CN104173286A - Azelastine composition and use - Google Patents
Azelastine composition and use Download PDFInfo
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- CN104173286A CN104173286A CN201410457775.1A CN201410457775A CN104173286A CN 104173286 A CN104173286 A CN 104173286A CN 201410457775 A CN201410457775 A CN 201410457775A CN 104173286 A CN104173286 A CN 104173286A
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Abstract
The invention relates to an azelastine composition and use, specifically relates to liquid compositions of azelastine, particularly relates to liquid compositions of azelastine hydrochloride and more particularly relates to a nonaqueous liquid composition. In one embodiment, the pharmaceutical composition contains azelastine or pharmaceutical salt thereof, polyhydric alcohol, polyethylene glycol and polyhydric alcohol fatty acid ester. The invention further relates to a preparation method of the liquid composition and pharmaceutical use of the liquid composition, for example, the invention further relates to the use of the composition in the treatment, relief or prevention of symptoms related to allergic and non-allergic diseases and the use in the treatment of dermatitis, such as allergic and/or contact dermatitis. The pharmaceutical composition disclosed by the invention can be in the dosage form of liniment or spray, so as to facilitate clinical use.
Description
Technical field
The present invention relates to the fluid composition of azelastine, particularly relate to a kind of fluid composition of azelastine hydrochloride, relate more particularly to a kind of fluid composition of non-water.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 the symptom of this based composition treatment, alleviation or prevention and anaphylaxis and nonallergic disease association, and for example purposes in treatment for example anaphylaxis of dermatitis and/or contact dermatitis.The present composition has beat all pharmaceutical properties.Especially, the fluid composition of azelastine of the present invention can use suitable Drug packing form, to offer clinical use with conventional liniment or spray.
Background technology
Azelastine, conventional its hydrochlorate (azelastine hydrochloride) clinically, molecular formula C22H24ClN3O.HCl, molecular weight: 418.36, CAS registration number: 79307-93-0, wherein science of culture name is called: (±)-1-(2H)-4-[(4-chlorphenyl) methyl]-2-(six hydrogen-1-methyl isophthalic acid H-azepan-4-yl)-phthalazone mono-hydrochloric salts, English chemical name is: (±)-1-(2H)-4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-phthalazinone, monohydrochloride, chemical constitution is:
Hydrochloric acid chlorine Zhuo Siting is that a kind of 2，3-benzodiazine ketone of new construction is the derivant of phthalazone, is a kind of potential long-acting antiallergic compound, has H1 receptor antagonist feature, has antiallergic, Zhichuan and antihistamine characteristic.Animal experimental data shows, the A-5610 of high concentration can stop the synthetic and release (for example: leukotriene, histamine, 5-hydroxy tryptamine) of some chemical mediator in anaphylaxis, when nose spray administration, allowing, under the maximal dose of application, Local toxic reaction or organ specificity toxic reaction not detected.
After oral drugs, A-5610 is absorbed by the body rapidly, and absolute bioavailability is up to 81%.Food is on absorbing without impact.The high tissue around that shows to distribute mainly of capacity distributing, protein bound level relatively low (80%-90%).Single medicine gives after A-5610, and the plasma clearance half-life, hydrochloric acid chlorine Zhuo Siting was 20 hours, and the nor-azelastine of curative active metabolite N-is approximately 45 hours.Excretion is mainly got rid of through feces.In feces, the lasting excretion of a small amount of medicine shows that medicine can carry out enterohepatic circulation.The A-5610 of nose spray application every day 0.56mg (is equivalent to 1 spray/every nostril repeatedly, 2 times/day), healthy volunteer's A-5610 Cmax Cpss is approximately 0.27ng/ml, and the nor-azelastine of its active metabolite N-can be detected (0.12ng/ml) at quantitative limit value or lower than quantitative level.
Allergic Rhinitis is repeatedly after nasal cavity drug application, blood plasma A-5610 level is slightly high compared with Healthy People, thereby show that whole body is to the level of drug absorption high (mainly may can better penetrate due to medicine the nasal mucosa of inflammation, be convenient to absorb).After the hydrochloric acid hydrogen Zhuo Siting of medication every day accumulated dose 0.56mg, (for example: 1 spray, every nostril, 2 times/day) medication is observed azelastine mean plasma concentration and is approximately 0.65ng/ml after 2 hours.The average blood plasma Css that A-5610 dosage is doubled to 1.12mg (example: 2 spray/every nostrils, 2 times/day) azelastine every day is 1.09ng/ml.Show that thus Drug level and dosage are proportional distributions.Although patient absorbs the drug, level is relatively high, and nasal cavity applied medicine systemic drug exposure level is than oral medication systemic drug exposure level low about 8 times (the oral medication dosage for the treatment of of allergic rhinitis is 4.4mg A-5610 every day) as calculated.
Azelastine can produce with the form of various salt.In medicine, the most frequently used form is A-5610, its for white, be almost that the scentless crystalline powder with strong bitterness exists.Other salt form that is applicable to pharmaceutical composition comprises pamoic acid azelastine, its bitterness than azelastine HC1 alleviates (referring to US Patent No. 5,232,919, the content that the document is disclosed is incorporated herein by reference), but effectiveness is also lower than A-5610.
Studies confirm that when the acceptable salt form of azelastine and physiology thereof is on the conjunctival sac that is directly applied to nasal mucosa and/or eye with corresponding preparation and show beneficial effect { referring to US Patent No. 5,164,194}.In allergic rhinitis (seasonality and/or Out of season), vasomotor rhinitis and anaphylaxis conjunctivitis, realizing thus symptom eliminates or alleviates significantly.
Although there is its effectiveness, A-5610 has strong bitterness.This bitterness is so strong, to such an extent as to finds even at dilution 1X10
6situation under still unhappy (referring to US Patent No. 5,164,194).In the time of intranasal delivery A-5610, do not think that this bitterness is problem (referring to above).But clinical research is subsequently verified, in fact, the bitterness of A-5610 is undesirable composition as the part that conventionally flows into pharyngeal medicine after intranasal administration downwards, experiences thereby cause patient not accommodate undesirable taste.For example, MedPointePharmaceuticals, Inc. (Somerset, NJ) in ASTELIN product description, record, in clinical research, have more significance,statistical (19.7% and 0.6%) compared with the incidence rate of the adverse consequences of this bitterness in the patient with ASTELINNasalSpray (containing 0.10%w/v A-5610) treatment and the patient's with solvent placebo treatment incidence rate.Equally, because eye drops and the fluid being combined to form of the tear of the lacrimal secretion bringing out are entered nose and are finally flowed into pharyngeal (referring to Day by nasolacrimal duct drain, N., " OphthalmicDosage Forms; ": in Pharmaceutical Preformulation and Formulation, Buffalo Grove, IL:Interpharm Press (2002)).The postnasal drip that the compositions that this class comprises A-5610 because of eye causes also may bring out thus patient's bitterness and uncomfortable taste and experience.Ukai etc. (US Patent No. 6,576,677) have disclosed polyvinylpyrrolidone and/or polyvinylpolypyrrolidone is being sheltered bitter drug, comprise the application in the taste of azelastine.Visible, azelastine as nose with or eye there is many limitation with administration, for example they are only used for the treatment of anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis clinically conventionally.
Therefore, the method for the symptom that has new treatment or prevention and anaphylaxis and nonallergic disease association is still expected in this area.New effective compositions is for example provided and/or uses it for treatment anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis and symptom such as anaphylaxis and/or the contact dermatitis etc. of other and anaphylaxis and nonallergic disease association.
Summary of the invention
The object of the present invention is to provide the method for the symptom of a kind for the treatment of or prevention and anaphylaxis and nonallergic disease association.New effective compositions is for example provided and/or uses it for treatment anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis and symptom such as anaphylaxis and/or the contact dermatitis etc. of other and anaphylaxis and nonallergic disease association.The inventor have been surprisingly found that, has advantages of that the pharmaceutical composition of the present invention's formula has following one or more aspect: stable chemical property, low zest, can be used for anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis and/or can be used for treating other and symptom such as anaphylaxis and/or the contact dermatitis etc. of anaphylaxis and nonallergic disease association.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition, wherein comprises: azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is the pharmaceutical composition that is liquid condition.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the azelastine that comprises 0.01～5g in its every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.02～2.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～2g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1g in every 100ml or its pharmaceutical salts.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said polyhydroxy-alcohol is selected from: ethylene glycol, propylene glycol, glycerol and combination thereof.In the present invention, ethylene glycol refers to 1，2-ethandiol, and propylene glycol refers to 1,2-PD, and glycerol refers to Glycerin.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the polyhydroxy-alcohol that comprises 5～50g in its every 100ml, the polyhydroxy-alcohol that for example comprises 7.5～40g in every 100ml, the polyhydroxy-alcohol that for example comprises 10～30g in every 100ml.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said polyhydroxy-alcohol fatty acid ester is selected from: glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester and combination thereof.Described glycerol fatty acid ester is the fatty acid ester of Glycerin.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said polyhydroxy-alcohol fatty acid ester is selected from: propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, glycerol monoacetate and combination thereof.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the polyhydroxy-alcohol fatty acid ester that comprises 50～95g in its every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 60～92.5g in every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 70～90g in every 100ml.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said polyhydroxy-alcohol fatty acid ester is to add with the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as the main amount solvent of most amounts in other words conj.or perhaps.Therefore, its addition can not done concrete restriction, for example can be to be similar to " aequum ", " appropriate, to add to 100ml ", " appropriate, to add to 100g ", " appropriate, to add to full dose " etc. or similar fashion statement.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is the pharmaceutical preparation being for external application.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is the pharmaceutical preparation for percutaneous dosing.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein also comprise Percutaneous absorption enhancer.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said Percutaneous absorption enhancer is selected from one or more materials below:
(1) cholic acid salt: glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, CDC, bird rope deoxycholate etc.;
(2) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, nutmeg acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate, triacetyl glycerine;
(3) alcohols; As isopropyl alcohol, 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 DMF, N,N-dimethylacetamide, 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, span 20 etc.; And/or
(9) the beta cyclodextrin class that beta cyclodextrin or alkyl replace: as dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc.If present, the consumption of Percutaneous absorption enhancer is to account for 0.5～5% of total composition, for example 0.5～2%, for example 0.5～1.5%.In the present invention, if not otherwise indicated, % refers to w/w percent.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is the medicine type of liniment or spray.
Further, second aspect present invention provides the method for pharmaceutical compositions, in described pharmaceutical composition, comprises: azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester; The method comprises the following steps:
Make azelastine or its pharmaceutical salts and described polyhydroxy-alcohol miscible;
Then by even to gained mixed solution and polyhydroxy-alcohol fatty acid ester, to obtain final product.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said pharmaceutical composition is the pharmaceutical composition that is liquid condition.
According to the method for the arbitrary embodiment of second aspect present invention, the azelastine that comprises 0.01～5g in the every 100ml of wherein said pharmaceutical composition or its pharmaceutical salts, the azelastine that for example comprises 0.02～2.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～2g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1g in every 100ml or its pharmaceutical salts.
According to the method for the arbitrary embodiment of second aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol is selected from: ethylene glycol, propylene glycol, glycerol and combination thereof.
According to the method for the arbitrary embodiment of second aspect present invention, the polyhydroxy-alcohol that comprises 5～50g in the every 100ml of wherein said pharmaceutical composition, the polyhydroxy-alcohol that for example comprises 7.5～40g in every 100ml, the polyhydroxy-alcohol that for example comprises 10～30g in every 100ml.
According to the method for the arbitrary embodiment of second aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol fatty acid ester is selected from: glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester and combination thereof.
According to the method for the arbitrary embodiment of second aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol fatty acid ester is selected from: propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, glycerol monoacetate and combination thereof.
According to the method for the arbitrary embodiment of second aspect present invention, the polyhydroxy-alcohol fatty acid ester that comprises 50～95g in the every 100ml of wherein said pharmaceutical composition, the polyhydroxy-alcohol fatty acid ester that for example comprises 60～92.5g in every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 70～90g in every 100ml.
According to the method for the arbitrary embodiment of second aspect present invention, polyhydroxy-alcohol fatty acid ester described in wherein said pharmaceutical composition is to add with the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as the main amount solvent of most amounts in other words conj.or perhaps.Therefore, its addition can not done concrete restriction, for example can be to be similar to " aequum ", " appropriate, to add to 100ml ", " appropriate, to add to full dose " etc. or similar fashion statement.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said pharmaceutical composition is the pharmaceutical preparation being for external application.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said pharmaceutical composition is the pharmaceutical preparation for percutaneous dosing.
According to the method for the arbitrary embodiment of second aspect present invention, in wherein said pharmaceutical composition, also comprise Percutaneous absorption enhancer.
According to the method for the arbitrary embodiment of second aspect present invention, Percutaneous absorption enhancer described in wherein said pharmaceutical composition is selected from one or more materials below:
(1) cholic acid salt: for example their sodium salts such as glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, CDC, bird rope deoxycholate;
(2) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, nutmeg acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate, triacetyl glycerine;
(3) alcohols; As isopropyl alcohol, 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 DMF, N,N-dimethylacetamide, 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, span 20 etc.; And/or
(9) the beta cyclodextrin class that beta cyclodextrin or alkyl replace: as dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc.If present, the consumption of Percutaneous absorption enhancer is to account for 0.5～5% of total composition, for example 0.5～2%, for example 0.5～1.5%.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said Percutaneous absorption enhancer adds in described pharmaceutical composition together with described polyhydroxy-alcohol.
According to the method for the arbitrary embodiment of second aspect present invention, as described in wherein said pharmaceutical composition embodiment as arbitrary in first aspect present invention.
According to the method for the arbitrary embodiment of second aspect present invention, wherein said pharmaceutical composition is the medicine type of liniment or spray.
Further, third aspect present invention provides azelastine or the purposes of its pharmaceutical salts in the medicine of preparation treatment or prevention inflammatory disease of the skin.
According to the purposes of the arbitrary embodiment of third aspect present invention, wherein said inflammatory disease of the skin is selected from: allergic dermatitis, contact dermatitis, eczema, acute urticaria.
According to the purposes of the arbitrary embodiment of third aspect present invention, wherein said medicine has the feature of pharmaceutical composition described in the arbitrary embodiment of first aspect present invention.
According to the purposes of the arbitrary embodiment of third aspect present invention, wherein said medicine is the medicine type of liniment or spray.
Further, fourth aspect present invention provides azelastine or its pharmaceutical salts in preparation treatment or has prevented inflammatory disease of the skin and substantially skin do not presented to the purposes in irritating external used medicine.Have been surprisingly found that, use formula of the present invention substantially not produce particularly local irritation of zest to skin, and the compositions of other formula presents skin irritation significantly.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, wherein said inflammatory disease of the skin is selected from: allergic dermatitis, contact dermatitis, eczema, acute urticaria.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, wherein said external used medicine is the pharmaceutical composition that is liquid condition.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, in wherein said pharmaceutical composition, comprise: azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, the azelastine that comprises 0.01～5g in the every 100ml of wherein said pharmaceutical composition or its pharmaceutical salts, the azelastine that for example comprises 0.02～2.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～2g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1g in every 100ml or its pharmaceutical salts.Under this concentration, when using the present composition when spray uses, can easily realize 0.02～2mg/ spray, for example the operational version of 0.14mg/ spray.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol is selected from: ethylene glycol, propylene glycol, glycerol and combination thereof.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, the polyhydroxy-alcohol that comprises 5～50g in the every 100ml of wherein said pharmaceutical composition, the polyhydroxy-alcohol that for example comprises 7.5～40g in every 100ml, the polyhydroxy-alcohol that for example comprises 10～30g in every 100ml.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol fatty acid ester is selected from: glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester and combination thereof.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, described in wherein said pharmaceutical composition, polyhydroxy-alcohol fatty acid ester is selected from: propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, glycerol monoacetate and combination thereof.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, the polyhydroxy-alcohol fatty acid ester that comprises 50～95g in the every 100ml of wherein said pharmaceutical composition, the polyhydroxy-alcohol fatty acid ester that for example comprises 60～92.5g in every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 70～90g in every 100ml.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, polyhydroxy-alcohol fatty acid ester described in wherein said pharmaceutical composition is to add with the form of body solvent.Term " body solvent " refers in liquid pharmaceutical formulation as the main amount solvent of most amounts in other words conj.or perhaps.Therefore, its addition can not done concrete restriction, for example can be to be similar to " aequum ", " appropriate, to add to 100ml ", " appropriate, to add to full dose " etc. or similar fashion statement.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, wherein said pharmaceutical composition is the pharmaceutical preparation being for external application.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, wherein said pharmaceutical composition is the pharmaceutical preparation for percutaneous dosing.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, in wherein said pharmaceutical composition, also comprise Percutaneous absorption enhancer.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, Percutaneous absorption enhancer described in wherein said pharmaceutical composition is selected from one or more materials below:
(1) cholic acid salt: glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, CDC, bird rope deoxycholate etc.;
(2) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, nutmeg acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate, triacetyl glycerine;
(3) alcohols; As isopropyl alcohol, 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 DMF, N,N-dimethylacetamide, 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, span 20 etc.; And/or
(9) the beta cyclodextrin class that beta cyclodextrin or alkyl replace: as dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc.If present, the consumption of Percutaneous absorption enhancer is to account for 0.5～5% of total composition, for example 0.5～2%, for example 0.5～1.5%.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, wherein said Percutaneous absorption enhancer adds in described pharmaceutical composition together with described polyhydroxy-alcohol.
According to the purposes of the arbitrary embodiment of fourth aspect present invention, as described in wherein said pharmaceutical composition embodiment as arbitrary in first aspect present invention.
According to the method for the arbitrary embodiment of fourth aspect present invention, wherein said pharmaceutical composition is the medicine type of liniment or spray.
Arbitrary embodiment of either side according to the present invention, wherein said pharmaceutical composition or external used medicine, it is anhydrous substantially.For example wherein the content of water is less than 5%, is preferably less than 3%.Certainly be inevitably as the micro-water of impurity, and this water content can't affect the realization of effect of the present invention.For example, the present invention below the water content in the each compositions of embodiment 1-9 after measured (Ka Erfeixiushi algoscopy) be all less than 3%.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Be further described to various aspects of the present invention below.
A-5610, (±)-1-(2H)-4-[(4-chlorphenyl) methyl]-2-(six hydrogen-1-methyl isophthalic acid H-azepan-4-yl)-phthalazone mono-hydrochloric salts, it is 2 of a kind of new construction, 3-phthalazone is the derivant of phthalazone, is used for the treatment of clinically anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis.As many noses liquid, sneeze and rhinocnesmus.Be applicable to adult or more than 6 years old and 6 years old child.
The drug interaction of A-5610: in the time drinking or use central nervous system depressant, forbidding this product, suppresses otherwise can increase the weight of central nervous system.Oral hydrochloride azelastine (4mg, 2 times/day), oral cimetidine (150mg, 2 times/day) can make the bioavailability of A-5610 improve 65% simultaneously.Oral hydrochloride azelastine is distinguished oral erythromycin (500mg, 3 times/day, continuous 7 days) and ketoconazole (200mg, 2 times/day, continuous 7 days) simultaneously, and the pharmacokinetics of erythromycin on A-5610 and QT interval are without impact.Ketoconazole without impact, but has interference to the determination of plasma concentration of A-5610 to QT interval.
The overdose of A-5610: there is no and use the excessive report of this product.Because every bottle of this product is only containing 10mg, therefore a large amount of this product that use of adult, can not cause other significant untoward reaction clinically except drowsiness.Clinical research show adult once oral 16mg can not increase side effect, up to the present still do not know the antidote of A-5610, as use overdose should take appropriate measures immediately.
The toxicological study of A-5610: genetoxic: Ames experiment, DNA damage repairing test, the test of mouse lymphocyte forward mutation, mouse microkernel test and rat marrow chromosomal aberration test are not all found genetoxic.
The genotoxicity of A-5610: Oral Administration in Rats A-5610 30mg/kg/ days is (with mg/m
2meter, is 240 times of the clinical maximum recommended dosage of people's nasal cavity administration) time, the fertility of male and female rat is had no to impact.Oral 68.6mg/kg/ days (with mg/m
2meter, is 550 times of the clinical maximum recommended dosage of people's nasal cavity administration), extend the emotionally same period of rat, and copulation activity and conceived quantity reduce.Corpus luteum number and implantation number reduce, but implantation rate is unaffected.The oral 68.6mg/kg/ days of mice, shows fetal toxicity, fetotoxicity and teratogenecity (outward appearance and skeletal abnormality).Oral Administration in Rats 30mg/kg/ days, finds ossified postpone (metacarpal bone is not grown), and the incidence rate of the 14th rib increases.Oral Administration in Rats 68.6mg/kg/ days, causes miscarriage and fetotoxicity.These wind bones of observing under high exposed amount dependency abnormal and mankind it be unclear that.Whether this product is secreted and be it be unclear that in human milk.
The carcinogenic test of A-5610: rat and mice oral hydrochloride azelastine 30mg/kg/ days and 25mg/kg/ days (mg/m
2meter, is 240 and 100 times of the clinical maximum recommended dosage of people's nasal cavity administration), continuous 24 months, do not find carcinogenecity.
The pharmacological action of A-5610: A-5610 and main metabolites thereof are histamine H 1 receptor antagonists, has antihistamine and anti-allergic effects.
The pharmacokinetics of A-5610: absorb and distribute: the pharmacokinetic of A-5610 nasal cavity applied medicine is less.Having the normal people of average steady state blood plasma concentration after bibliographical information 0.56mg nasal-cavity administration is 0.26ug/L, and rhinitis patient is 0.65ug/L, and this may be the result increasing due to rhinitis patient's counteract nasal mucosa permeability.Nasal-cavity administration onset in approximately 10 minutes, the sustainable 10-12 hour of drug effect, crosses blood drug level after 2-3 hour, and bioavailability can reach 40%.Metabolism and elimination: A-5610 generates main active demethylation azelastine through Petoxidation under cytochrome P450 effect, nasal spray administration, because main metabolites demethylation azelastine concentration is limit lower than analyzing and testing, therefore fails to detect.After nasal spray administration, in the time that A-5610 reaches stable state, the blood drug level of demethylation azelastine is the 20%-50% of azelastine.Experiment in vitro shows that blood plasma albumen and A-5610 and demethylation azelastine combination rate are respectively 88% and 97%.After nasal cavity applied medicine, the elimination of A-5610 remains by feces and urine and discharges.
The inventor has been found that the pharmaceutical composition with the present invention formula has following one or more aspect: stable chemical property, low zest, can be used for anaphylaxis seasonal rhinitis and anaphylaxis perennial rhinitis and/or can be used for treating other and symptom such as anaphylaxis and/or the contact dermatitis etc. of anaphylaxis and nonallergic disease association.
In addition, in view of product of the present invention has extremely low skin irritation, therefore it is specially adapted to infant or child, and this is very favourable for the scope of application that expands special population, also meets the trend that current national drops into energetically aspect children.
Detailed description of the invention
Can conduct further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.
Can conduct further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.
The below object of preparation process in order to give an example, and comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize according to existing knowledge the method that the present invention prepares liquid preparation that obtains completely.Dosing is prepared in various compositionss below, and if not otherwise indicated, total dosing amount of every batch is 10000ml.But while listing formula and preparation process, illustrate formula and method for making with the composition in every 100ml medicinal liquid.In the time of subpackage, every bottle liquid medicine amount is 10ml.
Detection method:
Following high performance liquid chromatography (it can be described as HPLC method of the present invention in the present invention) can be used for measuring active ingredient hydrochloric acid azelastine content in the various materials of the present invention and the content of various impurity.Specific as follows:
High performance liquid chromatography according to two annex VD of Chinese Pharmacopoeia version in 2010 is measured;
Mixed solvent: acetonitrile/water (45:55, V/V);
Test solution: the material to be measured that comprises 0.025g A-5610 is dissolved in mixed solvent, and be diluted to 50.0mL with mixed solvent, obtain (0.5mg/ml, if the concentration of material to be measured approaches this concentration or rarer than this concentration, needn't dilute and directly as test solution for measure);
Reference solution (a): 1.0mL test solution is diluted to 100.0mL with mixed solvent, gets this solution 1.0mL mixed solvent and be diluted to 10.0mL, obtain (0.5 μ g/ml);
Reference solution (b): 1mg azelastine impurity B, 1mg azelastine impurity D, 1mg azelastine impurity E be dissolved in test solution and be diluted to 100ml with test solution, obtaining (10 μ g/ml, 10 μ g/ml, 10 μ g/ml, 0.5mg/ml);
Chromatographic column: column length 250cm, internal diameter 4.6mm, immobile phase is itrile group silicagel column (10 μ m), 30 DEG C of column temperatures;
Mobile phase: 2.16g perfluorooctane sulfonate and potassium dihydrogen phosphate are dissolved in 740mL, are adjusted to pH3.0-3.1 with phosphoric acid,diluted, add 260mL, mix homogeneously, to obtain final product;
Flow velocity: 2.0mL/min;
Detector: uv-spectrophotometric detector, 210nm;
Sample size: 10 μ L;
The log time: 2 times of azelastine retention time;
Relative retention time: with azelastine (its retention time is about 8-9min): impurity A approximately 0.2, impurity B approximately 0.3, impurity C approximately 0.4, impurity D approximately 0.6, impurity E approximately 1.4;
System suitability:
In reference solution (b) chromatogram, impurity B peak and the peak-to-peak separating degree at least 4.0 of impurity D, impurity D peak and impurity E peak and the equal baseline separation of main peak.
Above-mentioned HPLC method specifies normally for the limit 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: be no more than separately the main peak area (, being all less than 0.1% separately) in reference solution (a) chromatogram.
Impurity A, B, C, D, E are respectively:
impurity A, phenylhydrazide;
and enantiomer, impurity B, 1-benzoyl-2-[(4RS)-1-methyl six hydrogen-1H-azepan-4-yl] 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, mention that " total impurities " refers to above-mentioned impurity A, B, C, D, E summation.
embodiment 1: pharmaceutical compositions
Formula:
| A-5610 | 0.5g， |
| propylene glycol | 20g, |
| azone | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.Can further this liquid medicine pharmaceutical composition be used respectively to the container subpackage of liniment and spray, make the form of liniment and spray, to facilitate clinical use (following embodiment all can so process).
embodiment 2: pharmaceutical compositions
Formula:
| a-5610 | 0.3g, |
| propylene glycol | 15g, |
| azone | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 3: pharmaceutical compositions
Formula:
| a-5610 | 0.75g, |
| propylene glycol | 25g, |
| azone | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 4: pharmaceutical compositions
Formula:
| a-5610 | 0.05g, |
| propylene glycol | 30g, |
| azone | 0.5g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 5: pharmaceutical compositions
Formula:
| A-5610 | 1g， |
| propylene glycol | 10g, |
| azone | 1.5g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 6: pharmaceutical compositions
Formula:
| a-5610 | 0.15g, |
| propylene glycol | 20g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 7: pharmaceutical compositions
Formula:
| a-5610 | 0.6g, |
| propylene glycol | 20g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 8: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| glycerol | 20g, |
| sodium deoxycholate | 0.75g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 9: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| propylene glycol | 10g, |
| glycerol | 10g, |
| oleic acid | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 21: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| propylene glycol | 20g, |
| azone | 1g, |
| water | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then by even to gained mixed solution and suitable quantity of water, mend and add water to full dose, to obtain final product.
embodiment 22: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| propylene glycol | 20g, |
| water | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then by even to gained mixed solution and suitable quantity of water, mend and add water to full dose, to obtain final product.
embodiment 23: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| glycerol | 20g, |
| sodium deoxycholate | 0.75g, |
| water | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described polyhydroxy-alcohol miscible; Then by even to gained mixed solution and suitable quantity of water, mend and add water to full dose, to obtain final product.
embodiment 24: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| ethanol | 20g, |
| azone | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 25: pharmaceutical compositions
Formula:
| a-5610 | 0.5g, |
| ethylene glycol | 20g, |
| azone | 1g, |
| glycerol triacetate | in right amount, add to 100ml. |
Method for making: make azelastine or its pharmaceutical salts and Percutaneous absorption enhancer and described alcohol miscible; Then gained mixed solution is even with appropriate polyhydroxy-alcohol fatty acid ester, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain final product.
embodiment 26: pharmaceutical compositions
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. |
Method for making: each material is added in suitable quantity of water it is dissolved, mend and add water to full dose, to obtain final product.
embodiment 27: pharmaceutical composition is provided
Provide following two kinds of commercially available formulation in liquid form: A-5610 eye drop (0.05%, 6ml:3mg, H20110343, MEDA company), A-5610 nasal spray (0.1%, 10ml:10mg, H20100536, MEDA company).
test example 1: study on the stability
Whole samples of above embodiment 1-9, embodiment 21-27 are sealed with vial, be placed under 40 DEG C of lucifuge conditions and place 6 months (in the present invention, the high-temperature treatment mode of this kind for its reserve temperature can be described as that high temperature June, 40 DEG C of June, high temperature are disposed June, 40 DEG C of June is disposed etc.), measures and calculates with this understanding each sample (0 month), active component content and total impurities content in (June) afterwards before this high-temperature treatment.
Calculate in each sample, in the time of 6 months, with respect to total impurities in this sample, the content 0 month time increases percent (for example, for embodiment 1 sample to total impurities, wherein the content of total impurities increases percent and refers to: the total impurities content in June of this sample deducts 0 month total impurities content gained difference and be multiplied by divided by 0 month total impurities content more again the result of 100% gained, represents with %).
In addition, calculate the remaining percent of each sample active component in the time of June, when in sample, active component content (mg/ml) was divided by 0 month when June, active component content (mg/ml) is multiplied by the result of 100% gained again, represents with %.
Result:
The content increase percent of whole sample total impuritieses of embodiment 1-9 is all in 27～53% scopes, and it is 35% that for example content of embodiment 1 total impurities increases percent; But surprisingly, the content of whole sample total impuritieses of embodiment 21-27 increases percent all in 167～258% scopes, it is 215% that for example content of embodiment 21 total impuritieses increases percent, even used glycerol triacetate still not use the sample of propylene glycol or glycerol in embodiment 24,25, the content of its total impurities increases percent and is also greater than 167%.
Whole samples of embodiment 1-9 and embodiment 21-27 are not but demonstrating the variation tendency such with total impurities aspect the remaining percent of active component, that is: the remaining percent of the active component of whole samples of embodiment 1-9 in the time of June is all in 95～99% scopes, and for example the remaining percent of embodiment 1 sample active component is 97.6%; The remaining percent of the active component of whole samples of embodiment 21-27 in the time of June is all in 95～98% scopes.Say from drug quality, in Long-term Storage process, keep low impurity content and high active component content to be necessary, thus, these compositionss with feature of the present invention of embodiment 1-9 have than the more excellent particularly stability of pharmaceutical properties of the compositions in prior art, commercially available prod or non-characteristic formula of the present invention.
test example 2: pharmacodynamics is investigated
Anaphylaxis contact scytitis is a clinical common class dermatosis, the cause of disease and pathogenesis complexity, and Yin Qichang has a strong impact on quality of life with symptoms such as skin itching maculo-papular rash.This test example is investigated the effect aspect for example anaphylaxis of anti-dermatitis and/or contact dermatitis of the present composition.
(1) material
Animal: SPF level ICR mice, male, body weight (25 ± 5) g, 4～5 weeks, is provided quality certification SCXK (Shanghai) 2007-0003 by Chinese Academy of Sciences's Shanghai Experimental Animal Center.
Medicine and reagent: embodiment 1 compositions (0.5%), embodiment 6 compositionss (0.4%), embodiment 21 compositionss (0.5%), embodiment 26 compositionss (0.15%); DNF (DNFB, German Merck company, analytical pure); Mice IL-4, IgE and INF-γ ELISA test kit (R & D Systems, Minneapolis, MN, the U.S.).
Instrument: calibrator (Guanglu Digital Measure-Control Co., Ltd., Guilin, precision 10 μ are m); Kryostatl720 paraffin slicing machine (U.S.); BX50F4 optical microscope (Japanese Olympus).
(2) method
Establishment of mouse model: reference " pharmacological experimental methodology " is by DNFB acetone olive oil solution (acetone-olive oil 4:1) sensitization and excite mouse skin to set up mouse allelgic contact dermatitis (ACD) model [Xu Shuyun, Bian Rulian, Chen Xiu, pharmacological experimental methodology [M]: Beijing people's health publishing house, 2002:1429].ICR mice is normally raised in SPF barrier system 1 week, and in experiment abdominal part depilation in first 1 day, the about 3cm × 3cm of scope, test the position of losing hair or feathers for the 1st day and be evenly coated with 1%DNFB acetone olive oil solution 50 μ L sensitization, tests and repeats to strengthen sensitization 1 time on the 2nd day.Test the 5th day, the each even painting 1%DNFB acetone olive oil solution of mice ears 10 μ L excite.Normal group is only coated with acetone olive oil solution (acetone-olive oil 4:1) in same area and compares.
Grouping and administration: 48 mices are divided into 6 groups at random, every group 8, be respectively normal group, model group, embodiment 1 compositions (20mg/kg), embodiment 6 compositionss (20mg/kg), embodiment 21 compositionss (20mg/kg), embodiment 26 compositionss (20mg/kg).Mice is evenly coated with medicine (four kinds of medicines) or water for injection (normal group, model group) in abdominal part depilation place by above-mentioned group technology every day after sensitization, within the 1st day and the 2nd day, is imposing the administration more later in 4 hours of 50 μ L acetone olive oil solutions.Modeling success and gathered edema scores of erythema and swelling data after, each treated animal is got blood to pluck eyeball method, cervical vertebra dislocation is subsequently 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 rear dropsy of ear erythema degree to mark, without 0 point of erythema, 1 point of slight visible erythema, 2 points of moderate erythema, 3 points of serious erythema, 4 points of edematous erythemas; Without 0 point of edema, 1 point of Mild edema, 2 points of intermediate edema, 3 points of serious edema.
Date processing: data represent with mean value ± SD, carries out statistical analysis with SPSS13.0 software, relatively adopts ANOVA One-way inspection and SNK-q to check between group.
(3) result
Mice ear excites obviously (P<0.01 compared with matched group) of model group mice ear degree after 24h, shows modeling success.
Compared with model, different pharmaceutical compositions presents inhibition mice ear degree in various degree, wherein 6 two kinds of compositionss of embodiment 1 and embodiment are compared with model group, all there is significant difference (P<0.05), completely regrettably, even under same dose, 26 two kinds of compositionss of embodiment 21 and embodiment all do not present significant difference compared with model group.
Each administration group mouse ear edema erythema also presents score value in various degree compared with model group, wherein 6 two kinds of compositionss of embodiment 1 and embodiment are compared with model group, all there is significant difference (P<0.05), completely regrettably, even under same dose, 26 two kinds of compositionss of embodiment 21 and embodiment all do not present significant difference compared with model group.Concrete outcome is in table 1.The compositions that these results show to have feature of the present invention can present the effect of good treatment allergic contact dermatitis, and prior art compositions can not realize this function.
Table 1: the impact (n=8) of compositions on mice ear degree and edema scores of erythema value
| 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: * and model group comparison, p<0.05.
Contact hyper sensitization dermatitis belongs to skin delayed hypersensitivity, it is the cell-mediated cell immune response of a kind of T, the cell participating in comprises 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 of setting up in this experiment is comparatively classical animal model, has successfully simulated by Th1 cell and the cell-mediated antigenic specificity skin allergy of Tc1.
This research is by successfully setting up ACD mouse model, investigate the impact of the present composition on the red and swollen degree of model ear, experimental result shows, the present composition can alleviate model ear swelling and inhibition edema erythema forms, and illustrates that the present composition has the effect of good anti-ACD.Well-known, above-mentioned ACD mouse model is a kind of pharmacodynamics model of allergic dermatitis and contact dermatitis of classics.
test example 3: medicine irritation test
(1) have been found that in above test example 2, in abdominal part administration place of mice, record the skin irritation of front administration place of every animal administration every day.Result demonstration, different reagents present zest in various degree, and major embodiment is erythrosis.Characterize with 5 points of chis the degree that reddens, 0 point of expression has no and reddens, and 1 submeter is shown with faint reddening, and the score value degree that reddens is more greatly larger, until 5 points reach the most serious, every group with its each animal from the 1st day to last day gained score value meansigma methods represent.Result: matched group must be divided into 0 point, 0.44 point of model group score (may cause due to DNFB), 6 groups of scores of embodiment 1 and embodiment be respectively 0.31 and 0.49 point (suitable with the model group that gives DNFB, show that this two treated animal gives after the present composition without skin irritation), but 26 groups of scores of embodiment 21 and embodiment are respectively 3.68 and 4.23 points, show that they present obvious zest to skin.
(2) animal is with test example 1, and medicine is embodiment 1-9, the whole samples of embodiment 21-27 gained, totally 17 groups, 5 mices of each administration group.
Mice is normally raised in SPF barrier system 1 week, and in experiment abdominal part depilation in first 1 day, the about 3cm × 3cm of scope, then smears medicine (taking A-5610 dosage as 20mg/kg), continuously coating 7 days every day in this depilation place.2-8 days after self administration of medication, for 5 animals of each administration group, observes its zest of coating position aspect the degree of reddening every day, records this treated animal and within 7 days, records moderate stimulation score value at this, calculates the meansigma methods of every group.Result, the zest score value of the each group of embodiment 1-9 is all less than 0.5, all in 0～0.33 scope, show and there is no zest, but completely surprisingly the zest score value of 8 of the each sample of embodiment 21-27 groups, all in 2.87～4.23 scopes, shows that they present obvious skin irritation.
industrial applicability
The invention provides a kind of azelastine compositions and purposes.Particularly, the present invention relates to the fluid composition of azelastine, particularly relate to a kind of fluid composition of azelastine hydrochloride, relate more particularly to a kind of fluid composition of non-water.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 the symptom of this based composition treatment, alleviation or prevention and anaphylaxis and nonallergic disease association, and for example purposes in treatment for example anaphylaxis of dermatitis and/or contact dermatitis.The present composition has beat all pharmaceutical properties.
Claims (10)
1. a pharmaceutical composition, wherein comprises: azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester.
2. the pharmaceutical composition of claim 1, is characterized in that:
It is the pharmaceutical composition that is liquid condition;
The azelastine that comprises 0.1～5g in its every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.02～2.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～2g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1.5g in every 100ml or its pharmaceutical salts, the azelastine that for example comprises 0.05～1g in every 100ml or its pharmaceutical salts;
Wherein said polyhydroxy-alcohol is selected from: ethylene glycol, propylene glycol, glycerol and combination thereof;
The polyhydroxy-alcohol that comprises 5～50g in its every 100ml, the polyhydroxy-alcohol that for example comprises 7.5～40g in every 100ml, the polyhydroxy-alcohol that for example comprises 10～30g in every 100ml;
Wherein said polyhydroxy-alcohol fatty acid ester is selected from: glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester and combination thereof;
Wherein said polyhydroxy-alcohol fatty acid ester is selected from: propylene glycol monoacetate, propylene-glycol diacetate, glycerol triacetate, glycerol diacetate esters, glycerol monoacetate and combination thereof; And/or
The polyhydroxy-alcohol fatty acid ester that comprises 50～95g in its every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 60～92.5g in every 100ml, the polyhydroxy-alcohol fatty acid ester that for example comprises 70～90g in every 100ml.
3. the pharmaceutical composition of claim 1, is characterized in that:
It is the pharmaceutical preparation being for external application;
It is the pharmaceutical preparation for percutaneous dosing;
Wherein also comprise Percutaneous absorption enhancer;
Wherein said Percutaneous absorption enhancer is selected from one or more materials below:
(1) cholic acid salt: glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, CDC, bird rope deoxycholate etc.,
(2) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, nutmeg acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate, triacetyl glycerine,
(3) alcohols; As isopropyl alcohol, 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 DMF, N,N-dimethylacetamide, 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, span 20 etc., and/or
(9) the beta cyclodextrin class that beta cyclodextrin or alkyl replace: as dimethyl beta cyclodextrin, hydroxypropyl beta cyclodextrin etc.;
The consumption of Percutaneous absorption enhancer is to account for 0.5～5% of total composition, for example 0.5～2%, for example 0.5～1.5%; And/or this pharmaceutical composition is the medicine type of liniment or spray.
4. the method for pharmaceutical compositions, comprises in described pharmaceutical composition: azelastine or its pharmaceutical salts, polyhydroxy-alcohol, polyhydroxy-alcohol fatty acid ester; The method comprises the following steps:
Make azelastine or its pharmaceutical salts and described polyhydroxy-alcohol miscible;
Then by even to gained mixed solution and polyhydroxy-alcohol fatty acid ester, to obtain final product.
5. the method for claim 4, wherein said pharmaceutical composition is as described in claim 1-4 any one, or wherein said pharmaceutical composition is as described in the arbitrary embodiment of description first aspect of the present invention.
6. the method for claim 5, wherein also comprises Percutaneous absorption enhancer in pharmaceutical composition, described Percutaneous absorption enhancer adds in described pharmaceutical composition together with described polyhydroxy-alcohol.
7. azelastine or its pharmaceutical salts purposes in the medicine of preparation treatment or prevention inflammatory disease of the skin.
8. the purposes of claim 7, wherein said inflammatory disease of the skin is selected from: allergic dermatitis, contact dermatitis, eczema, acute urticaria; Or described medicine has the feature of pharmaceutical composition described in claim 1-4 any one.
9. azelastine or its pharmaceutical salts are treated or prevent inflammatory disease of the skin and substantially skin do not presented to the purposes in irritating external used medicine in preparation.
10. the purposes of claim 9, wherein said external used medicine is the pharmaceutical composition as described in claim 1-4 any one, or pharmaceutical composition as described in the arbitrary embodiment of description first aspect of the present invention.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1674910A (en) * | 2002-06-14 | 2005-09-28 | 希普拉有限公司 | Combination of azelastine and steroids |
| CN101098714A (en) * | 2004-11-24 | 2008-01-02 | 美邦特保健有限公司 | Compositions comprising azelastine and methods of use thereof |
| KR20100010208A (en) * | 2008-07-22 | 2010-02-01 | 한국콜마 주식회사 | Solution-type preparation containing azelastine |
-
2014
- 2014-09-10 CN CN201410457775.1A patent/CN104173286B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1674910A (en) * | 2002-06-14 | 2005-09-28 | 希普拉有限公司 | Combination of azelastine and steroids |
| CN101098714A (en) * | 2004-11-24 | 2008-01-02 | 美邦特保健有限公司 | Compositions comprising azelastine and methods of use thereof |
| KR20100010208A (en) * | 2008-07-22 | 2010-02-01 | 한국콜마 주식회사 | Solution-type preparation containing azelastine |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| Publication number | Publication date |
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| CN104173286B (en) | 2017-03-01 |
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