CN107929738A - A kind of composition of hydrochloric azelastine - Google Patents
A kind of composition of hydrochloric azelastine Download PDFInfo
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- CN107929738A CN107929738A CN201711218503.6A CN201711218503A CN107929738A CN 107929738 A CN107929738 A CN 107929738A CN 201711218503 A CN201711218503 A CN 201711218503A CN 107929738 A CN107929738 A CN 107929738A
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- azelastine
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- polyhydroxy
- hydrochloric
- alcohol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Abstract
The invention discloses a kind of composition of hydrochloric azelastine, it is characterised in that：Its component includes：Azelastine or its pharmaceutical salts, glucocorticoid, polyhydroxy-alcohol and skin penetration enhancer；Included in wherein 100 grams of said compositions：1 5g of azelastine or its pharmaceutical salts, 50 95g of 0.1 10g of glucocorticoid, 5 50g of polyhydroxy-alcohol and skin penetration enhancer.Mainly solve common antiallergy, the side effect with the single hormone medication of reduction soon of action speed.Stable chemical property, low irritation, available for treat it is other with anaphylaxis and the relevant symptom of non-allergic disease such as anaphylaxis and/or contact dermatitis.
Description
Technical field
The present invention relates to a kind of composition of hydrochloric azelastine, more particularly to a kind of hydrochloric azelastine group of external application
The liniment of compound.
Background technology
Research confirms that azelastine and its acceptable salt form of physiology are glued being directly applied to nose with corresponding preparation
Beneficial effect is shown when on the conjunctival sac of film and/or eye.Thus in allergic rhinitis (seasonal and/or Out of season), blood
Symptom eliminates or significant alleviation are realized in the easypro contracting rhinitis of pipe and allergic conjunctivitis.
Despite the presence of its validity, azelastine hydrochloride has strong bitter taste, and this bitter taste is too strong, even if dilution 106
Times, also remain irritating taste.The bitter taste of this azelastine hydrochloride, after intranasal administration, be delivered to it is pharyngeal,
So as to cause the taste of discomfort and stimulation.Polyvinyl pyridine alkanone and/or copolymerization have been used in U.S. Patent No. 6,576,677
Ketone is tieed up, to cover the bitter taste of azelastine hydrochloride.
Azelastine, clinically commonly uses its hydrochloride (azelastine hydrochloride), molecular formula
C22H24ClN3O.HCl, molecular weight：418.36 CAS registration numbers：79307-93-0, wherein science of culture are entitled：(±)-1-
(2H) -4- [(4- chlorphenyls) methyl] -2- (hexahydro -1- methyl isophthalic acid H- azepan -4- bases)-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 are：
Hydrochloric acid chlorine Zhuo Siting is a kind of derivative of 2,3- phthalazones, that is, phthalazone of new construction, is a kind of potential
Long-acting antiallergy compound, has the characteristics that H1 receptor antagonists, has antiallergy, Zhichuan and antihistamine characteristic.Zoopery number
According to showing, the azelastine hydrochloride of high concentration can prevent some chemical mediators in allergic reaction synthesis and release (such as：In vain
Triolefin, histamine, serotonin), when smearing administration, in the case where allowing the maximum dose of application, it is not detected by Local toxic reaction
Or organo-specific toxicity's reaction.
After oral drugs, azelastine hydrochloride is absorbed by the body rapidly, and absolute bioavailability is up to 81%.Food is to inhaling
Receive without influence.The capacity height of distribution shows distribution mainly in surrounding tissue, and protein-bound water puts down relatively low (80%-
90%).After single medicine gives azelastine hydrochloride, when plasma clearance half-life period hydrochloric acid chlorine Zhuo Siting is 20 small, curative activity
Metabolite N- removes first azelastine when being about 45 small.Excretion is mainly excluded through excrement.The lasting row of a small amount of medicine in excrement
Let out and show that medicine can carry out intestines liver circulation.Smear the azelastine hydrochloride cream using 0.56mg, healthy will daily repeatedly
Hope person's azelastine hydrochloride Cmax Cpsses are about 0.027ng/ml, its active metabolite N- removes first azelastine
It can be detected (0.012ng/ml) in quantitative limit value or less than quantitative level.
After allergic skin patient smears drug application repeatedly, blood plasma azelastine hydrochloride is horizontal slightly compared with Healthy People
Height, so as to show that whole body (mainly can may preferably penetrate the dermis of skin of inflammation to the level height of drug absorption due to medicine
Layer, easy to absorb).After the hydrochloric acid hydrogen Zhuo Siting creams of daily medication accumulated dose 0.56mg (such as：2 times/day), medication 2 is small
When after observe azelastine mean plasma concentration be about 0.065ng/ml.Azelastine hydrochloride dosage is doubled to daily
1.12mg (example：4 times/day) the mean plasma steady state concentration of azelastine is 0.109ng/ml.Drug level is indicated above with using
Pharmaceutical quantities are proportional distributions.Although patient's level of absorbing the drug is relatively low, the exposure of dermatologic systemic drug is computed
Level is about 8 times lower than oral medication systemic drug exposure level, and (the oral medication dosage for the treatment of allergic rhinitis is daily
4.4mg azelastine hydrochlorides).
Azelastine can be produced in the form of various salt.The most common form is azelastine hydrochloride in medicine, it is
White, the almost scentless crystalline powder with strong bitterness exists.Suitable for other salt form bags of pharmaceutical composition
Include pamoic acid azelastine, its bitter taste than azelastine HC1 mitigate (referring to United States Patent (USP) US5,232,919, by the document
Disclosure is incorporated herein by reference), but validity is also below azelastine hydrochloride.
Therefore, new treatment or prevention and anaphylaxis and the relevant symptom of non-allergic disease are still expected to have in this area
Method.Such as new effective composition is provided and/or uses it for treatment and anaphylaxis and the relevant disease of non-allergic disease
Shape is such as anaphylaxis and/or contact dermatitis.
Report in clinical studies, it is local bad when glucocorticoid treatment anaphylaxis or contact dermatitis is used alone
Reaction (adult and adolescent patient) red swelling of the skin (8%), skin burns sense (4%), skin irritatin sense (6%) and exanthemv
(1%), when these adverse reactions are common in exclusive use glucocorticoids liniment.
In pediatric patient, red swelling of the skin (10%), skin burns sense (6%), skin irritatin sense (8%) and exanthemv
(1%) incidence is higher than placebo.
Long-term inhale embrocates the following adverse reaction of single glucocorticoid treatment solution (ointment) generation：
1) the hyperfunction syndrome of cortex hormone function；
2) induce or aggravate infection.Main cause reduces resistance of the body to pathogenic microorganism for hormone.
3) induce or aggravate canker.
4) hypertension and artery sclerosis are induced.
5) osteoporosis, muscular atrophy, wound healing delay.
6) mental disease and epilepsy are induced.
7) upgrowth and development of children is suppressed.
8) other：Negative nitrogen balance, appetite increase, low blood calcium, hyperglycaemia tendency, digestibility festers, glad.
9) caput femoris necrosis.
The content of the invention
The technical problem to be solved in the present invention is：A kind of composition of hydrochloric azelastine is provided, plays common anti-mistake
It is quick, and the drug effect side effect with the single hormone medication of reduction soon.Affected part is directly applied to using ointment dosage form at the same time, is made
With with lesion, avoid and give people bitter taste into oral cavity and feel and inadaptable.
The technical scheme is that：A kind of composition of hydrochloric azelastine, its component include：Azelastine or its
Pharmaceutical salts, glucocorticoid, polyhydroxy-alcohol and skin penetration enhancer,；Included in wherein 100 grams of said compositions：Azelastine
Or its pharmaceutical salts 1-5g, glucocorticoid 0.1-10g, polyhydroxy-alcohol 5-50g and skin penetration enhancer 50-95g.
Included in 100 grams of said compositions：Azelastine or its pharmaceutical salts 0.2-2.5g, glucocorticoid 0.5-
10g, polyhydroxy-alcohol 7.5-40g and skin penetration enhancer 60-92.5g.
Included in 100 grams of said compositions：Azelastine or its pharmaceutical salts 0.2-1.5g, glucocorticoid 1-10g,
Polyhydroxy-alcohol 10-30g and skin penetration enhancer 70-90g.The polyhydroxy-alcohol is selected from：Ethylene glycol, propane diols, glycerine and
It is combined.The glucocorticoid is beclomeasone propionate, budesonide, fluticasone propionate or health acid Mometasone.It is described
Polyhydroxy-alcohol fatty acid ester is selected from：Glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester, three second of glycerine
Acid esters and combinations thereof.The composition is the pharmaceutical preparation being for external application.The composition is the medicine system for percutaneous dosing
Agent.
The skin penetration enhancer includes polyhydroxy-alcohol fatty acid ester.
The composition is cream or ointment.
Beneficial effects of the present invention：Common antiallergy is mainly solved, action speed is fast and reduces single hormone medication
Side effect.It is stable chemical property, low irritation, other with anaphylaxis and the relevant disease of non-allergic disease available for treating
Shape is such as anaphylaxis and/or contact dermatitis.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general
And/or specific description.Although for realize many materials used in the object of the invention and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.
Following embodiments further illustrate the present invention, rather than the limitation present invention.
Hereafter preparation process is for the purpose of citing, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize to obtain the method that the present invention prepares liquid preparation completely according to existing knowledge.Below
Prepare in various compositions, if not otherwise indicated, total amount of preparation of every batch of is 10000g.But list formula and prepared
Cheng Shi, formula and preparation method are illustrated with forming in every 100g medicaments.In packing, every bottle of pharmaceutical quantities are 10g.
Detection method：
Following high performance liquid chromatography (it can be described as the HPLC methods of the present invention in the present invention) can be used for the measure present invention
The content of active ingredient hydrochloric acid azelastine content and various impurity in various materials.It is specific as follows：
It is measured according to the high performance liquid chromatography of two annex VD of Chinese Pharmacopoeia version in 2010；
Mixed solvent：Acetonitrile/water (45:55, V/V)；
Test solution：Material to be measured comprising 0.025g azelastine hydrochlorides is dissolved in the mixed solvent, and with mixing
Solvent is diluted to 50.0mL, up to (0.5mg/ml, if the concentration of material to be measured close to this concentration or diluter than this concentration,
It need not then dilute and be used to measure directly as test solution)；
Reference solution (a)：1.0mL test solution is diluted to 100.0mL with mixed solvent, takes this solution 1.0mL to use mixed
Bonding solvent is diluted to 10.0mL, up to (0.5 μ g/ml)；
Reference solution (b)：1mg azelastines impurity B, 1mg azelastine impurity D, 1mg azelastines impurity E are dissolved
In testing in solution and being diluted to 100ml with test solution, up to (10 μ g/ml, 10 μ g/ml, 10 μ g/ml, 0.5mg/ml)；
Chromatographic column：Column length 250cm, internal diameter 4.6mm, stationary phase are itrile group silicagel column (10 μm), 30 DEG C of column temperature；
Mobile phase：2.16g perfluorooctane sulfonates and potassium dihydrogen phosphate are dissolved in 740mL, with phosphoric acid,diluted adjust to
PH3.0-3.1, adds 260mL, is uniformly mixed, to obtain the 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：
In reference solution (b) chromatogram, the separating degree at least 4.0 between impurity B peak and impurity D peaks, impurity D peaks and impurity
E peaks and the equal baseline separation of main peak.
Above-mentioned HPLC methods are provided for the limit of azelastine hydrochloride bulk pharmaceutical chemicals：
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 no more 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- benzoyls -2- [(4RS) -1- methyl hexahydro -
1H- azepan -4- bases] diazane；
Impurity C, 2- [(4- chlorphenyls) acetyl group] benzoic acid；
Impurity D, 4- (4- chlorphenyls) phthalazines -1 (2H) -one；
Impurity E, 3- (4- chlorobenzenes 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：
| Azelastine hydrochloride | 0.5g, |
| Glucocorticoid | 0.3g |
| Propane diols | 20g, |
| Azone | 1g, |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer (polyhydroxy-alcohol fatty acid ester) and the polyhydroxy
Base alcohol is miscible；Then it is gained mixed solution and appropriate polyhydroxy-alcohol fatty acid ester is uniform, add polyhydroxy-alcohol fatty acid ester extremely
Full dose, to obtain the final product.It can be made and put on the skin further by the liquid medicine pharmaceutical composition respectively using liniment and the containers of spray
Agent and the form of spray, to facilitate Clinical practice (following embodiment can be processed as).
Embodiment 2：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 3g, |
| Glucocorticoid | 0.5g |
| Glycerine | 15g, |
| Azone | 1g, |
| Methyl glycol fatty acid ester | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 3：Prepare pharmaceutical composition
Formula：
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 4：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.2g, |
| Glucocorticoid | 0.1g |
| Propane diols | 30g, |
| Azone | 0.5g, |
| Glycerol fatty acid ester | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 5：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 1g, |
| Glucocorticoid | 1.5g |
| Propane diols | 10g, |
| Azone | 1.5g |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 6：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.4g, |
| Propane diols | 20g, |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and the polyhydroxy-alcohol miscible；Then by gained mixed solution and in right amount
Polyhydroxy-alcohol fatty acid ester is uniform, adds polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 7：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.6g, |
| Propane diols | 20g, |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and the polyhydroxy-alcohol miscible；Then by gained mixed solution and in right amount
Polyhydroxy-alcohol fatty acid ester is uniform, adds polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 8：Prepare pharmaceutical composition
Formula：
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 9：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.5g, |
| Propane diols | 10g, |
| Glycerine | 10g, |
| Oleic acid | 1g, |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Mixed solution and appropriate polyhydroxy-alcohol fatty acid ester it is uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 21：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.5g, |
| Propane diols | 20g, |
| Azone | 1g, |
| Water | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Obtain mixed solution and suitable quantity of water is uniform, benefit adds water to full dose, to obtain the final product.
Embodiment 22：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.5g, |
| Propane diols | 20g, |
| Water | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Obtain mixed solution and suitable quantity of water is uniform, benefit adds water to full dose, to obtain the final product.
Embodiment 23：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.5g, |
| Glycerine | 20g, |
| Deoxysodium cholate | 0.75g, |
| Water | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the polyhydroxy-alcohol miscible；Then by institute
Obtain mixed solution and suitable quantity of water is uniform, benefit adds water to full dose, to obtain the final product.
Embodiment 24：Prepare pharmaceutical composition
Formula：
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the alcohol miscible；Then gained is mixed
Solution and appropriate polyhydroxy-alcohol fatty acid ester are uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 25：Prepare pharmaceutical composition
Formula：
| Azelastine hydrochloride | 0.5g, |
| Ethylene glycol | 20g, |
| Azone | 1g, |
| Glycerine triacetate | In right amount, 100g is added to. |
Preparation method：Make azelastine or its pharmaceutical salts and skin penetration enhancer and the alcohol miscible；Then gained is mixed
Solution and appropriate polyhydroxy-alcohol fatty acid ester are uniform, add polyhydroxy-alcohol fatty acid ester to full dose, to obtain the final product.
Embodiment 26：Prepare pharmaceutical composition
It is formulated (200580046487.6Ex1)：
| Azelastine hydrochloride | 0.15g |
| Hydroxypropyl methylcellulose 2900, USP4000 | 0.1g |
| Natrium adetate | 0.05g |
| Sorbierite 70% | 6.4g |
| Sodium citrate dihydrate | 0.068g |
| Sucralose | 0.15g |
| 50% solution of benzalkonium chloride | 0.025g |
| Water | In right amount, 100ml is added to. |
Preparation method：Each material, which is added in suitable quantity of water, makes its dissolving, and benefit adds water to full dose, to obtain the 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,
H20160343, MEDA company), azelastine hydrochloride nasal spray (0.1%, 10ml：10mg, H20160536, MEDA company).
Test example 1：Study on the stability
Whole samples of above example 1-9, embodiment 21-27 are sealed with vial, are placed under the conditions of 40 DEG C of lucifuges
Place 6 months (in the present invention, such a high-temperature treatment mode for its reserve temperature can be described as high temperature June, 40 DEG C
June, disposal in high temperature June, 40 DEG C of disposal in June etc.), measure and calculate on this condition each sample (0 before this high-temperature treatment
Month), the active component content and total impurities content in rear (June).
Calculate in each sample, total impurities is at 6 months relative to content increase of the total impurities at 0 month in the sample
Percentage (such as refer to for 1 sample of embodiment, the content increase percentage of wherein total impurities：The total impurities in June of the sample contains
Amount subtract difference obtained by 0 month total impurities content again divided by 0 month total impurities content multiplied by with 100% gained as a result, with % tables
Show).
In addition, calculate each sample active ingredient remnants percentages at June, i.e., active component content during June in sample
(mg/ml) divided by 0 month active component content (mg/ml) multiplied by with 100% gained as a result, being represented with %.
As a result：
The content of whole sample total impuritieses of embodiment 1-9 increases percentage in the range of 27~53%, such as implements
The content increase percentage of 1 total impurities of example is 35%；But it was unexpectedly determined that whole sample total impuritieses of embodiment 21-27
Content increase percentage in the range of 167~258%, such as 21 total impurities of embodiment content increase percentage be
215%, even having used glycerine triacetate in embodiment 24,25 but the examination of propane diols or glycerine being not used
Sample, the content increase percentage of its total impurities are also more than 167%.
Whole samples of embodiment 1-9 and embodiment 21-27 do not shown but in terms of active ingredient remnants percentages with
Variation tendency as total impurities, i.e.,：Active ingredient remnants percentage of the whole samples of embodiment 1-9 at June is 95
In the range of~99%, such as 1 Sample activity component remnants percentages of embodiment are 97.6%；Whole samples of embodiment 21-27
Active ingredient remnants percentages at June are in the range of 95~98%.For drug quality, in long-term storage process
In, keep low impurity content and high active component content to be necessary, thus, embodiment 1-9 these there is this hair
The composition of bright feature has more excellent in the composition of the prior art, commercial product or non-invention characteristic formula than it
Pharmaceutical properties particularly stability.
Test example 2：Pharmacodynamics is investigated
Allergic Contact scytitis is clinical common a kind of skin disease, and the cause of disease and pathogenesis are complicated, Yin Qichang
Quality of life is seriously affected with symptoms such as skin itching maculo-papular rash.This test example investigate the present composition in anti-dermatitis
Such as the effect in terms of anaphylaxis and/or contact dermatitis.
(1) material
Animal：SPF grades of ICR mouse, male, weight (25 ± 5) g, 4~5 weeks, by Chinese Academy of Sciences Shanghai experimental animal
The heart provides, quality certification number SCXK (Shanghai) 2007-0003.
Medicine and reagent：1 composition of embodiment (0.5%), 6 composition of embodiment (0.4%), 21 composition of embodiment
(0.5%), 26 composition of embodiment (0.15%)；2,4-dinitrofluorobenzene (DNFB, German Merck companies, analysis are pure)；Mouse
IL-4, IgE and INF- γ ELISA kits (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 light microscopes (Japanese Olympus).
(2) method
Establishment of mouse model：Reference《Pharmacological experimental methodology》With DNFB acetone olive oil solution (acetone-olive oil 4：1)
Sensitization and excitation mouse skin establish mouse allelgic contact dermatitis (ACD) model, and [Xu Shuyun, Bian Rulian, Chen Xiu, pharmacology are real
The proved recipe science of law [M]：Beijing people's health publishing house, 2002：1429].ICR mouse are normally raised in 1 week in SPF barrier systems,
Belly depilation in 1 day, scope about 3cm × 3cm before experiment, test the 1st day depilation position and are uniformly coated with 1%DNFB acetone olive oil
50 μ L sensitization of solution, tests repetition in the 2nd day and strengthens sensitization 1 time.Test the 5th day, mouse ears are each uniformly to apply 1%DNFB acetone olives
10 μ L of olive oil solution are excited.Normal group is only coated with acetone olive oil solution (acetone-olive oil 4 in same area：1)
Compare.
Packet and administration：48 mouse are randomly divided into 6 groups, every group 8 are respectively normal group, model group, embodiment 1
Composition (20mg/kg), 6 composition of embodiment (20mg/kg), 21 composition of embodiment (20mg/kg), 26 composition of embodiment
(20mg/kg).Mouse be uniformly coated with belly depilation daily after sensitization by above-mentioned group technology medicine (four kinds of medicines) or
Person's water for injection (normal group, model group), the 1st day and the 2nd day impose 50 μ L acetone olive oil solutions 4 it is small when after again to
Medicine.After modeling succeeds and gathered oedema scores of erythema and swelling degrees of data, each group animal takes blood, subsequent cervical vertebra to pluck eyeball method
Dislocation is put to death, and it is fixed in 4% neutral paraformaldehyde solution to remove mouse ears.
Mice ear degree：24h measures mouse bilateral ear swelling degree with calibrator before excitation and after excitation, and to excitation
Dropsy of ear erythema degree scores afterwards, and no erythema 0 is divided, and slight visible erythema 1 is divided, and moderate erythema 2 is divided, and Severe erythema 3 divides, water
Swollen property erythema 4 is divided；No oedema 0 is divided, and Mild edema 1 is divided, and intermediate edema 2 is divided, and Severe edema 3 divides.
Data processing：Data are represented with mean value ± SD, carry out statistical analysis with SPSS13.0 softwares, comparison among groups uses
ANOVAOne-way is examined and SNK-q is examined.
(3) result
Obvious (compared with the control group P of model group mice ear degree after mouse ear excitation 24h<0.01) modeling, is shown
Success.
Compared with model, different degrees of suppression mice ear degree, wherein embodiment 1 is presented in different pharmaceutical composition
With 6 two kinds of compositions of embodiment compared with model group, significant difference (P is respectively provided with<0.05), completely regrettably, even if
Under same dose, significant difference is not presented in 26 two kinds of compositions of embodiment 21 and embodiment compared with model group.
Different degrees of score value, wherein embodiment 1 is also presented in each administration group mouse dropsy of ear erythema compared with model group
With 6 two kinds of compositions of embodiment compared with model group, significant difference (P is respectively provided with<0.05), completely regrettably, even if
Under same dose, significant difference is not presented in 26 two kinds of compositions of embodiment 21 and embodiment compared with model group.Specifically
It the results are shown in Table 1.These are the result shows that excellent treatment Allergic Contact skin can be presented in the composition with feature of present invention
Scorching effect, and prior art compositions can not achieve this function.
Table 1：Influence (n=8) of the composition to mice ear degree and oedema scores of erythema value
| Group | Swelling/mm | Scores of erythema |
| Control 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：* compared with model group, p<0.05.
Contact hyper sensitization dermatitis belongs to cutaneous delayed-type hypersensitivity, is a kind of cell immune response of T cell mediation,
The cell of participation includes Th1 cells, 1 type cytotoxic cell (Tc1), and Th2 types 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 models established in this experiment are more classical animal moulds
Type, successfully simulates by the cell-mediated antigentic specificity cutaneous anaphylaxis of Th1 cells and Tc1.
This research has investigated the present composition to model ear redness degree by being successfully established ACD mouse model
Influence, test result indicates that, the present composition can mitigate model ear swelling and suppress model oedema erythema and be formed, and say
The bright present composition has the function that good anti-ACD.It is well known that above-mentioned ACD mouse model is a kind of classical mistake
The pharmacodynamics model of quick property dermatitis and contact dermatitis.
Meanwhile the action speed of drug effect is observed and recorded, after self administration of medication, the drug effect time of embodiment 1-5 each groups is 5 points
Clock, the drug effect time of embodiment 6-9 each groups is 20 minutes, and the drug effect time of each samples of embodiment 21-27 is 20 points
Clock.
Test example 3：Medicine irritation is tested
(1) it has been found that in above test example 2, at the belly administration of mouse, before recording every animal daily administration
Skin irritation at administration.The results show that different degrees of irritation is presented in different reagents, erythrosis is mainly reflected in.
Reddened degree with 5 points of rulers characterization, 0 point represents to have no and reddens, and 1 point indicates faint and reddens, and the score value degree that reddens more greatly is bigger, directly
Most serious is reached to 5 points, every group is represented with its each animal from the 1st day to the average value of last day institute's score value.As a result：Control group
0 point is scored at, model group score 0.44 is divided (being probably caused by due to DNFB), and 6 groups of scores of embodiment 1 and embodiment are respectively
0.31 and 0.49 point (it is suitable with the model group for giving DNFB, show that this two groups of animals pierce after giving the present composition without skin
Swash property), but 26 groups of scores of embodiment 21 and embodiment are respectively 3.68 and 4.23 points, and it is obvious to show that skin is presented in they
Irritation.
(2) animal is with test example 1, medicine whole samples obtained by embodiment 1-9, embodiment 21-27, totally 17 groups,
5 mouse of each administration group.
Mouse is normally raised in 1 week in SPF barrier systems, and the belly depilation in 1 day before experiment, scope about 3cm × 3cm, connects
And smear medicine (dosage is counted as 20mg/kg using azelastine hydrochloride), continuous coating 7 days at depilation daily herein.After self administration of medication
The 2-8 days, for 5 animals of each administration group, its irritation of coating position in terms of the degree of reddening is observed daily, is recorded
This group of animal recorded moderate stimulation score value at this 7 days, calculated every group of average value.As a result, the irritation of embodiment 1-9 each groups point
Value is respectively less than 0.5, in the range of 0~0.33, shows and there is no irritation, but it is completely surprising that embodiment
The irritation score value of 8 groups of each samples of 21-27 shows that obvious skin irritatin is presented in they in the range of 2.87~4.23
Property.
Claims (10)
- A kind of 1. composition of hydrochloric azelastine, it is characterised in that：Its component includes：Azelastine or its pharmaceutical salts, sugar Cortin, polyhydroxy-alcohol and skin penetration enhancer,；Included in wherein 100 grams of said compositions：Azelastine or its pharmaceutical salts 0.2-5g, glucocorticoid 0.1-10g, polyhydroxy-alcohol 5-50g and skin penetration enhancer 50-95g.
- A kind of 2. composition of hydrochloric azelastine according to claim 1, it is characterised in that：Described 100 grams should Included in composition：Azelastine or its pharmaceutical salts 0.2-2.5g, glucocorticoid 0.5-10g, polyhydroxy-alcohol 7.5-40g and thoroughly Skin sorbefacient 60-92.5g.
- A kind of 3. composition of hydrochloric azelastine according to claim 1, it is characterised in that：Described 100 grams should Included in composition：Azelastine or its pharmaceutical salts 0.2-1.5g, glucocorticoid 1-10g, polyhydroxy-alcohol 10-30g and transdermal Sorbefacient 70-90g.
- A kind of 4. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The polyhydroxy-alcohol choosing From：Ethylene glycol, propane diols, glycerine and combinations thereof.
- A kind of 5. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The sugared cortical hormone Element is beclomeasone propionate, budesonide, fluticasone propionate or health acid Mometasone.
- A kind of 6. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The polyhydroxy alcohol ester Fat acid esters is selected from：Glycol fatty acid ester, methyl glycol fatty acid ester, glycerol fatty acid ester, glycerine triacetate and its group Close.
- A kind of 7. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The composition is The pharmaceutical preparation being for external application.
- A kind of 8. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The composition is For the pharmaceutical preparation of percutaneous dosing.
- A kind of 9. composition of hydrochloric azelastine according to one of claim 1-3, it is characterised in that：Described is saturating Skin sorbefacient includes polyhydroxy-alcohol fatty acid ester.
- A kind of 10. composition of hydrochloric azelastine according to claim 1, it is characterised in that：The composition For cream or ointment.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0780127A1 (en) * | 1995-12-19 | 1997-06-25 | The Procter & Gamble Company | A nasal spray containing a steroid and a antihistamine |
| CN1674910A (en) * | 2002-06-14 | 2005-09-28 | 希普拉有限公司 | Combination of azelastine and steroids |
| CN101460060A (en) * | 2006-03-01 | 2009-06-17 | 特莱斯特拉塔公司 | Composition and method for topical treatment of tar-responsive dermatological disorders |
| CN104173286A (en) * | 2014-09-10 | 2014-12-03 | 贵州云峰药业有限公司 | Azelastine composition and use |
-
2017
- 2017-11-28 CN CN201711218503.6A patent/CN107929738A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0780127A1 (en) * | 1995-12-19 | 1997-06-25 | The Procter & Gamble Company | A nasal spray containing a steroid and a antihistamine |
| CN1674910A (en) * | 2002-06-14 | 2005-09-28 | 希普拉有限公司 | Combination of azelastine and steroids |
| CN101460060A (en) * | 2006-03-01 | 2009-06-17 | 特莱斯特拉塔公司 | Composition and method for topical treatment of tar-responsive dermatological disorders |
| CN104173286A (en) * | 2014-09-10 | 2014-12-03 | 贵州云峰药业有限公司 | Azelastine composition and use |
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