CN108567782A - A kind of posaconazole externally-applied medicinal composition, preparation method and the usage - Google Patents
A kind of posaconazole externally-applied medicinal composition, preparation method and the usage Download PDFInfo
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- CN108567782A CN108567782A CN201810732469.2A CN201810732469A CN108567782A CN 108567782 A CN108567782 A CN 108567782A CN 201810732469 A CN201810732469 A CN 201810732469A CN 108567782 A CN108567782 A CN 108567782A
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- posaconazole
- pharmaceutical composition
- composition according
- pharmaceutically acceptable
- cyclodextrin
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- 230000004797 therapeutic response Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
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- Communicable Diseases (AREA)
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Abstract
The invention belongs to technical field of medicine, a kind of posaconazole externally-applied medicinal composition, preparation method and the usage are disclosed.The pharmaceutical composition contains active constituent posaconazole, beta cyclodextrin and pharmaceutically acceptable auxiliary material, and wherein posaconazole and beta cyclodextrin weight ratio are 1:1~4.5.By being dissolved in posaconazole in the pharmaceutically acceptable solvent containing beta cyclodextrin, various auxiliary materials are added, stirs evenly and is prepared.The pharmaceutical composition can be used for treating dermatophytid infection.It is low that the present invention solves posaconazole dissolubility, the shortcomings that quality of the pharmaceutical preparations is unstable, skin irritation not high to the penetrability of skin, avoids hepatotoxicity wind agitation and gastrointestinal side effect of the posaconazole during body metabolism, a kind of new administration route is provided for patient, improves patient's compliance.
Description
Technical field
The invention belongs to technical field of medicine, more particularly to a kind of posaconazole externally-applied medicinal composition, its preparation
Method and purposes.
Background technology
Dermatophytid infection is worldwide extremely widespread at present, mainly invades skin, hair by tinea bacterium, refers to (toe)
Caused by first-class body surface, it can cause tissue reaction after infecting human body and erythematous papules, blister, the scales of skin that peel off, disconnected hair, alopecia occurs
With deck change etc..Mainly the systemic therapy including Perorally administrable antimicrobial medicine and externally applied drug are local for the treatment of dermatophytid infection at this stage
Treatment or both is used in combination, but curative effect is unsatisfactory, easily recurs, and existing drug has certain toxic side effect or irritation, patient
Compliance is poor, and treatment course is long, seriously affects the quality of life of patient.
Posaconazole is the second generation antifungal drug in triazole class being derived from Itraconazole, and FDA ratifies for invading
Property fungal infection prevention, treat monilial infection, Fluconazole and the refractory monilial infection of Itraconazole；European Union EMA is also criticized
The mutatis mutandis invasive aspergillosis refractory in amphotericin B or Itraconazole, fusaridiosis, chromoblastomycosis and mycetoma,
Coccidioidomycosis (including Fluconazole is refractory) is severe disease or immune deficiency and reads the poor oropharynx of local therapeutic response
The first-line treatment drug of pearl bacterium disease.In vitro study finds that MIC (minimum inhibitory concentration) value of posaconazole is relatively low, is in triazole type
Activity it is strongest, to the saccharomycete including candida albicans, cryptococcus of intractable and recurrent, Aspergillus, dimorphic fungi,
Dermatophyte has very strong activity, still effective to the Candida albicans of Itraconazole, voriconazole and fluconazole resistant.
Posaconazole only has injection and peroral dosage form at present, the disadvantage is that there are certain hepatotoxicities, and in treatment phase
Between common gastrointestinal discomfort and headache etc. adverse reactions.In conjunction with superpower anti-of the Therapy characteristics and posaconazole of dermatophytid infection
Bacterium activity, a kind of posaconazole external preparation that can be directly acted on lesions position and reduce adverse reaction of exploitation are meaningful.
The original Formulations for systemic administration of posaconazole is changed to local topical administration, using skin histology as permeability barrier, limitation posaconazole exists
Whole Body infiltration rate avoids hepatotoxicity wind agitation and gastrointestinal side effect of the posaconazole during body metabolism, improves trouble
Person's compliance.
Posaconazole is not soluble in water, is insoluble in acetone, methanol, ethyl alcohol equal solvent, and patent CN102958528A discloses one
The posaconazole venoclysis liquid that kind is stablized with beta-cyclodextrin, but not yet in relation to preparing posaconazole external application using beta-cyclodextrin
The document report of preparation.
Invention content
The first aspect technical problems to be solved of the present invention are to provide a kind of posaconazole drug containing beta-cyclodextrin
Composition, the pharmaceutical composition can be used for preparing the external preparation of posaconazole and be used for antifungal therapy.
Posaconazole externally-applied medicinal composition of the present invention, contains active constituent posaconazole, beta-cyclodextrin and medicine
Acceptable auxiliary material on.Wherein posaconazole and beta-cyclodextrin weight ratio are 1:1~4.5, preferably 1:1.5~4, further
Preferably 1:2~4, more preferably 1:2~3.It can be 0.5%~5% that posaconazole, which accounts for pharmaceutical composition gross weight, preferably
1%~5%, further preferably 1~3% are still more preferably 1.2~2.5%.
Beta-cyclodextrin of the present invention can be selected from hydroxypropyl-β-cyclodextrin or Sulfobutyl ether β _ cyclodextrin one kind or
A variety of combinations, preferably is selected from Sulfobutyl ether β _ cyclodextrin.
Pharmaceutical composition of the present invention can be prepared into various dosage forms, including but not limited to gelling agent, cream, soft
Paste, aerosol or spray, externally used solution etc..
Pharmaceutically acceptable auxiliary material of the present invention is selected from percutaneous penetrating agent, pharmaceutically acceptable solvent, moisturizing
Agent, oleaginous base, aqueous matrix, emulsifier, antioxidant, preservative or it is one or more.The pharmaceutical composition of the present invention, it is excellent
It selects pharmaceutically acceptable auxiliary material to contain percutaneous penetrating agent, pharmaceutically acceptable solvent and moisturizer, on this basis may be used
Various suitable dosage forms are prepared into increase other auxiliary materials, wherein it is used as general external preparation, in order to improve quality stability,
Prevent drug rotten, preservative or antioxidant therein are particularly preferred, for example are being prepared into gelling agent, cream, ointment
When agent, aerosol or spray, preservative or antioxidant can also be added simultaneously.
Pharmaceutical composition of the present invention is pharmaceutically acceptable in order to be suitable for being prepared into the exterior-applied formulations such as gel or emulsifiable paste
Auxiliary material in addition to selected from percutaneous penetrating agent, pharmaceutically acceptable solvent and moisturizer, can further comprise emulsifier and oil
Property matrix or aqueous matrix can further contain preservative or anti-to further increase the quality long-time stability of preparation
The pharmaceutically acceptable auxiliary material such as oxygen agent.
Percutaneous penetrating agent of the present invention be selected from azone, diethylene glycol monoethyl ether, sorbester p17, Tween 80, menthol or
One or more in isopropyl myristate, the weight ratio of wherein posaconazole and percutaneous penetrating agent can be 1:0.2~5,
Preferably 1:0.:5~3, further preferably 1:0.5~2, it is still more preferably 1:0.5~1.6.
Pharmaceutical composition of the present invention can be added various pharmaceutically acceptable when being prepared into various dosage forms
Solvent, such as water or organic solvent.The wherein described organic solvent is preferably from dimethyl sulfoxide (DMSO)；Posaconazole with can pharmaceutically connect
The weight ratio for the solvent received is 1：1~80, preferably 1：3~50, further preferably 1：5~35.
Moisturizer of the present invention is one or more in glycerine, propylene glycol or sorbierite；Posaconazole and guarantor
The weight ratio of humectant is 1：1~30, preferably 1：2~20, further preferably 1：3~15.
Oleaginous base of the present invention is selected from the one or more of stearic acid, paraffin, vaseline and vegetable oil；Posaconazole
Weight ratio with oleaginous base is 1：2~30, preferably 1：2.5~20, further preferably 1：5~15.The paraffin is excellent
It is selected as atoleine, the vaseline is preferably albolene.Pharmaceutical composition described in this when being prepared into gel preparations,
Pharmaceutically acceptable auxiliary material particularly be suitble to include oleaginous base or aqueous matrix one or two.
The one kind of aqueous matrix of the present invention in carbomer, cellulose derivative, higher alcohol or polyethylene glycol
Or it is a variety of；The weight ratio of posaconazole and aqueous matrix is 1：0.1~80, preferably 1：0.5~60, further preferably 1：
0.6~20.The higher alcohol is hexadecanol, but does not include menthol；The polyethylene glycol be PEG400 or PEG4000 or they
Combination.Pharmaceutical composition described in this when being prepared into cream form, pharmaceutically acceptable auxiliary material be particularly suitble to include
Aqueous matrix.
Emulsifier of the present invention is selected from triethanolamine, lauryl sodium sulfate, tristerin or poly yamanashi esters
It is one or more；The emulsifier accounts for the 2%~30% of gross weight, preferably 3%~15%, further preferably 5%~
10%.When being prepared into gel preparations, pharmaceutically acceptable auxiliary material is particularly suitble to include breast pharmaceutical composition described in this
Agent.
Antioxidant of the present invention be selected from sulphite for example sodium hydrogensulfite, cysteine, di-tert-butyl hydroxy toluene,
Potassium sorbate it is one or more；The weight ratio of posaconazole and antioxidant is 1：0.01~0.5, preferably 1：0.05~0.3,
Further preferably 1：0.1~0.2.
Preservative of the present invention includes one in benzoic acid and its salt, paraben esters and its sodium salt, anesin
Kind is a variety of；Wherein the weight ratio of posaconazole and preservative is 1：0.001~0.5, preferably 1：0.05~0.3, further
Preferably 1：0.08~0.2.The paraben esters and its sodium salt include methyl hydroxybenzoate, ethylparaben, propylben, Buddhist nun
Pool golden butyl ester and soluble metyl hydroxybenzoate, nipagin A sodium, soluble propylhydroxybenzoate, nipabutyl sodium etc. have good anti-
Rotten effect.
The second aspect technical problems to be solved of the present invention are to provide a kind of posaconazole external application containing beta-cyclodextrin
Posaconazole is dissolved in the pharmaceutically acceptable solvent containing beta-cyclodextrin, so by the preparation method of pharmaceutical composition first
After add various auxiliary materials, stir evenly, conventional treatment to obtain the final product.
Third aspect of the present invention technical problems to be solved are to provide a kind of posaconazole externally-applied medicinal composition and are used for
Prepare the purposes in the drug of local topical administration treatment dermatophytid infection disease.
Posaconazole externally-applied medicinal composition provided by the invention because beta-cyclodextrin and posaconazole form packet and
Object, achieves that stable quality, bacteriostasis are strong, coating is convenient, Small side effects, can effectively prevent the good result of recurrence.
In the present invention, posaconazole is not soluble in water, can increase posaconazole in external application using hydrophilic beta-cyclodextrin
Dissolubility in pharmaceutical base, while improving the stability of posaconazole.
The preparation method of the posaconazole external preparation containing beta-cyclodextrin of the present invention includes the following steps：
For gelling agent, posaconazole is dissolved in the aqueous solution of beta-cyclodextrin, is added to the aqueous gel being fully swollen
In matrix, the gelling agent to get water white transparency is stirred evenly.
It is water phase by the aqueous solution that posaconazole is dissolved in beta-cyclodextrin, by oil-phase component and water-phase component for cream
80 DEG C, during the oil phase is added to the aqueous phase are separately heated to, is stirred well to condensation to get O/W type emulsions.
For ointment, posaconazole is dissolved in the organic solvent of beta-cyclodextrin, the ointment bases of fusing is added, stirs
It mixes uniformly to get white translucent shape ointment.
For gas/spray, posaconazole is dissolved in the aqueous solution of beta-cyclodextrin, adds preservative etc., dispersion is equal
It is even, it is sub-packed in defined spray device.
It needs to add other auxiliary materials in the preparation method of above-mentioned each dosage form, according to auxiliary material property and dosage form in appropriate steps
It is added, the technology that adding technology is known to the skilled person.
Advantageous effect of the present invention：
External preparation produced by the present invention is in-vitro percutaneous to use BaMa miniature pig skin of abdomen for skin model through experiment, real
Experiment device is Franz diffusion cells, and effective diffusion area is 2cm2, reception tank solution is 7.4 phosphate buffers of 7ml pH, real
Continuing magnetic force stirs during testing, and mixing speed is 600~800rpm, the use of peripheral circulation water-bath maintenance system temperature is 32
℃。
It is identified through X-ray diffraction method and infra-red sepectrometry, posaconazole and beta-cyclodextrin are formed in embodiment 2,3,4,5
Inclusion compound rather than mixture.
The present invention fundamentally overcomes the defect of dermatophytid infection treatment at this stage, provides the strong pool of antibacterial activity
Saperconazole external preparation, limitation posaconazole avoid posaconazole during body metabolism in Whole Body infiltration rate
Hepatotoxicity wind agitation and gastrointestinal side effect.And the posaconazole of beta-cyclodextrin inclusion compound can uniformly be scattered in oil in the external preparation prepared
Property or aqueous matrix in, keep the quality of the pharmaceutical preparations uniform, property stablize；It is small to the irritation of skin during medication, improve patient
Compliance.
The present invention increases posaconazole in external application system using the unique void structure of beta-cyclodextrin and hydrophilic, oil-wet behavior
Dissolubility in agent matrix, while making posaconazole slow release in skin, reduce irritation wind of the posaconazole to skin
Danger.
Specific implementation mode
The present invention is illustrated in more detail by following examples, it should be apparent that：The content of present invention is by no means limited to institute
For embodiment, or it is showed only as embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, further includes the arbitrary combination between each specific implementation mode, still falls within the protection of the present invention
Range.
Explanation：Menthol is percutaneous penetrating agent in following embodiment.
Embodiment 1
Posaconazole gelling agent at being grouped as：
| Posaconazole | 20g |
| Carbomer | 12g |
| Glycerine | 100g |
| Propylene glycol | 100g |
| Menthol | 10g |
| Azone | 10g |
| Sodium hydrogensulfite | 3g |
| Triethanolamine | 10g |
| Purified water | 735g |
| It amounts to | 1000g |
Gelling agent preparation method：
(1) sodium hydrogensulfite of recipe quantity is dissolved in the water of 60% recipe quantity, is added with stirring the carbomer of recipe quantity,
It is uniform to being swollen to continue stirring.
(2) water of residue 40% and propylene glycol is miscible, the dissolving of recipe quantity posaconazole is added, it is sweet to add recipe quantity
Oil, menthol and azone.
(3) posaconazole solution is added in carbomer swelling object and is stirred evenly, the triethanolamine of recipe quantity is added, stirring is equal
Even to get posaconazole gelling agent, but gained posaconazole gelling agent is opaque, places be layered for a long time.
Embodiment 2
The posaconazole gelling agent of beta-cyclodextrin inclusion compound at being grouped as：
| Sulfobutyl ether β _ cyclodextrin | 55g |
| Posaconazole | 20g |
| Carbomer | 12g |
| Glycerine | 80g |
| Propylene glycol | 100g |
| Menthol | 10g |
| Azone | 10g |
| Sodium hydrogensulfite | 3g |
| Triethanolamine | 10g |
| Purified water | 700g |
| It amounts to | 1000g |
Gelling agent preparation method：
(1) sodium hydrogensulfite of recipe quantity is dissolved in the water of 60% recipe quantity, is added with stirring the carbomer of recipe quantity,
It is uniform to being swollen to continue stirring.
(2) water of residue 40% and propylene glycol is miscible, addition beta-cyclodextrin stirring and dissolving is complete, and the husky health of pool is then added
Azoles dissolves, and forms inclusion complex in solution, adds recipe quantity glycerine, menthol and azone.
(3) beta-cyclodextrin posaconazole inclusion complex in solution is added in carbomer swelling object and is stirred evenly, recipe quantity is added
Triethanolamine stirs evenly the posaconazole gelling agent to get water white transparency.
Embodiment 3
The posaconazole cream of beta-cyclodextrin inclusion compound at being grouped as：
Cream preparation method：
(1) it is oil phase, heat preservation to 80 DEG C of additions by the melting of recipe quantity stearic acid, atoleine and albolene heating water bath
Recipe quantity triethanolamine and azone.
(2) recipe quantity glycerol and water are miscible, beta-cyclodextrin dissolving is added under condition of water bath heating completely, is then added
Recipe quantity posaconazole and ethylparaben dissolving are entirely water phase.
(3) stirring while adding during the oil phase is added to the aqueous phase in 80 DEG C of water-bath, 15~stop heating after twenty minutes, after
Continuous stirring is to room temperature to get posaconazole cream.
Embodiment 4
The posaconazole ointment of beta-cyclodextrin inclusion compound at being grouped as：
| Sulfobutyl ether β _ cyclodextrin | 30g |
| Posaconazole | 10g |
| Hexadecanol | 20g |
| PEG 400 | 150g |
| Dimethyl sulfoxide (DMSO) | 50g |
| Glycerine | 150g |
| PEG 4000 | 569g |
| Ethylparaben | 1g |
| Isopropyl myristate | 10g |
| Menthol | 10g |
| It amounts to | 1000g |
Ointment preparation method：
(1) beta-cyclodextrin of recipe quantity, PEG 400, glycerine and dimethyl sulfoxide (DMSO) are mixed, is stirred continuously, adds at room temperature
Posaconazole, ethylparaben, isopropyl myristate and the menthol for entering recipe quantity continue stirring and make it completely dissolved, be
Solution A.
(2) hexadecanol of recipe quantity, 4000 heating water baths of PEG are dissolved to clarification, and are stirred continuously and are allowed to cool, be
Second liquid.
(3) it when second liquid is cooled to 50 DEG C, is added slowly in solution A, is stirred continuously to room temperature to get white translucent
Shape ointment.
Embodiment 5
The posaconazole spray of beta-cyclodextrin inclusion compound at being grouped as：
| Sulfobutyl ether β _ cyclodextrin | 60g |
| Posaconazole | 25g |
| Tween 80 | 20g |
| Propylene glycol | 80g |
| Menthol | 20g |
| Sodium benzoate | 5g |
| Purified water | 790g |
| It amounts to | 1000g |
The preparation method of spray：
(1) beta-cyclodextrin of recipe quantity, Tween 80, propylene glycol are added in the purified water of recipe quantity, at room temperature constantly
Stirring and dissolving, the posaconazole that recipe quantity is added continue to stir to dissolve completely, add recipe quantity menthol and benzoic acid
Sodium is stirred continuously and is uniformly dispersed.
(2) above-mentioned finely dispersed solution is sub-packed in defined spray device.
Embodiment 6：In-vitro percutaneous permeability test
The hair on BaMa miniature pig skin of abdomen is shaved totally with electric shaver, subcutaneous fat is removed, is rushed with physiological saline
It is in store in -70 DEG C after wash clean.
Using Franz diffusion cells, the physiological saline of the in vitro pigskin after defrosting is eluted totally, vertical diffusion cell is fixed on
Between two ponds, towards reception tank, about 2g external preparations are added to supply pool skin corium in stratum corneum side in supply pool, in reception tank plus
Enter 7mL receiving liquids (7.4 phosphate buffers of pH).Continuing magnetic force stirs in experimentation, and mixing speed is 600~800rpm,
The use of peripheral circulation water-bath maintenance system temperature it is 32 DEG C.It is sampled from reception tank respectively at 2h, 4h, 6h, 8h, 10h, 12h
5mL, while the fresh receiving liquid of equivalent isothermal is added into acceptable solution.
Table 1 different Percutaneous permeabilities and skin hold-up of the prescription posaconazole external preparation through BaMa miniature pig skin 12h
(n=4).
| Embodiment | 12h Percutaneous permeabilities Q12(μg/cm2) | 12h skin hold-ups QR(μg/g) |
| 1 | 123.51±21.32 | 174.21±32.45 |
| 2 | 374.23±33.37 | 356.23±39.71 |
| 3 | 396.72±48.87 | 405.69±40.29 |
| 4 | 305.47±52.33 | 324.47±29.65 |
| 5 | 261.22±32.26 | 271.51±27.98 |
Conclusion：The posaconazole external preparation prescription of beta-cyclodextrin inclusion compound is in the percutaneous transmission through 12h as can be seen from Table 1
After experiment, the Percutaneous permeability and skin hold-up of posaconazole are higher than the prescription without beta-cyclodextrin, different beta-cyclodextrins
Percutaneous permeability and skin are detained slight difference between the posaconazole external preparation prescription of inclusion.The use of beta-cyclodextrin can increase
Add posaconazole in the intercellular delay of keratoderma, directly act on dermatophytid infection position, plays quickly antibacterial
Effect.
Embodiment 7：Formulation Skin irritant experiment
Experimental animal selects male rabbit, selects that chaeta is smooth rich in glossy, and skin is without symptoms such as rednesses.By back both sides
The rabbit hair is removed, and a rabbit skin is avoided damage to, and is tested after placing 12h.The preceding tween of experiment and physiological saline wiping man rabbit
External preparation prepared by embodiment 1,2,3,4 is smeared in skin, rabbit back side of being in after skin surface drying, and the other side is smeared
10% sodium dodecyl sulfate aqueous solution does positive control, test medicine applying amount about 0.5g, application area be 2.5cm ×
Wipe residual tested material with warm water after 2.5cm, 4h application, to 1h after removal, for 24 hours, the redness of 48h, 72h family's rabbit skin and
The situation of bearing pods scores, and standards of grading refer to Draize methods, and irritation Assessment for classification is with reference to following sequence：
0.0~0.4：It is reactionless；
0.5~1.9：Minor response；
2.0~4.9：Medium reaction；
5.0~8.0：Severe reaction.
Irritant experiment result (n=6) of 2 external preparation of table to family's rabbit skin.
Conclusion：Acute skin irritation test result shows the posaconazole external application of beta-cyclodextrin inclusion compound of the present invention
Preparation is nonirritant to the rank of rabbit skin irritation, but the prescription without beta-cyclodextrin has family's rabbit skin slight thorn
Swash.The use of beta-cyclodextrin slows down the speed that posaconazole enters skin, reduces the irritation to skin, can be that the mankind are practical
Safety during use provides safeguard.
Claims (17)
1. a kind of posaconazole externally-applied medicinal composition, contain active constituent posaconazole, beta-cyclodextrin and pharmaceutically acceptable
Auxiliary material, it is characterised in that posaconazole and beta-cyclodextrin weight ratio are 1:1~4.5, preferably 1:1.5~4, further preferably
It is 1:2~4, more preferably 1:2~3.
2. pharmaceutical composition according to claim 1, it is characterised in that the posaconazole accounts for the 0.5%~5% of gross weight,
Preferably 1%~5%, further preferably 1~3% are still more preferably 1.2~2.5%.
3. pharmaceutical composition according to claim 1, it is characterised in that the beta-cyclodextrin is selected from hydroxy propyl-Beta-ring paste
One or more, the preferred Sulfobutyl ether β _ cyclodextrin of essence or Sulfobutyl ether β _ cyclodextrin.
4. pharmaceutical composition according to claim 1, it is characterised in that the dosage form of described pharmaceutical composition is gelling agent, breast
Paste, ointment, aerosol or spray.
5. pharmaceutical composition according to claim 1, it is characterised in that the pharmaceutically acceptable auxiliary material is selected from percutaneous
Penetrating agent, pharmaceutically acceptable solvent, moisturizer, oleaginous base, aqueous matrix, emulsifier, antioxidant, preservative or one
Kind is a variety of.
6. pharmaceutical composition according to claim 5, it is characterised in that the pharmaceutically acceptable auxiliary material is selected from percutaneous
Penetrating agent, pharmaceutically acceptable solvent and moisturizer further contain preservative or antioxidant.
7. pharmaceutical composition according to claim 5, it is characterised in that the pharmaceutically acceptable auxiliary material is selected from percutaneous
Penetrating agent, pharmaceutically acceptable solvent, moisturizer, emulsifier and oleaginous base or aqueous matrix, further contain anti-corrosion
Agent or antioxidant.
8. pharmaceutical composition according to claim 5, it is characterised in that the percutaneous penetrating agent is selected from azone, diethylene glycol
It is one or more in single ethylether, sorbester p17, Tween 80, menthol or isopropyl myristate；Particularly, husky health is preferably moored
The weight ratio of azoles and percutaneous penetrating agent is 1:0.2~5, more preferably 1:0.:5~3, further preferably 1:0.5~2, more into
One step is preferably 1:0.5~1.6.
9. pharmaceutical composition according to claim 5, it is characterised in that the pharmaceutically acceptable solvent be selected from water or
Organic solvent, the organic solvent can be selected from dimethyl sulfoxide (DMSO).
10. pharmaceutical composition according to claim 5, it is characterised in that the moisturizer is selected from glycerine, propylene glycol or mountain
It is one or more in pears alcohol；The weight ratio of posaconazole and moisturizer is 1：1~30, preferably 1：2~20, further preferably
It is 1：3~15.
11. pharmaceutical composition according to claim 5, it is characterised in that the oleaginous base is selected from stearic acid, paraffin, all
Intellectual circle and vegetable oil it is one or more；The weight ratio of posaconazole and oleaginous base is 1：2~30, preferably 1：2.5~20,
Further preferably 1：5~15.
12. pharmaceutical composition according to claim 5, it is characterised in that the aqueous matrix is selected from carbomer, cellulose
It is one or more in derivative, higher alcohol or polyethylene glycol；The weight ratio of posaconazole and aqueous matrix is 1：0.1~80,
Preferably 1：0.5~60, further preferably 1：0.6~20；The higher alcohol is hexadecanol, does not include menthol；It is described poly-
Ethylene glycol is PEG400 or PEG4000 or their combination.
13. pharmaceutical composition according to claim 5, it is characterised in that the emulsifier is selected from triethanolamine, dodecane
Base sodium sulphate, tristerin or poly yamanashi esters it is one or more；The emulsifier accounts for the 2%~30% of gross weight, excellent
It is selected as 3%~15%, further preferably 5%~10%.
14. pharmaceutical composition according to claim 5, it is characterised in that the antioxidant is selected from sulphite such as sulfurous acid
Hydrogen sodium, cysteine, di-tert-butyl hydroxy toluene, potassium sorbate it is one or more；The weight ratio of posaconazole and antioxidant
It is 1：0.01~0.5, preferably 1：0.05~0.3, further preferably 1：0.1~0.2.
15. pharmaceutical composition according to claim 5, it is characterised in that the preservative includes benzoic acid and its salt, Buddhist nun
It is one or more in the golden ester of pool and its sodium salt, anesin；The weight ratio of posaconazole and preservative is 1：0.001~
0.5, preferably 1：0.05~0.3, further preferably 1：0.08~0.2.
16. according to the preparation method of the pharmaceutical composition described in claim 1~15, it is characterised in that：Posaconazole is dissolved in
In pharmaceutically acceptable solvent containing beta-cyclodextrin, various auxiliary materials are added, are stirred evenly.
17. any posaconazole externally-applied medicinal compositions of claim 1-15 are used to prepare local topical administration treatment skin
Purposes in the drug of fungal infection disease.
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| CN201810732469.2A CN108567782A (en) | 2018-07-05 | 2018-07-05 | A kind of posaconazole externally-applied medicinal composition, preparation method and the usage |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111514146A (en) * | 2020-04-28 | 2020-08-11 | 山西振东泰盛制药有限公司 | Pharmaceutical composition containing posaconazole |
| CN113750034A (en) * | 2020-06-05 | 2021-12-07 | 中南大学湘雅三医院 | Ear temperature-sensitive gel and preparation method thereof |
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| CN113750034A (en) * | 2020-06-05 | 2021-12-07 | 中南大学湘雅三医院 | Ear temperature-sensitive gel and preparation method thereof |
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Address after: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant after: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant after: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant before: SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |
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Address after: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant after: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant after: SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant before: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |
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