CN104173286B - Azelastine compositionss and purposes - Google Patents
Azelastine compositionss and purposes Download PDFInfo
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- CN104173286B CN104173286B CN201410457775.1A CN201410457775A CN104173286B CN 104173286 B CN104173286 B CN 104173286B CN 201410457775 A CN201410457775 A CN 201410457775A CN 104173286 B CN104173286 B CN 104173286B
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Abstract
The present invention relates to azelastine compositionss and purposes, specifically, the present invention relates to the fluid composition of azelastine, more particularly to a kind of fluid composition of azelastine hydrochloride, relate more particularly to a kind of non-aqueous fluid composition.In one embodiment, comprise in described pharmaceutical composition：Azelastine or its pharmaceutical salts, polyhydroxy-alcohol, Polyethylene Glycol, polyhydroxy-alcohol fatty acid ester.The invention still further relates to the preparation method of this fluid composition and their pharmaceutical applications, for example the invention still further relates to the purposes of this kind of composition treatment, alleviation or the prevention symptom related to anaphylaxis and non-allergic disease, and the purposes for example in treating dermatitis such as anaphylaxis and/or contact dermatitis.Pharmaceutical composition of the present invention can adopt the medicine type of liniment or spray to facilitate Clinical practice.
Description
Technical field
The present invention relates to the fluid composition of azelastine, more particularly to a kind of liquid combination of azelastine hydrochloride
Thing, relates more particularly to a kind of non-aqueous fluid composition.The invention still further relates to the preparation method of this fluid composition and it
Pharmaceutical applications, for example the invention still further relates to this kind of composition treatment, alleviation or prevention with anaphylaxis and non-allergic disease
The purposes of related symptom, and the purposes for example in treatment dermatitis such as anaphylaxis and/or contact dermatitis.Of the present invention group
Compound has beat all pharmaceutical properties.Especially, the fluid composition of azelastine of the present invention can be using suitable medicine
Agent packaged form, to be supplied to Clinical practice with conventional liniment or spray.
Background technology
Azelastine, clinically commonly uses its hydrochlorate (azelastine hydrochloride), molecular formula
C22H24ClN3O.HCl, molecular weight：418.36, CAS registration number：79307-93-0, wherein science of culture are entitled：(±)-1-
(2H) -4- [(4- chlorphenyl) methyl] -2- (hexahydro -1- methyl isophthalic acid H- azepan -4- base)-phthalazone mono-hydrochloric salts, English
Science of culture is entitled：(±)-1-(2H)-4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-
Azepin-4-yl)-phthalazinone, monohydrochloride, chemical constitution is：
Hydrochloric acid chlorine Zhuo Siting be a kind of new construction 2，3-benzodiazine ketone be phthalazone derivant, be a kind of potential
Long-acting antiallergic compound, has H1 receptor antagonist feature, has antiallergic, Zhichuan and antihistamine characteristic.Zoopery number
According to showing, the A-5610 of high concentration can stop in anaphylaxiss the synthesis of some chemical mediators and release (for example：In vain
Triolefin, histamine, 5-hydroxy tryptamine), nose spray administration when, allow application maximal dose under, be not detected by Local toxic reaction or
Organo-specific toxicity reacts.
After oral drugs, A-5610 is absorbed by the body rapidly, and absolute bioavailability is up to 81%.Food is to suction
Receiving no affects.The capacity height of distribution shows that distribution is mainly organized around, and protein-bound water puts down relatively low (80%-
90%).After single medicine gives A-5610, plasma clearance half-life hydrochloric acid chlorine Zhuo Siting is 20 hours, curative activity
The nor- azelastine of metabolite N- is about 45 hours.Excretion is mainly excluded through feces.The lasting row of a small amount of medicine in feces
Let out and show that medicine can carry out enterohepatic circulation.The A-5610 of daily nose spray application 0.56mg (is equivalent to 1 spray/every repeatedly
Nostril, 2 times/day), healthy volunteer's A-5610 Cmax Cpss is about 0.27ng/ml, its active metabolism
The nor- azelastine of product N- can be detected (0.12ng/ml) in quantitative limit value or less than quantitative level.
Allergic Rhinitis repeatedly after nasal cavity drug application, omit compared with Healthy People by blood plasma A-5610 level
Height, thus show that whole body (mainly can preferably penetrate the nasal mucosa of inflammation, just to the level height of drug absorption because of medicine
In absorption).After the hydrochloric acid hydrogen Zhuo Siting of daily medication accumulated dose 0.56mg (for example：1 spray, every nostril, 2 times/day) medication 2 hours
After observe that azelastine mean plasma concentration is about 0.65ng/ml.A-5610 dosage is doubled to daily
1.12mg (example：2 sprays/every nostril, 2 times/day) the mean plasma steady state concentration of azelastine is 1.09ng/ml.It is indicated above using
Concentration is proportional distribution to dosage.Although patient absorbs the drug, level of relative is higher, is computed nasal cavity applied medicine complete
Lower than the oral medication systemic drug exposure level about 8 times (medicament for oral use for the treatment of allergic rhinitises of body drug exposure levels
Measure as daily 4.4mg A-5610).
Azelastine can be produced in the form of various salt.In medicine, the most frequently used form is A-5610, and it is
White, the almost scentless crystalline powder with strong bitterness exists.It is applied to other salt form bags of pharmaceutical composition
Include pamoic acid azelastine, its bitterness than azelastine HC1 mitigate (referring to United States Patent (USP) US5,232,919, by the document
Disclosure is incorporated herein by reference), but effectiveness is also below A-5610.
Research confirms that azelastine and its acceptable salt form of physiology glue being directly applied to nose with corresponding preparation
Beneficial effect { referring to United States Patent (USP) US5,164,194 } is shown when on the conjunctival sac of film and/or eye.Thus in allergic rhinitises
Symptom eliminates or significant alleviation is realized in (seasonal and/or Out of season), vasomotor rhinitises and anaphylaxis conjunctivitises.
Despite the presence of its effectiveness, but A-5610 has strong bitterness.This bitterness is so strong, so that
In discovery even in dilution 1X106In the case of still unhappy (referring to United States Patent (USP) US5,164,194).In intranasal delivery
It is not regarded as during A-5610 that this bitterness is problem (seeing above).However, subsequent clinical research has confirmed, real
On border, the bitterness of A-5610 is undesirable as generally flowing downwardly into the part of pharyngeal medicine after intranasal administration
Composition, thus lead to patient not accommodate undesirable taste experience.For example, MedPointePharmaceuticals, Inc.
(Somerset, NJ), described in ASTELIN@product description, in clinical studies, the adverse consequencess of this bitterness exist
Incidence rate in the patient being treated with ASTELIN@NasalSpray (containing 0.10%w/v A-5610) is pacified with solvent
The incidence rate consoling the patient of agent treatment is compared with more significance,statistical (19.7% and 0.6%).Equally, because of eye drops and
Induction the tear of lacrimal secretion combination formed fluid by nasolacrimal duct drain enter nose and finally flow into pharyngeal (referring to
Day, N., " OphthalmicDosage Forms, " exists：Pharmaceutical Preformulation and
In Formulation, Buffalo Grove, IL:Interpharm Press(2002)).This kind of give to comprise hydrochloric acid because of eye
The postnasal drip that the compositionss of azelastine lead to thus is likely to induce the bitterness of patient and uncomfortable taste experience.Ukai etc.
(United States Patent (USP) US6,576,677) discloses Polyvinylpyrrolidone and/or Crospovidone and is sheltering bitter drug, including nitrogen
Application in the taste of Zhuo Siting.It can be seen that, azelastine as nose with or ophthalmically acceptable administration there is many limitation, for example they
Clinically it is generally used only for treating allergic seasonal rhinitis and anaphylaxis perennial rhinitiss.
Therefore, this area is still expected to have new treatment or is prevented the symptom related to anaphylaxis and non-allergic disease
Method.New effective compositionss are for example provided and/or use it for treating allergic seasonal rhinitis and anaphylaxis perennially
Rhinitis and other the symptom such as anaphylaxis and/or contact dermatitis etc. related to anaphylaxis and non-allergic disease.
Content of the invention
It is an object of the invention to provide a kind of treat or prevent the symptom related to anaphylaxis and non-allergic disease
Method.New effective compositionss are for example provided and/or use it for treating allergic seasonal rhinitis and anaphylaxis perennially
Rhinitis and other the symptom such as anaphylaxis and/or contact dermatitis etc. related to anaphylaxis and non-allergic disease.This
A person of good sense is surprisingly it has been found that have the advantages that the pharmaceutical composition of inventive formulation has one or more aspects as follows：Surely
Fixed chemical property, low zest, can be used for allergic seasonal rhinitis and anaphylaxis perennial rhinitiss and/or can be used for
Treatment other the symptom such as anaphylaxis and/or contact dermatitis etc. related to anaphylaxis and non-allergic disease.Base of the present invention
Find in this and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition, wherein comprise：Azelastine or its pharmaceutical salts,
Polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the drug regimen in liquid condition
Thing.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, comprises 0.01～5g's in its every 100ml
Azelastine or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.02～2.5g, for example often in every 100ml
Comprise azelastine or its pharmaceutical salts of 0.05～2g in 100ml, such as in every 100ml, comprise the azelastine of 0.05～1.5g
Or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.05～1g in every 100ml.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said polyhydroxy-alcohol is selected from：Second two
Alcohol, propylene glycol, glycerol, and combinations thereof.In the present invention, ethylene glycol refers to 1，2-ethandiol, and propylene glycol refers to 1,2- the third two
Alcohol, glycerol refers to Glycerin.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, comprises the many of 5～50g in its every 100ml
Hydroxyl alcohol, such as comprise the polyhydroxy-alcohol of 7.5～40g, such as comprise the polyhydroxy of 10～30g in every 100ml in every 100ml
Alcohol.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said polyhydroxy-alcohol fatty acid ester choosing
From：Glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester, and combinations thereof.Described glycerol fatty acid ester is
The fatty acid ester of 1,2,3- glycerol.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said polyhydroxy-alcohol fatty acid ester choosing
From：Propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, glycerol list acetic acid
Ester, and combinations thereof.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, comprises the many of 50～95g in its every 100ml
Hydroxyl alcohol fatty acid ester, such as comprise the polyhydroxy-alcohol fatty acid ester of 60～92.5g, such as comprise in every 100ml in every 100ml
The polyhydroxy-alcohol fatty acid ester of 70～90g.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said polyhydroxy-alcohol fatty acid ester is
Added in the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as primary amount in other words conj.or perhaps absolutely
The solvent of quantity mostly.Therefore, its addition can be not especially limited, for example can with similar to " aequum ", " appropriate,
Add to 100ml ", " appropriate, add to 100g ", " appropriate, to add to full dose " etc. or similar fashion statement.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the pharmaceutical preparation being for external application.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the pharmaceutical preparation for percutaneous dosing.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also comprises Percutaneous absorption enhancer.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said Percutaneous absorption enhancer is selected from
One or more following material：
(1) cholic acid salt：Glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, goose deoxygenate
Cholate, bird rope deoxycholate etc.；
(2) saturation or unsaturated fatty acid and its ester：As lauric acid, Oleic acid, nutmeg acid, capric acid, laurate, octanoic acid
Ester, decanoin, cetylate, ethyl lactate, triacetyl glycerine；
(3) alcohols；As isopropanol, hexadecanol, lauryl alcohol, oleyl alcohol etc.；
(4) ethers：Polyoxyethylene laurel ether, polyoxyethylene octyl ether etc.；
(5) sulfoxide type：As dodecyl methyl sulfoxide, dimethyl sulfoxide etc.；
(6) amide-type：As N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, hexamethylene lauramide；
(7) lactams：Azone, laurocapram, dodecyl Azone, hold together cattle base Azone etc.；
(8) ion-type, nonionic surfactant：As sodium lauryl sulphate, SUNSOFT 700P-2, Tween 80, department
Disk 20 etc.；And/or
(9) the beta cyclodextrin class of beta cyclodextrin or alkyl replacement：As dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc..If
If presence, the consumption of Percutaneous absorption enhancer is account for total composition 0.5～5%, such as 0.5～2%, such as 0.5～
1.5%.In the present invention, if not otherwise indicated, % refers to w/w percent.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is the medicament shape of liniment or spray
Formula.
Further, second aspect present invention provides the method preparing pharmaceutical composition, wraps in described pharmaceutical composition
Contain：Azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester；The method comprises the following steps：
Make azelastine or its pharmaceutical salts miscible with described polyhydroxy-alcohol；
Then by gained mixed solution with polyhydroxy-alcohol fatty acid ester uniformly, obtain final product.
The method of any embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is in liquid condition
Pharmaceutical composition.
The method of any embodiment according to a second aspect of the present invention, comprises in the every 100ml of wherein said pharmaceutical composition
The azelastine of 0.01～5g or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.02～2.5g in every 100ml,
For example comprise azelastine or its pharmaceutical salts of 0.05～2g in every 100ml, such as in every 100ml, comprise the nitrogen of 0.05～1.5g
Zhuo Siting or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.05～1g in every 100ml.
The method of any embodiment according to a second aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
It is selected from：Ethylene glycol, propylene glycol, glycerol, and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, comprises 5 in the every 100ml of wherein said pharmaceutical composition
The polyhydroxy-alcohol of～50g, such as comprise the polyhydroxy-alcohol of 7.5～40g, such as comprise 10～30g in every 100ml in every 100ml
Polyhydroxy-alcohol.
The method of any embodiment according to a second aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is selected from：Glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester, and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is selected from：Propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, the third three
Alcohol monoacetate, and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, comprises in the every 100ml of wherein said pharmaceutical composition
The polyhydroxy-alcohol fatty acid ester of 50～95g, such as comprise the polyhydroxy-alcohol fatty acid ester of 60～92.5g, for example often in every 100ml
The polyhydroxy-alcohol fatty acid ester of 70～90g is comprised in 100ml.
The method of any embodiment according to a second aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is to be added in the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as primary amount
The solvent of most amounts in other words conj.or perhaps.Therefore, its addition can be not especially limited, for example can be with similar to " balance
Amount ", " appropriate, to add to 100ml ", " appropriate, to add to full dose " etc. or similar fashion statement.
The method of any embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is the medicine being for external application
Preparation.
The method of any embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is for percutaneous dosing
Pharmaceutical preparation.
The method of any embodiment according to a second aspect of the present invention, also comprises transdermal and inhales in wherein said pharmaceutical composition
Receive accelerator.
The method of any embodiment according to a second aspect of the present invention, Transdermal absorption described in wherein said pharmaceutical composition
Accelerator is selected from one or more following material：
(1) cholic acid salt：Glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, goose deoxygenate
Such as their sodium salts such as cholate, bird rope deoxycholate；
(2) saturation or unsaturated fatty acid and its ester：As lauric acid, Oleic acid, nutmeg acid, capric acid, laurate, octanoic acid
Ester, decanoin, cetylate, ethyl lactate, triacetyl glycerine；
(3) alcohols；As isopropanol, hexadecanol, lauryl alcohol, oleyl alcohol etc.；
(4) ethers：Polyoxyethylene laurel ether, polyoxyethylene octyl ether etc.；
(5) sulfoxide type：As dodecyl methyl sulfoxide, dimethyl sulfoxide etc.；
(6) amide-type：As N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, hexamethylene lauramide；
(7) lactams：Azone, laurocapram, dodecyl Azone, hold together cattle base Azone etc.；
(8) ion-type, nonionic surfactant：As sodium lauryl sulphate, SUNSOFT 700P-2, Tween 80, department
Disk 20 etc.；And/or
(9) the beta cyclodextrin class of beta cyclodextrin or alkyl replacement：As dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc..If
If presence, the consumption of Percutaneous absorption enhancer is account for total composition 0.5～5%, such as 0.5～2%, such as 0.5～
1.5%.
The method of any embodiment according to a second aspect of the present invention, wherein said Percutaneous absorption enhancer is many with described
Hydroxyl alcohol is added in described pharmaceutical composition together.
The method of any embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition first party for example of the present invention
Described in any embodiment of face.
The method of any embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition is liniment or spraying
The medicine type of agent.
Further, third aspect present invention provides azelastine or its pharmaceutical salts in preparation treatment or prevention dermal inflammatory
Purposes in the medicine of disease.
The purposes of any embodiment according to a third aspect of the present invention, wherein said inflammatory disease of the skin is selected from：Anaphylaxis
Dermatitis, contact dermatitis, eczema, acute urticaria.
The purposes of any embodiment according to a third aspect of the present invention, wherein said medicine has first aspect present invention and appoints
The feature of one embodiment described pharmaceutical composition.
The purposes of any embodiment according to a third aspect of the present invention, wherein said medicine is the medicine of liniment or spray
Dosage form formula.
Further, fourth aspect present invention provides azelastine or its pharmaceutical salts in preparation treatment or prevention dermal inflammatory
Disease and substantially the purposes in irritating external used medicine is not assumed to skin.It has been unexpectedly discovered that using this
Invention formula does not substantially produce zest particularly local irritation to skin, and the compositionss of other formula significantly assume skin
Skin zest.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said inflammatory disease of the skin is selected from：Anaphylaxis
Dermatitis, contact dermatitis, eczema, acute urticaria.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said external used medicine is the medicine in liquid condition
Compositions.
The purposes of any embodiment according to a fourth aspect of the present invention, comprises in wherein said pharmaceutical composition：Nitrogen Zhuo Si
Spit of fland or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester.
The purposes of any embodiment according to a fourth aspect of the present invention, comprises in the every 100ml of wherein said pharmaceutical composition
The azelastine of 0.01～5g or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.02～2.5g in every 100ml,
For example comprise azelastine or its pharmaceutical salts of 0.05～2g in every 100ml, such as in every 100ml, comprise the nitrogen of 0.05～1.5g
Zhuo Siting or its pharmaceutical salts, such as comprise azelastine or its pharmaceutical salts of 0.05～1g in every 100ml.At this concentration, when
Using the present composition as spray use when, can be easily achieved 0.02～2mg/ spray, such as 0.14mg/ spray use
Scheme.
The purposes of any embodiment according to a fourth aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
It is selected from：Ethylene glycol, propylene glycol, glycerol, and combinations thereof.
The purposes of any embodiment according to a fourth aspect of the present invention, comprises 5 in the every 100ml of wherein said pharmaceutical composition
The polyhydroxy-alcohol of～50g, such as comprise the polyhydroxy-alcohol of 7.5～40g, such as comprise 10～30g in every 100ml in every 100ml
Polyhydroxy-alcohol.
The purposes of any embodiment according to a fourth aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is selected from：Glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester, and combinations thereof.
The purposes of any embodiment according to a fourth aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is selected from：Propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, the third three
Alcohol monoacetate, and combinations thereof.
The purposes of any embodiment according to a fourth aspect of the present invention, comprises in the every 100ml of wherein said pharmaceutical composition
The polyhydroxy-alcohol fatty acid ester of 50～95g, such as comprise the polyhydroxy-alcohol fatty acid ester of 60～92.5g, for example often in every 100ml
The polyhydroxy-alcohol fatty acid ester of 70～90g is comprised in 100ml.
The purposes of any embodiment according to a fourth aspect of the present invention, polyhydroxy-alcohol described in wherein said pharmaceutical composition
Fatty acid ester is to be added in the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as primary amount
The solvent of most amounts in other words conj.or perhaps.Therefore, its addition can be not especially limited, for example can be with similar to " balance
Amount ", " appropriate, to add to 100ml ", " appropriate, to add to full dose " etc. or similar fashion statement.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said pharmaceutical composition is the medicine being for external application
Preparation.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said pharmaceutical composition is for percutaneous dosing
Pharmaceutical preparation.
The purposes of any embodiment according to a fourth aspect of the present invention, also comprises transdermal and inhales in wherein said pharmaceutical composition
Receive accelerator.
The purposes of any embodiment according to a fourth aspect of the present invention, Transdermal absorption described in wherein said pharmaceutical composition
Accelerator is selected from one or more following material：
(1) cholic acid salt：Glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, goose deoxygenate
Cholate, bird rope deoxycholate etc.；
(2) saturation or unsaturated fatty acid and its ester：As lauric acid, Oleic acid, nutmeg acid, capric acid, laurate, octanoic acid
Ester, decanoin, cetylate, ethyl lactate, triacetyl glycerine；
(3) alcohols；As isopropanol, hexadecanol, lauryl alcohol, oleyl alcohol etc.；
(4) ethers：Polyoxyethylene laurel ether, polyoxyethylene octyl ether etc.；
(5) sulfoxide type：As dodecyl methyl sulfoxide, dimethyl sulfoxide etc.；
(6) amide-type：As N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, hexamethylene lauramide；
(7) lactams：Azone, laurocapram, dodecyl Azone, hold together cattle base Azone etc.；
(8) ion-type, nonionic surfactant：As sodium lauryl sulphate, SUNSOFT 700P-2, Tween 80, department
Disk 20 etc.；And/or
(9) the beta cyclodextrin class of beta cyclodextrin or alkyl replacement：As dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc..If
If presence, the consumption of Percutaneous absorption enhancer is account for total composition 0.5～5%, such as 0.5～2%, such as 0.5～
1.5%.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said Percutaneous absorption enhancer is many with described
Hydroxyl alcohol is added in described pharmaceutical composition together.
The purposes of any embodiment according to a fourth aspect of the present invention, wherein said pharmaceutical composition first party for example of the present invention
Described in any embodiment of face.
The method of any embodiment according to a fourth aspect of the present invention, wherein said pharmaceutical composition is liniment or spraying
The medicine type of agent.
According to any embodiment of either side of the present invention, wherein said pharmaceutical composition or external used medicine, its
Substantially anhydrous.The content of such as wherein water is less than 5%, preferably smaller than 3%.Certainly, the micro water as impurity is
Inevitably, and this water content can't affect the realization of effect of the present invention.For example, Examples below 1-9 of the present invention
(Ka Erfeixiushi algoscopy) is respectively less than 3% to water content in each compositionss after measured.
Arbitrary technical characteristic that any embodiment of either side of the present invention or this either side has is equally applicable
Other any embodiment or any embodiment of other either side, as long as they will not be conflicting, certainly mutual
Between where applicable, if necessary can individual features be made suitably modify.Make into one with feature to various aspects of the present invention below
The description of step.
All documents recited in the present invention, their full content is incorporated herein by, and if these are civilian
When implication expressed by offering is inconsistent with the present invention, it is defined by the statement of the present invention.Additionally, the present invention use various terms and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term referring to and phrase if any inconsistent with common art-recognized meanings, with institute of the present invention table
The implication stated is defined.
It is further described to various aspects of the present invention below.
A-5610, (±) -1- (2H) -4- [(4- chlorphenyl) methyl] -2- (hexahydro -1- methyl isophthalic acid H- azacyclo-
Heptane -4- base)-phthalazone mono-hydrochloric salts, be a kind of new construction 2，3-benzodiazine ketone be phthalazone derivant, clinically
For treating allergic seasonal rhinitis and anaphylaxis perennial rhinitiss.As many noses liquid, sneeze and rhinocnesmus.Be applied to adult or
6 years old and more than 6 years old child.
The drug interaction of A-5610：When drinking or using central nervous system depressant, disable this product,
Central nervous system impression otherwise can be increased.Oral hydrochloride azelastine (4mg, 2 times/day), is administered orally cimetidine simultaneously
(150mg, 2 times/day) can make the bioavailability of A-5610 improve 65%.Oral hydrochloride azelastine distinguishes mouth simultaneously
Take erythromycin (500mg, 3 times/day, continuous 7 days) and Ketoconazole (200mg, 2 times/day, continuous 7 days), erythromycin is tall and erect to hydrochloric acid nitrogen
Between the pharmacokineticss of STING and QT, the phase no affects.Ketoconazole phase between QT no affects, but dense to the blood medicine of A-5610
Degree mensure has interference.
The overdose of A-5610：There is no the report excessive using this product.Because every bottle of this product is containing only 10mg, because
This adult uses this product in a large number, will not cause clinically other significantly untoward reaction except drowsiness.Clinical research shows to be grown up
16mg is once administered orally will not increase side effect, up to the present still do not know the antidote of A-5610, such as using medicine mistake
Amount should take appropriate measures immediately.
The toxicological study of A-5610：Genetoxic：Ames experiment, DNA damage repairing test, mouse lymphocyte
Forward mutation test, mouse microkernel test and rat marrow chromosomal aberration test all do not find genetoxic.
The genotoxicity of A-5610：Oral Administration in Rats A-5610 30mg/kg/ days is (with mg/m2Meter, is people
240 times of intranasal administration clinic maximum recommended dosage) when, impact is had no on the fertility of male and female rat.Oral 68.6mg/
Kg/ days (with mg/m2Meter, is 550 times of people's intranasal administration clinic maximum recommended dosage), the emotionally same period of rat extends, and hands over
Join activity and pregnant quantity reduces.Corpus luteum number and implantation number reduce, but implantation rate is unaffected.Mouse oral 68.6mg/kg/
My god, show fetal toxicity, fetotoxicity and teratogenecity (outward appearance and skeletal abnormality).Oral Administration in Rats 30mg/kg/ days, finds bone
Change and postpone (metacarpal bone is not developed), the incidence rate of the 14th rib increases.Oral Administration in Rats 68.6mg/kg/ days, causes miscarriage and fetus poison
Property.The wind bone that these are observed under high exposed amount is abnormal unclear with the dependency of the mankind.Whether this product divides in human milk
Secrete unclear.
The carcinogenic test of A-5610：Rat and Mouse oral A-5610 30mg/kg/ days and 25mg/kg/
My god (mg/m2Meter, is 240 and 100 times of people's intranasal administration clinic maximum recommended dosage), continuous 24 months, do not find carcinogenic
Property.
The pharmacological action of A-5610：A-5610 and its main metabolites are histamine H1-receptor antagonisms
Agent, has antihistamine and anti-allergic effects.
The pharmacokineticss of A-5610：Absorb and distribution：The pharmacokineticss of A-5610 nasal cavity applied medicine
Research is less.There are average steady state blood plasma concentration normally artificial 0.26ug/L after document report 0.56mg nasal-cavity administration, patients with rhinitis
The result increasing for 0.65ug/L, the nasal mucosa permeability that this is likely due to patients with rhinitis.Nasal-cavity administration onset in about 10 minutes,
Drug effect sustainable 10-12 hour, crosses after 2-3 hour and arrives blood drug level, and bioavailability can reach 40%.Metabolism and elimination：Salt
Sour azelastine generates main active demethylation azelastine, nose through Petoxidation under cytochrome P450 effect
Spray doses are less than analysis test limit due to main metabolites demethylation azelastine concentration, thus fail to detect.Nose sprays
After mist agent administration, when A-5610 reaches stable state, the blood drug level of demethylation azelastine is the 20%- of azelastine
50%.Experiment in vitro shows blood plasma albumen and A-5610 and demethylation azelastine combination rate be respectively 88% and
97%.After nasal cavity applied medicine, the elimination of A-5610 remains by feces and urine ejection.
It has been found by the present inventors that the pharmaceutical composition with inventive formulation has the excellent of one or more aspects as follows
Point：Stable chemical property, low zest, can be used for allergic seasonal rhinitis and anaphylaxis perennial rhinitiss and/or can
For treating other the symptom such as anaphylaxis and/or contact dermatitis etc. related to anaphylaxis and non-allergic disease.
In addition, in view of product of the present invention has extremely low skin irritation, therefore it is particularly well-suited to infant or child,
This is extremely advantageous for the scope of application of expansion special population, also complies with currently country and puts into energetically in terms of children
Trend.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention does not limit
In following embodiments.One of skill in the art is it is understood that on the premise of without departing substantially from the spirit and scope of the present invention, permissible
Various change and modification are carried out to the present invention.The present invention to test used in material and test method carry out generality
And/or specifically describe.Although for realize many materials that the object of the invention used and operational approach be it is known in the art that
But the present invention still here describes in detail as far as possible.
The present invention can be conducted further description by the following examples, however, the scope of the present invention does not limit
In following embodiments.One of skill in the art is it is understood that on the premise of without departing substantially from the spirit and scope of the present invention, permissible
Various change and modification are carried out to the present invention.The present invention to test used in material and test method carry out generality
And/or specifically describe.Although for realize many materials that the object of the invention used and operational approach be it is known in the art that
But the present invention still here describes in detail as far as possible.Following examples further illustrate the present invention, rather than limit this
Bright.
Hereafter preparation process is for the purpose illustrated, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize, according to existing knowledge, the method obtaining that the present invention prepares liquid preparation completely.Below
Join liquid and prepare in various compositionss, if not otherwise indicated, the liquid measure of always joining of every batch is 10000ml.But list formula and preparation
During process, formula and preparation method are illustrated with the composition in every 100ml medicinal liquid.In subpackage, every bottle liquid medicine amount is 10ml.
Detection method：
Following high performance liquid chromatography (it can be described as the HPLC method of the present invention in the present invention) can be used for measuring the present invention
Active ingredient hydrochloric acid azelastine content in various materials and the content of various impurity.Specific as follows：
High performance liquid chromatography according to Chinese Pharmacopoeia two annex VD of version in 2010 is measured；
Mixed solvent：Acetonitrile/water (45:55, V/V)；
Test solution：The material to be measured comprising 0.025g A-5610 is dissolved in mixed solvent, and with mixing
Solvent dilution to 50.0mL, obtain final product (0.5mg/ml, if the concentration of material to be measured is close to this concentration or diluter than this concentration,
Then need not dilute and be used for measuring directly as test solution)；
Reference solution (a)：1.0mL test solution mixed solvent is diluted to 100.0mL, takes this solution 1.0mL with mixing
Bonding solvent is diluted to 10.0mL, obtains final product (0.5 μ g/ml)；
Reference solution (b)：By 1mg azelastine impurity B, the dissolving of 1mg azelastine impurity D, 1mg azelastine impurity E
It is diluted to 100ml in test solution and with test solution, obtain final product (10 μ g/ml, 10 μ g/ml, 10 μ g/ml, 0.5mg/ml)；
Chromatographic column：Column length 250cm, internal diameter 4.6mm, fixing phase is itrile group silicagel column (10 μm), 30 DEG C of column temperature；
Mobile phase：2.16g perfluorooctane sulfonate and potassium dihydrogen phosphate are dissolved in 740mL, with phosphoric acid,diluted adjust to
PH3.0-3.1, adds 260mL, mix homogeneously, obtains final product；
Flow velocity：2.0mL/min；
Detector：Uv-spectrophotometric detector, 210nm；
Sample size：10μL；
The log time：2 times of azelastine retention time；
Relative retention time：With azelastine (its retention time is about 8-9min)：Impurity A about 0.2, impurity B about 0.3,
Impurity C about 0.4, impurity D about 0.6, impurity E about 1.4；
System suitability：
Separating degree at least 4.0, impurity D peak and impurity in reference solution (b) chromatogram, between impurity B peak and impurity D peak
E peak and the equal baseline separation of main peak.
Above-mentioned HPLC method is typically for the limit regulation of A-5610 crude drug：
Correction factor：Impurity B=3.6, impurity D=0.7, impurity E=2.1；
Impurity A, B, C, D, E：The main peak area being each less than in reference solution (a) chromatogram (that is, is each respectively less than
0.1%).
Impurity A, B, C, D, E are respectively：
Impurity A, phenylhydrazide；
And enantiomer, impurity B, 1- benzoyl -2- [(4RS) -1- methyl hexahydro -
1H- azepan -4- base] diazane；
Impurity C, 2- [(4- chlorphenyl) acetyl group] benzoic acid；
Impurity D, 4- (4- chlorphenyl) phthalazines -1 (2H) -one；
Impurity E, 3- (4- chlorobenzene methylene) isobenzofuran -1 (3H) -one.
Above-mentioned impurity is known in the art.
Hereinafter, refer to that " total impurities " refers to above-mentioned impurity A, B, C, D, E summation.
Embodiment 1：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Propylene glycol | 20g, |
| Azone | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.One can be entered
This liquid medicine pharmaceutical composition respectively using the containers of liniment and spray, is made the form of liniment and spray by step,
To facilitate Clinical practice (following embodiment all can be processed as).
Embodiment 2：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.3g, |
| Propylene glycol | 15g, |
| Azone | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 3：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.75g, |
| Propylene glycol | 25g, |
| Azone | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 4：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.05g, |
| Propylene glycol | 30g, |
| Azone | 0.5g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 5：Prepare pharmaceutical composition
Formula：
| A-5610 | 1g, |
| Propylene glycol | 10g, |
| Azone | 1.5g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 6：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.15g, |
| Propylene glycol | 20g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts miscible with described polyhydroxy-alcohol；Then by gained mixed solution with appropriate
Polyhydroxy-alcohol fatty acid ester uniformly, is added polyhydroxy-alcohol fatty acid ester to full dose, is obtained final product.
Embodiment 7：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.6g, |
| Propylene glycol | 20g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts miscible with described polyhydroxy-alcohol；Then by gained mixed solution with appropriate
Polyhydroxy-alcohol fatty acid ester uniformly, is added polyhydroxy-alcohol fatty acid ester to full dose, is obtained final product.
Embodiment 8：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Glycerol | 20g, |
| Sodium deoxycholate | 0.75g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 9：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Propylene glycol | 10g, |
| Glycerol | 10g, |
| Oleic acid | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, add polyhydroxy-alcohol fatty acid ester to full dose, obtain final product.
Embodiment 21：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Propylene glycol | 20g, |
| Azone | 1g, |
| Water | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with suitable quantity of water uniformly, mend and add water to full dose, obtain final product.
Embodiment 22：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Propylene glycol | 20g, |
| Water | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with suitable quantity of water uniformly, mend and add water to full dose, obtain final product.
Embodiment 23：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Glycerol | 20g, |
| Sodium deoxycholate | 0.75g, |
| Water | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described polyhydroxy-alcohol；Then by institute
Obtain mixed solution with suitable quantity of water uniformly, mend and add water to full dose, obtain final product.
Embodiment 24：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Ethanol | 20g, |
| Azone | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described alcohol；Then gained is mixed
Solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, is added polyhydroxy-alcohol fatty acid ester to full dose, is obtained final product.
Embodiment 25：Prepare pharmaceutical composition
Formula：
| A-5610 | 0.5g, |
| Ethylene glycol | 20g, |
| Azone | 1g, |
| Glycerol triacetate | In right amount, add to 100ml. |
Preparation method：Make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer miscible with described alcohol；Then gained is mixed
Solution with appropriate polyhydroxy-alcohol fatty acid ester uniformly, is added polyhydroxy-alcohol fatty acid ester to full dose, is obtained final product.
Embodiment 26：Prepare pharmaceutical composition
Formula (200580046487.6Ex1)：
| A-5610 | 0.15g |
| Hypromellose 2900, USP4000 | 0.1g |
| Disodium edetate | 0.05g |
| Sorbitol 70% | 6.4g |
| Sodium citrate dihydrate | 0.068g |
| Sucralose | 0.15g |
| Benzalkonium chloride 50% solution | 0.025g |
| Water | In right amount, add to 100ml. |
Preparation method：Each material is added to makes it dissolve in suitable quantity of water, mend and add water to full dose, obtain final product.
Embodiment 27：Pharmaceutical composition is provided
Following two commercially available formulation in liquid form are provided：Azelastine Hydrochloride Eye Drops (0.05%, 6ml：3mg,
H20110343, MEDA company), Azelastine Hydrochloride Nasal Spray (0.1%, 10ml：10mg, H20100536, MEDA company).
Test example 1：Study on the stability
Whole samples of above example 1-9, embodiment 21-27 are sealed with vial, under the conditions of being placed in 40 DEG C of lucifuges
Place 6 months (in the present invention, this kind of high-temperature treatment mode for its reserve temperature can be described as high temperature June, 40 DEG C
June, high temperature June are disposed, 40 DEG C of June is disposed etc.), measure and calculate with this understanding each sample (0 before this high-temperature treatment
Month), the active component content in rear (June) and total impurities content.
Calculate in each sample, when 6 months, with respect to total impurities in this sample, the content when 0 month increased total impurities
(for example for embodiment 1 sample, the content of wherein total impurities increases percent and refers to percent：The June total impurities of this sample contains
Amount deducts 0 month total impurities content gained difference and is multiplied by the result of 100% gained again divided by 0 month total impurities content again, with % table
Show).
In addition, calculating each sample active component remnants percent when June, i.e. active component content during June in sample
(mg/ml) it is multiplied by the result of 100% gained divided by active component content (mg/ml) when 0 month again, represented with %.
Result：
The content of whole sample total impuritieses of embodiment 1-9 increases percent all in the range of 27～53%, for example, implement
It is 35% that the content of example 1 total impurities increases percent；But it was unexpectedly determined that whole sample total impuritieses of embodiment 21-27
Content increase percent all in the range of 167～258%, the content of such as embodiment 21 total impurities increases percent and is
215%, even employing glycerol triacetate in embodiment 24,25 but not using the examination of propylene glycol or glycerol
Sample, the content of its total impurities increases percent and is also more than 167%.
Whole samples of embodiment 1-9 and embodiment 21-27 active component remnants percent in terms of but do not show with
Variation tendency as total impurities, that is,：The active component remnants percent when June for the whole samples of embodiment 1-9 is all 95
In the range of～99%, for example embodiment 1 Sample activity composition remnants percent is 97.6%；Whole samples of embodiment 21-27
Active component remnants percent when June is all in the range of 95～98%.For drug quality, in Long-term Storage process
In, keep low impurity content and high active component content be a need for, thus, embodiment 1-9 these there is this
The compositionss of bright feature have than the compositionss in prior art, commercially available prod or non-invention characteristic formula more excellent
Pharmaceutical properties particularly stability.
Test example 2：Pharmacodynamicss are investigated
Allergic Contact scytitiss are clinical common class dermatosiss, and the cause of disease and pathogenesis are complicated, Yin Qichang
Have a strong impact on quality of life with symptoms such as skin itching maculo-papular rash.This test example investigate the present composition in anti-dermatitis
The effect of such as anaphylaxis and/or contact dermatitis aspect.
(1) material
Animal：SPF level ICR mice, male, body weight (25 ± 5) g, 4～5 weeks, by Chinese Academy of Sciences's Shanghai laboratory animal
The heart provides, quality certification number SCXK (Shanghai) 2007-0003.
Medicine and reagent：Embodiment 1 compositionss (0.5%), embodiment 6 compositionss (0.4%), embodiment 21 compositionss
(0.5%), embodiment 26 compositionss (0.15%)；DNF (analysis is pure for DNFB, German Merck company)；Mice
IL-4, IgE and INF- γ ELISA kit (R＆D Systems, Minneapolis, MN, the U.S.).
Instrument：Calibrator (Guanglu Digital Measure-Control Co., Ltd., Guilin, 10 μm of precision)；Kryostatl720 paraffin is cut
Piece machine (U.S.)；BX50F4 optical microscope (Japanese Olympus).
(2) method
Establishment of mouse model：Reference《Pharmacological experimental methodology》With DNFB acetone olive oil solution (acetone-olive oil 4：1)
[Xu Shuyun, Bian Rulian, Chen Xiu, pharmacology is real with exciting mouse skin to set up mouse allelgic contact dermatitis (ACD) model for sensitization
The proved recipe science of law [M]：Beijing people's health publishing house, 2002：1429].ICR mice is normally raised 1 week in SPF barrier system,
In experiment abdominal part depilation in first 1 day, scope about 3cm × 3cm, the 1st day depilation position of experiment is uniformly coated with 1%DNFB acetone olive oil
Solution 50 μ L sensitization, experiment repeats strengthening sensitization 1 time on the 2nd day.Test the 5th day, each uniform painting 1%DNFB acetone olive of mice ears
Olive oil solution 10 μ L is excited.Normal group is only coated with acetone olive oil solution (acetone-olive oil 4 in same area：1)
Compare.
Packet and administration：48 mices are randomly divided into 6 groups, every group 8, respectively normal group, model group, embodiment 1
Compositionss (20mg/kg), embodiment 6 compositionss (20mg/kg), embodiment 21 compositionss (20mg/kg), embodiment 26 compositionss
(20mg/kg).Mice by above-mentioned group technology be uniformly coated with abdominal part depilation daily after sensitization medicine (four kinds of medicines) or
Person's water for injection (normal group, model group), the 1st day and the 2nd day after imposing 50 μ L acetone olive oil solution 4 hours again to
Medicine.Modeling success after having gathered edema scores of erythema and swelling degrees of data, each group animal takes blood to pluck eyeball method, subsequent cervical vertebra
Dislocation is put to death, and takes off mice ears fixing in 4% neutral paraformaldehyde solution.
Mice ear degree：Before exciting and after exciting, 24h measures mice bilateral ear swelling degree with calibrator, and to exciting
Dropsy of ear erythema degree is scored afterwards, no 0 point of erythema, slightly 1 point of visible erythema, 2 points of moderate erythema, 3 points of Severe erythema, water
4 points of swollen property erythema；No 0 point of edema, 1 point of Mild edema, 2 points of intermediate edema, 3 points of Severe edema.
Data processing：Data is represented with mean value ± SD, carries out statistical analysiss with SPSS13.0 software, compares employing between group
ANOVA One-way inspection and SNK-q inspection.
(3) result
Mouse ear excites after 24h model group mice ear degree substantially (compared with matched group P<0.01), show modeling
Success.
Compared with model, different pharmaceutical compositionss assume different degrees of suppression mice ear degree, wherein embodiment 1
With 6 two kinds of compositionss of embodiment compared with model group, it is respectively provided with significant difference (P<0.05), completely regrettably, even if
Under same dose, 26 two kinds of compositionss of embodiment 21 and embodiment all do not assume significant difference compared with model group.
Each administration group mice dropsy of ear erythema also assumes different degrees of score value, wherein embodiment 1 compared with model group
With 6 two kinds of compositionss of embodiment compared with model group, it is respectively provided with significant difference (P<0.05), completely regrettably, even if
Under same dose, 26 two kinds of compositionss of embodiment 21 and embodiment all do not assume significant difference compared with model group.Specifically
The results are shown in Table 1.These results show that the compositionss with feature of present invention can assume excellent treatment Allergic Contact skin
Scorching effect, and prior art compositions do not enable this function.
Table 1：The impact (n=8) to mice ear degree and edema scores of erythema value for the compositionss
| Group | Swelling/mm | Scores of erythema |
| Matched group | 0.01±0.01 | — |
| Model group | 0.19±0.07 | 5.93±1.38 |
| Embodiment 1 | 0.10±0.05* | 3.47±0.73* |
| Embodiment 6 | 0.11±0.04* | 3.63±0.91* |
| Embodiment 21 | 0.17±0.07 | 5.17±1.32 |
| Embodiment 26 | 0.16±0.06 | 5.26±1.18 |
Note：* compare with model group, p<0.05.
Contact hyper sensitization dermatitis belongs to cutaneous delayed-type allergy, is a kind of cell immune response of T cell mediation,
The cell participating in includes Th1 cell, 1 type cytotoxic cell (Tc1), and Th2 type cell [Wagner AH, Wittjen I,
Stojanovic T,et a l.Signal transducer and activator of transcription 1
decoyoligodeoxynucleotide suppression of contact hypersensitivity[J].J A
llergy Clin Immunol,2008,121(1):158].The ACD model set up in this experiment is more classical animal mould
Type, successfully simulates the antigenic specificity skin allergy cell-mediated by Th1 cell and Tc1.
This research, by being successfully established ACD mouse model, has investigated the present composition to model ear redness degree
Impact, test result indicate that, the present composition can mitigate model ear swelling and inhibition edema erythema is formed, and says
The bright present composition has the effect of good anti-ACD.It is well known that above-mentioned ACD mouse model is a kind of classical mistake
Quick property dermatitis and the pharmacodynamics model of contact dermatitis.
Test example 3：Medicine irritation is tested
(1) have been found that in above test example 2, at the abdominal part administration of mice, before recording the daily administration of every animal
Skin irritation at administration.Result shows, different reagents assume different degrees of zest, are mainly reflected in erythrosises.
Characterize the degree that reddens with 5 points of chis, 0 point of expression has no and redden, 1 point indicates faint and reddens, the score value degree that reddens more greatly is bigger, directly
Reach most serious to 5 points, every group is represented from the 1st day to the meansigma methodss of last day institute's score value with its each animal.Result：Matched group
0 point must be divided into, 0.44 point of model group score (is likely due to what DNFB caused), embodiment 1 and 6 groups of scores of embodiment are respectively
0.31 and 0.49 point (suitable with the model group giving DNFB, show that this two groups of animals give after the present composition no skin thorn
Sharp property), but embodiment 21 and 26 groups of scores of embodiment are respectively 3.68 and 4.23 points, show that they present significantly to skin
Zest.
(2) animal with test example 1, medicine is embodiment 1-9, the whole sample of embodiment 21-27 gained, totally 17 groups,
5 mices of each administration group.
Mice is normally raised 1 week in SPF barrier system, in experiment abdominal part depilation in first 1 day, scope about 3cm × 3cm, connects
And at here depilation, smear medicine (dosage is counted as 20mg/kg with A-5610), continuous coating 7 days daily.After self administration of medication
The 2-8 days, for 5 animals of each administration group, observe its coating position zest in terms of the degree of reddening, record daily
This group animal recorded moderate stimulation score value at this 7 days, calculated every group of meansigma methodss.As a result, the zest of embodiment 1-9 each group is divided
Value is respectively less than 0.5, and all in the range of 0～0.33, display there is no zest, but it is completely surprising that embodiment
The zest score value of 8 groups of each sample of 21-27, all in the range of 2.87～4.23, shows that they assume obvious skin irritation
Property.
Industrial applicability
The invention provides a kind of azelastine compositionss and purposes.In particular it relates to the liquid of azelastine
Compositionss, more particularly to a kind of fluid composition of azelastine hydrochloride, relate more particularly to a kind of non-aqueous liquid group
Compound.The invention still further relates to the preparation method of this fluid composition and their pharmaceutical applications, for example the invention still further relates to this
The purposes of based composition treatment, the alleviation or prevention symptom related to anaphylaxis and non-allergic disease, and for example in treatment
Purposes in dermatitis such as anaphylaxis and/or contact dermatitis.The present composition has beat all pharmaceutical properties.
Claims (14)
1. a kind of pharmaceutical composition in liquid condition, wherein consists of：Azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy
Base alcohol fatty acid ester is glycerol triacetate；Described polyhydroxy-alcohol is selected from：Propylene glycol, glycerol, and combinations thereof；This medicine group
Comprise azelastine or its pharmaceutical salts of 0.05 ~ 2g in the every 100ml of compound, comprise the polyhydroxy-alcohol of 5 ~ 50g in every 100ml, often
The polyhydroxy-alcohol fatty acid ester of 50 ~ 95g is comprised in 100ml.
2. the pharmaceutical composition of claim 1, comprises azelastine or its pharmaceutical salts of 0.05 ~ 1.5g in its every 100ml.
3. the pharmaceutical composition of claim 1, comprises azelastine or its pharmaceutical salts of 0.05 ~ 1g in its every 100ml.
4. the pharmaceutical composition of claim 1, comprises the polyhydroxy-alcohol of 7.5 ~ 40g in its every 100ml.
5. the pharmaceutical composition of claim 1, comprises the polyhydroxy-alcohol of 10 ~ 30g in its every 100ml.
6. the pharmaceutical composition of claim 1, comprises the polyhydroxy-alcohol fatty acid ester of 60 ~ 92.5g in its every 100ml.
7. the pharmaceutical composition of claim 1, comprises the polyhydroxy-alcohol fatty acid ester of 70 ~ 90g in its every 100ml.
8. the pharmaceutical composition of claim 1, it is the pharmaceutical preparation being for external application.
9. the pharmaceutical composition of claim 1, it is the pharmaceutical preparation for percutaneous dosing.
10. the pharmaceutical composition of claim 1, this pharmaceutical composition is the medicine type of liniment or spray.
The method of 11. preparation claim 1 described pharmaceutical compositions, the method comprises the following steps：
Make azelastine or its pharmaceutical salts miscible with described polyhydroxy-alcohol；
Then by gained mixed solution with polyhydroxy-alcohol fatty acid ester uniformly, obtain final product.
12. azelastines or its pharmaceutical salts purposes in the medicine of preparation treatment or prevention inflammatory disease of the skin, described medicine
There is the feature of claim 1-10 any one described pharmaceutical composition.
The purposes of 13. claim 12, wherein said inflammatory disease of the skin is selected from：Allergic dermatitises, contact dermatitis, eczema,
Acute urticaria.
14. azelastines or its pharmaceutical salts in preparation treatment or are prevented inflammatory disease of the skin and are not substantially assumed thorn to skin
Purposes in the external used medicine of sharp property, wherein said external used medicine is the drug regimen as described in any one of claim 1-10
Thing.
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| CN104857518A (en) * | 2015-05-28 | 2015-08-26 | 云南白药集团无锡药业有限公司 | Novel chemical skin penetration enhancer containing cholic acid group |
| CN106492219A (en) * | 2016-11-30 | 2017-03-15 | 郑州仁宏医药科技有限公司 | A kind of Western medicine compound for treating skin eczema and its application |
| CN107929738A (en) * | 2017-11-28 | 2018-04-20 | 贵州云峰药业有限公司 | A kind of composition of hydrochloric azelastine |
| CN110721189A (en) * | 2019-11-19 | 2020-01-24 | 贵州云峰药业有限公司 | Skin disinfectant |
| CN118271291A (en) * | 2024-04-01 | 2024-07-02 | 广东先强药业有限公司 | Preparation method and application of high-purity azelastine hydrochloride |
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| GB2389530B (en) * | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| SI2486942T1 (en) * | 2004-11-24 | 2019-03-29 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
| KR101052947B1 (en) * | 2008-07-22 | 2011-07-29 | 한국콜마 주식회사 | Azelastine Liquid Formulation |
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