CN106038480B - A kind of aqueous liquid preparation that light is stable - Google Patents
A kind of aqueous liquid preparation that light is stable Download PDFInfo
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- CN106038480B CN106038480B CN201610231858.8A CN201610231858A CN106038480B CN 106038480 B CN106038480 B CN 106038480B CN 201610231858 A CN201610231858 A CN 201610231858A CN 106038480 B CN106038480 B CN 106038480B
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- aqueous liquid
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- 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
- A61K9/08—Solutions
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of aqueous liquid preparations that light is stable.Specifically, the present invention relates to a kind of aqueous liquid preparations containing (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid or its medicinal acid addition salt and selected from boric acid, the excipient of borax, stablize to light.
Description
Technical field
The present invention relates to a kind of aqueous liquid preparations that light is stable, contain (+)-(S) -4- { 4- [(4- chlorphenyl) (2-
Pyridine) methoxyl group] piperidines } butyric acid or its medicinal acid addition salt and the excipient selected from boric acid, borax.
Background technique
Bepotastine besilate is that thousand longevity company of Japan and ISTA drugmaker permit through day Honda side drugmaker of Mitsubishi
The histamine H 1 receptor antagonist of joint development, 1.5% eye drop preparation (Bepreve) in September, 2009 obtain U.S. FDA approval
Listing, for treating allergic conjunctivitis with the itch of sign and symptom.
EP0335586 discloses the structure of bepotastine, chemistry entitled (+)-(S) -4- { 4- [(4- chlorphenyl) earliest
(2- pyridine) methoxyl group] piperidines } butyric acid, and confirm it with antihistaminic effect and anti-allergic effects.WO9829409 is disclosed
Bepotastine is suitable for the pharmaceutical acceptable salt of exploitation, particularly discloses its benzene sulfonate, as shown in following structural formula:
Bepotastine and its medicinal acid addition salt in aqueous solution to photo-labile, over time be easy discoloration or
Precipitating, this has made it be difficult to use as aqueous liquid preparation.In answering for aqueous liquid preparation such as eye drops and nasal drop etc.
With in situation, can be used comprising by being housed in the medium method of the container of light shield, but actually it is difficult to complete light shield.
Summary of the invention
The present invention is intended to provide including stable (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines }
The aqueous liquid preparation of butyric acid or its medicinal acid addition salt.
In the scenario above, the present invention has carried out various researchs, as a result, it has been found that by be added boric acid, borax can light it is steady
Fixed (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid and its medicinal acid addition salt in water, and
The present invention is completed by further studying.
The present invention provides a kind of aqueous liquid preparations, contain (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) first
Oxygroup] piperidines } butyric acid or its officinal salt, and the light stabilizer selected from one or both of boric acid, borax.
In a preferred embodiment of the present invention, glycerol is free of in the aqueous liquid preparation.
(+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid or its medicinal acid addition salt
Concentration range can for 0.1w/v% between 2.0w/v%.
In order to be suitable for human administration, the aqueous liquid preparation should have suitable pH value, of the invention preferred
Embodiment in, the aqueous liquid preparation have 6.0-8.0 pH value.
Aqueous liquid preparation of the invention can exist in a variety of forms, such as injection, eye drops.
In the present invention, as the medicinal of (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid
Acid-addition salts, it can be mentioned that for example with the salt of halogen acids such as hydrochloride, hydrobromate etc.；With the salt such as sulfate of inorganic acid, nitre
Hydrochlorate, phosphate etc.；With the salt such as acetate of organic acid, propionate, hydroxyl acetate, 2 hydroxy propanoic acid salt, acetonate, third
Diacid salt, succinate, maleate, fumarate, Dihydroxyfumaric acid salt, oxalates, benzoate, cinnamate, water
Poplar hydrochlorate, mesylate, esilate, benzene sulfonate, tosilate, cyclamate, 4-ASA salt
Deng；Etc..It is typically preferred to acid-addition salts for above compound of the invention, the more preferable benzene sulphur among these acid-addition salts
Hydrochlorate and benzoate, a particularly preferred benzene sulfonate.
In aqueous liquid preparation of the invention, (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines }
Butyric acid or its as the content of the medicinal acid addition salt of a benzene sulfonate usually pass through about 0.1w/v%, preferably from about 0.3w/v%,
The more preferably from about lower limit of 0.5w/v% and about 2.0w/v%, the upper limit of preferably from about 1.5w/v% indicate, the bound is according to using
Purpose and symptom degree suitably increase or decrease.
In the present invention, it is boric acid, borax as preferred light stabilizer, and is applied in combination.
In aqueous liquid preparation of the invention, wherein boric acid content is typically about 0.01w/v% to 10w/v%, preferably
0.05w/v% to 5w/v%, more preferable 0.1w/v% to 1.5w/v%, most preferably from about 0.8w/v% to 1.2w/v%；Borax
Identical content range may be selected.
Can be suitably by usually used various additives such as preservative, waterborne liquid of the invention is added in chelating agent etc.
Preparation.
As preservative, it can be mentioned that such as quaternary ammonium salt such as benzalkonium chloride, chlorhexidine gluconate etc., P-hydroxybenzoic acid
Ester such as methyl p-hydroxybenzoate, propylparaben etc., sorbic acid and its salt etc..As chelating agent, it can be mentioned that second
Edetate disodium, citric acid etc..
In aqueous liquid preparation of the invention, if do not damage the purpose of the present invention can be properly joined into it is other identical
Or different types of effective component.
In the present invention, contain (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyrrole by the way that boric acid and/or borax to be added
Pyridine) methoxyl group] piperidines butyric acid or its medicinal acid addition salt aqueous liquid preparation, (+)-(S) -4- { 4- [(4- chlorine can be improved
Phenyl) (2- pyridine) methoxyl group] piperidines butyric acid or its medicinal acid addition salt, especially a benzene sulfonate bepotastine benzene sulphur
The photostability of hydrochlorate, and stable aqueous liquid preparation can be produced.Because light stabilization method through the invention can be with
The aqueous liquid preparation stable to light is obtained, aqueous liquid preparation of the invention is advantageously used in treatment allergic conjunctivitis, spring
Season conjunctivitis etc..
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
EXPERIMENTAL EXAMPLE 1, boric acid solution, borax soln and boric acid, borax combination solution are to Bepotastine besilate
The influence of photostability
Test method
The aqueous liquid preparation (preparation 1-4) comprising Bepotastine besilate of the expression of table 1 is conventionally prepared,
And it is filled into the medicinal eye drop bottle of low density polyethylene (LDPE), 5ml/ bottles.Sample irradiates 5 days, 10 under 4500lx illumination condition
It, observes the appearance of the liquid preparation of each preparation.
Table 1
Test result:
Appearance of the preparation 1 after light irradiation is blackish green, and observes precipitating.Sample is shallow after preparation 2-3 illumination 5 days
Yellow.Solution appearance is achromaticity and clarification after 4 illumination of preparation 10 days, and a certain amount of boric acid-borax buffering is added as the result is shown to can be with
Improve stability of Bepotastine besilate under the conditions of light irradiates.
The influence of EXPERIMENTAL EXAMPLE 2, citric acid, glycerol and mannitol to the photostability of Bepotastine besilate
Test method
Conventionally prepare table 2 expression the aqueous liquid preparation comprising Bepotastine besilate, and with
The processing of the identical method of EXPERIMENTAL EXAMPLE 1, observes the appearance of the liquid preparation of every kind of preparation.
Table 2
| Preparation | 5 | 6 | 7 | 8 |
| Bepotastine besilate | 75mg | 75mg | 75mg | 75mg |
| Benzalkonium chloride | 0.15mg | 0.15mg | 0.15mg | 0.15mg |
| Borax | 50.0mg | / | / | / |
| Boric acid | 25.0mg | / | / | / |
| Citric acid | / | 100mg | / | / |
| Glycerol | / | / | 30mg | / |
| Mannitol | / | / | / | 50mg |
| Sodium hydroxide | / | In right amount | In right amount | In right amount |
| Water for injection | To 5ml | To 5ml | To 5ml | To 5ml |
| pH | 7.0 | 7.0 | 6.9 | 6.8 |
Test result: for comprising boric acid-borax buffering pair preparation 5, appearance does not have change after strong illumination 10 days,
Still achromaticity and clarification is without precipitating.For preparation 6-8 after strong illumination 5 days, solution colour became yellow green, at strong illumination 10 days
Afterwards, solution colour is in blackish green, and has precipitating, illustrate the addition of citric acid, glycerol and mannitol and have not been changed bepotastine
Stability of the benzene sulfonate under illumination condition.
The influence of EXPERIMENTAL EXAMPLE 3, Bepotastine besilate concentration to the photostability of Bepotastine besilate
Test method:
Conventionally prepare aqueous liquid preparation (the preparation 9- comprising Bepotastine besilate of the expression of table 3
11) it, and in method identical with EXPERIMENTAL EXAMPLE 1 handles, observes the appearance of the liquid preparation of every kind of preparation.
Table 3
| Preparation | 9 | 10 | 11 |
| Bepotastine besilate | 25mg | 50mg | 100mg |
| Benzalkonium chloride | 0.15mg | 0.15mg | 0.15mg |
| Borax | 15mg | 30mg | 60mg |
| Boric acid | 8mg | 15mg | 30mg |
| Water for injection | To 5ml | To 5ml | To 5ml |
| pH | 6.7 | 6.8 | 6.8 |
Test result: it solution appearance and is had not been changed after being placed 10 days under 11 illumination condition of preparation 9- preparation, is still colourless
Clear illustrates that the photostability of Bepotastine besilate can be buffered within the scope of a certain concentration by boroborax to changing
It is kind.
Embodiment 1: eye drops
Embodiment 2: eye drops
Embodiment 3: eye drops
Embodiment 4: eye drops
Embodiment 5: eye drops
Embodiment 6: eye drops
Embodiment 7: eye drops
Claims (4)
1. a kind of aqueous liquid preparation contains (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid
The weight ratio of benzene sulfonate, and the light stabilizer being made of the mixture of boric acid and borax, the boric acid and borax be 1:1 extremely
The concentration range of 1:5, (+)-(S) -4- { 4- [(4- chlorphenyl) (2- pyridine) methoxyl group] piperidines } butyric acid benzene sulfonate is
0.1w/v% to 2.0w/v%, the concentration of the boric acid are 0.1w/v% to 1.5w/v%, and the borate concentration range is 0.1w/
V% to 1.5w/v%.
2. aqueous liquid preparation according to claim 1, wherein the aqueous liquid preparation has the pH value of 6.0-8.0.
3. aqueous liquid preparation according to claim 1 is eye drops.
4. aqueous liquid preparation according to claim 1, wherein the weight ratio of the boric acid and borax is 1:1 to 1:2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015101808693 | 2015-04-16 | ||
| CN201510180869 | 2015-04-16 |
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| CN106038480A CN106038480A (en) | 2016-10-26 |
| CN106038480B true CN106038480B (en) | 2019-02-22 |
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| CN107141775A (en) * | 2017-04-25 | 2017-09-08 | 柳州市乾阳机电设备有限公司 | Resistance to optical thin film |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5290774A (en) * | 1989-08-03 | 1994-03-01 | Eisai Co., Ltd. | Photostabilizing method for ophthalmic solutions and the resulting ophthalmic solutions therefrom |
| CN1612734A (en) * | 2002-07-31 | 2005-05-04 | 千寿制药株式会社 | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014024794A (en) * | 2012-07-27 | 2014-02-06 | Nippon Tenganyaku Kenkyusho:Kk | Aqueous composition containing timolol or pharmaceutically acceptable salt thereof and photostabilization method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5290774A (en) * | 1989-08-03 | 1994-03-01 | Eisai Co., Ltd. | Photostabilizing method for ophthalmic solutions and the resulting ophthalmic solutions therefrom |
| CN1612734A (en) * | 2002-07-31 | 2005-05-04 | 千寿制药株式会社 | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
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