluminum tube uses the product of Sanying Package Materials Co ltd, Shanghai, low
Borosilicate glass ampoule uses the product of the clear and bright pharmaceutical pack Co., Ltd in Cangzhou.
Above-described embodiment carries out 10g/ branch according to the packaging material of following table（Bottle）It packs, measurement content before packing, after packaging
It takes and respectively takes 20（Bottle）Stored under the conditions of high temperature and humidity, storage condition be relative humidity 75% ± 5%, 40 DEG C ± 5 DEG C of temperature, 1
10 are taken after a month（Bottle）Content is measured, takes 10 after 3 months again（Bottle）Content is measured, it, will for the ease of embodying product specification
1 month after preservation, 3 months medicament contgs are compared with packing prodrug content（I.e. to pack prodrug content as 100%）
Drug to the corresponding time retains ratio, obtains a result and carries out mathematical statistics.
Experimental result：（, n=10）
By above-mentioned it is demonstrated experimentally that the topical composition without containing edetate sodium or mosatil is in aluminum pipe, clad aluminum
The speed manage, degraded in the packaging of low borosilicate glass ampoule is all faster than the topical compositions using edetate sodium or mosatil
Object, that is to say, that more stablized using the topical composition of edetate sodium or mosatil.
2 efficacy experiment of Pharmacological Examples
Experimental animal：Albino guinea-pig, level-one, half male and half female, weight 200-250g plant in Britain
Infect fungi：Alpha fungus (bacterium T5c, T. men-tagrophyte, trichophyton), by China Microbiological
Culture presevation administration committee medical mycology center provides, and restoring its pathogenicity before testing is inoculated in husky fort agar
(Sabrouraud dextrose agar SDA) slant tube, 26 DEG C are cultivated, and are carefully scraped bacterium colony after 10 d, are used physiology salt
Water is made containing spore count 105/ ml suspensions
Take cavy, electricity consumption is pushed away loses hair or feathers 3cm × 8cm areas in its back side, for 24 hours after, with the broken depilation of sterile fine sandpaper sassafras
Face centre skin is degree with slight oozing of blood, and it is 2cm × 6cm rectangle wound faces to cause area, then is uniformly inoculated on wound face
Above-mentioned bacterial strains suspension, per 1cm2It is inoculated with 1ml.Room temperature is kept for 30 DEG C, and animal inoculation pvaccination fungi goes out skin and fash, squama occurs after 10d
Bits or or crust, scraping fash, the scales of skin that peel off or the visible alpha fungus mycelia of crust microscopy and spore., with " 0,1,2,3,4 "
Classification indicates that lesion degree, criterion are：0 point indicates no skin lesion, and 1 point is dotted erythema, and 2 points are gamut erythema, 3
It is divided into the red and swollen, scales of skin that peel off, 4 points are the erythema to overrun, incrustation.Take scoring for 3,4 points of cavy, random grouping, every group 10
The drug that embodiment obtains is given, as a result see the table below：
Experimental method, each experimental group are administered once a day, and it is primary uniformly to smear experimental drug in experimental animal affected part every time,
Each group is administered that emulsifiable paste amount is identical, and 3d, 7d after administration respectively score to experimental animal affected part every time
Shown using edetate sodium as the pharmaceutical composition of chelating agent by pharmacological evaluation and does not use edetate sodium for chelating
The effect of pharmaceutical composition of agent, is approximate, and the effect of pharmaceutical composition of the use mosatil as chelating agent is better than
Pharmaceutical composition is stated, especially when the content of mosatil is more than 0.025% or more, effect is more obvious, and when it contains
When measuring more down to 0.01%, effect is general, and after content is more than 1%, continues growing mosatil dosage, curative effect increase is simultaneously
Unobvious.And different types of Donisolone, the collaboration effect of curative effect enhancing is produced after mosatil is added
Fruit.Illustrate that mosatil can generate synergy with glucocorticoid, enhances its therapeutic effect.
3 pigmentation of Pharmacological Examples is tested
Experiment material and method：The fragrant pig at 2.5 monthly ages is taken, weight is between 12 ± 0.3kg, and every group 2, every pig takes
Leg, abdomen white fur 6 positions as target site, take the foreleg, back leg, abdomen 2cmX2cm of symmetrical both sides to shave
Hair, 5 times a day, each coating 0.1g gives embodiment 1-1 to 1-6,3-1,4-1,5-1,6- respectively according to grouping left-hand portion
1, the drug that 7-1,8-1,9-1 are obtained, right side position is to embodiment 2-1 to 2-6,3-2,4-2,5-2,6-2,7-2,8-2,9-2
Obtained drug carries out tissue pathological slice and is hematoxylin eosin staining (hematoxylin-eosin after 100 days
) and immunohistochemical staining staining.
As a result：There is melanocytosis and moves up phenomenon in fragrant pig left-hand portion skin area, and degree is approximate, and right side region
Domain melanocytosis moves up phenomenon unobvious, and related to Ca-EDTA sodium content, wherein on 2-1 groups melanocytosis
Shifting ratio is about the 90-95% of left-hand portion skin, and 2-2,2-3,2-4,2-5,2-6 melanocytosis move up phenomenon about
It is the 80-90% of left-hand portion skin.And it is thin using the drug test melanocyte that 3-2,4-2,5-2,6-2,7-2,8-2,9-2 are obtained
Born of the same parents increase move up phenomenon the obtained drug study group of corresponding 3-1,4-1,5-1,6-1,7-1,8-1,9-1 90% hereinafter,
This proves that mosatil is not likely to produce pigmentation compared with edetate sodium while ensureing curative effect.
Claims (33)
1. a kind of pharmaceutical composition contains the glucocorticoid as active constituent and one or more excipient substances, institute
It states and contains mosatil in excipient substance, pharmaceutical composition prepares paste making agent, gelling agent, and the content of mosatil is
0.01-2%。
2. pharmaceutical composition as described in claim 1, it is characterized in that the glucocorticoid with being selected from fluocinolone acetonide, cloth how
Moral, cortisone, hydrocortisone, fluorometholone, dexamethasone, prednisolone, prednisone, Rimexolone（Rimexolone）, chlorine
It can be held in the palm for bold and vigorous promise, ciclesonide, alclometasone, beclomethasone, betamethasone, Chloroprednisone, clobetasol, clobetasone, chlorine
Dragon, chlorine wave Buddhist nun alcohol, deflazacort, Desoximetasone, diflorasone, diflucortolone, Difluprednate, Flucloronide, flumethasone, fluorine
Buddhist nun shrinkage porosite, fluocortolone, fluperolone, Fluprednidene, fluprednisolone, fludroxycortide, Halcinonide, Buprofein, Halometasone, halogen
Prednisone, Hydrocortamate, medrysone, meprednisone, methylprednisolone, Mometasone, paramethasone, prednicarbate, wave prednylidene 21-diethylaminoacetatte, song
Anxi dragon, Triamcinolone acetonide, Amcinonide, fluticasone, desonide, mazipredone, Tixocortol and its pharmaceutical salt or ester
One or more of.
3. pharmaceutical composition as described in claim 1, it is characterized in that the glucocorticoid is light selected from Fluocinonide, fluorine
Pine, hydrogenation can obtain loose, butyric acid hydrocortisone, dexamethasone, dexamethasone acetate, beclomeasone propionate, prednicarbate, Qu An
Nai De, triamcinolone acetonide acetate, halobetasol propionate, clobetasol propionate, Halometasone, fluticasone propionate, momestasone furoate, Kazakhstan
One or more of Xi Naide, Methylprednisolone Aceponate, prednisone acetate, Econopred.
4. pharmaceutical composition as described in claim 1, it is characterized in that the content of mosatil is 0.025-1%.
5. pharmaceutical composition as described in claim 1, it is characterized in that the content of the glucocorticoid is 0.01%~2%.
6. pharmaceutical composition as described in claim 1, it is characterized in that the content of the glucocorticoid is 0.02%~1%.
7. pharmaceutical composition as described in claim 1, it is characterized in that the excipient substance includes pH adjusting agent, Antimicrobial preservative
Agent, antioxidant, cosolvent, osmotic pressure regulator, viscosity modifier, surfactant, rheology control agent, moisturizer, matrix,
It is one or more of the alcohol of liquid under skin penetration enhancer, water, room temperature.
8. pharmaceutical composition as claimed in claim 7, it is characterized in that the pH adjusting agent be phosphoric acid and its salt, boric acid and its
Salt, citric acid and its salt, acetic acid and its salt, tartaric acid and its salt, hydrochloric acid and its salt, sodium hydroxide, potassium hydroxide, sodium carbonate,
One or more of potassium carbonate, sodium bicarbonate, saleratus, tromethamine.
9. pharmaceutical composition as claimed in claim 7, it is characterized in that the pH adjusting agent be phosphoric acid and its salt, citric acid and its
In salt, acetic acid and its salt, hydrochloric acid and its salt, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus
One or more.
10. pharmaceutical composition as claimed in claim 7, it is characterized in that the osmotic pressure regulator is glycerine, propylene glycol, chlorination
One or more of sodium, potassium chloride, D-sorbite, mannitol.
11. pharmaceutical composition as claimed in claim 7, it is characterized in that the viscosity modifier is sodium carboxymethylcellulose, hydroxyl
Ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, polyvinylpyrrolidine
One or more of alkanone, dosage are 0.1%~2%.
12. pharmaceutical composition as claimed in claim 7, it is characterized in that the surfactant be nonionic surfactant or
Lauryl sodium sulfate.
13. pharmaceutical composition as claimed in claim 12 is gathered it is characterized in that the nonionic surfactant is Tween-80
Ethylene oxide rilanit special 60, polyethylene glycol-stearate, Macrogol 4000, lecithin, sucrose ester are polyxyethylated
Ether, one or more of polyoxyethylene polyoxypropylene glycol, poloxamer, tyloxapol, peregal A, dosage 0.1%
~2%.
14. pharmaceutical composition as claimed in claim 7, it is characterized in that moisturizer is one kind in glycerine, propylene glycol, sorbierite
Or it is several.
15. pharmaceutical composition as claimed in claim 7, it is characterized in that moisturizer is one or more of propylene glycol, glycerine.
16. pharmaceutical composition as claimed in claim 7, it is characterized in that skin penetration enhancer is menthol, borneol, essential oil
Class, isopropyl myristate, oleic acid, oleyl alcohol, cyclopentadecanone, Monoolein, propylene glycol monolaurate, polyethylene glycol
Monolaurate, 2- n-nonyls -1,3-dioxolane, 2-（N, N- dimethylamino）Propionic acid-dodecyl ester or its salt derive
Object, 2 ethyl hexanoic acid -2- ethylhexyls, Isosorbide dimethyl ether, -2 ketone of 4- decyls oxazolidine, 3- methyl -4- decyl oxazoles
One or more of -2 ketone of alkane, dimethyl-p-aminobenzoate monooctyl ester, OctMet, octyl salicylate.
17. pharmaceutical composition as claimed in claim 7, it is characterized in that the alcohol under room temperature being liquid is monohydric alcohol, polyalcohol
It is one or more of.
18. pharmaceutical composition as claimed in claim 7, it is characterized in that the alcohol under room temperature being liquid is that monohydric alcohol and polyalcohol are mixed
Close object.
19. pharmaceutical composition as claimed in claim 18, it is characterized in that the monohydric alcohol is ethyl alcohol, isopropanol, polyalcohol is
Propylene glycol, glycerine.
20. pharmaceutical composition as claimed in claim 18, it is characterized in that the monohydric alcohol is ethyl alcohol, isopropanol, polyalcohol is
Glycerine.
21. pharmaceutical composition as claimed in claim 7, it is characterized in that the antioxidant is vitamin C, sodium pyrosulfite
One or more of.
22. pharmaceutical composition as claimed in claim 7, it is characterized in that the antibiotic antiseptic be benzalkonium chloride, benzethonium chloride,
In sorbic acid, potassium sorbate, methyl p-hydroxybenzoate, ethyl-para-hydroxybenzoate, propylparaben, chlorobutanol
One or more.
23. pharmaceutical composition as claimed in claim 7, it is characterized in that the matrix is vaseline, lanolin, dimethyl-silicon
One or more of oil, atoleine, beeswax, spermaceti, stearic acid, vegetable oil, octadecyl alcolol, hexadecanol, carbomer.
24. pharmaceutical composition as claimed in claim 7, it is characterized in that the rheology control agent is carbomer.
25. pharmaceutical composition as described in claim 1, it is characterized in that the pharmaceutical composition, prepares paste making agent, it is described
Excipient substance contains moisturizer 1%~15%, oil-phase component 20%~30%, and the oil-phase component includes consolidating in oil-phase component
One or more of body, consistency modifiers, emulsifier.
26. pharmaceutical composition as claimed in claim 25, it is characterized in that the solid in the oil-phase component includes octadecyl alcolol, consolidates
One or more of body paraffin, beeswax, stearic acid, the oil-phase component solid dosage are 1%~15%.
27. pharmaceutical composition as claimed in claim 25, it is characterized in that the consistency modifiers are selected from vaseline, wool
The dosage of one or more of fat, dimethicone, atoleine, the consistency modifiers is 5%~20%.
28. pharmaceutical composition as claimed in claim 25, it is characterized in that the emulsifier is selected from lauryl sodium sulfate, average
Add one or more of A-20, the dosage of the emulsifier is 0.5-5%.
29. pharmaceutical composition as claimed in claim 25, it is characterized in that the one kind of the moisturizer in glycerine, propylene glycol
Or several, dosage 3%-10%.
30. pharmaceutical composition as claimed in claim 7, it is characterized in that described pharmaceutical composition, is made gelling agent, described is auxiliary
For material containing water and as rheology control agent carbomer, dosage is the 0.1%~1% of pharmaceutical composition weight.
31. pharmaceutical composition as claimed in claim 30, it is characterized in that the carbomer is carbomer 934 and/or carbomer
940 and/or Carbopol 941, dosage 0.2% to 0.5%.
32. pharmaceutical composition as described in claim 1, it is characterized in that the packaging material for being in direct contact pharmaceutical composition contains gold
Belong to.
33. pharmaceutical composition as claimed in claim 32, it is characterized in that the metal is aluminium.
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| CN201210378729.3A CN103705922B (en) | 2012-10-08 | 2012-10-08 | Using glucocorticoid as the externally-applied medicinal composition of active constituent |
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| CN201210378729.3A CN103705922B (en) | 2012-10-08 | 2012-10-08 | Using glucocorticoid as the externally-applied medicinal composition of active constituent |
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| CN106474062A (en) * | 2015-08-27 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of external spraying agent containing desonide |
| KR101892908B1 (en) * | 2015-11-02 | 2018-08-29 | 아주대학교산학협력단 | Pharmaceutical Composition for Treating Non-small Cell lung Cancer Comprising Glucocorticoids |
| US11260062B2 (en) | 2015-11-02 | 2022-03-01 | Ajou University Industry-Academic Cooperation Foundation | Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound |
| CN107260665B (en) * | 2016-04-08 | 2021-03-30 | 天津金耀集团有限公司 | Mometasone furoate suspension composition for inhalation |
| CN107519493A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition containing Azulene sulfonate |
| CN107519181A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition using Methylprednisolone Aceponate as active component |
| CN108158992B (en) * | 2018-03-22 | 2020-07-28 | 重庆华邦制药有限公司 | Emulsifiable paste preparation containing alclometasone dipropionate |
| CN109125256B (en) * | 2018-10-18 | 2020-10-27 | 江西国药有限责任公司 | Prednisolone injection and preparation method thereof |
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