CN1228053C - Eye drop containing diuridine phosphoric acid - Google Patents
Eye drop containing diuridine phosphoric acid Download PDFInfo
- Publication number
- CN1228053C CN1228053C CNB021321000A CN02132100A CN1228053C CN 1228053 C CN1228053 C CN 1228053C CN B021321000 A CNB021321000 A CN B021321000A CN 02132100 A CN02132100 A CN 02132100A CN 1228053 C CN1228053 C CN 1228053C
- Authority
- CN
- China
- Prior art keywords
- eye drop
- benzalkonium chloride
- dup
- phosphoric acid
- bak
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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Classifications
-
- 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
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The purpose of the invention is to provide a clear and stable multidose-type eye drop containing P<SP>1</SP>,P<SP>4</SP>-di(uridine-5')tetraphosphoric acid or a salt thereof. This eye drop is obtained by formulating a benzalkonium chloride having twelve carbons in the alkyl group so as not to get cloudy due to the formulation variation in the benzalkonium chloride.
Description
Technical field
The present invention relates to cooperate carbon number 12 benzalkonium chloride (below be abbreviated as BAK-C
12) as antiseptic and contain the diuridine phosphoric acid (below be abbreviated as DUP) of following general formula (1) expression or its esters as the clear and bright and stable eye drop of effective ingredient.
(in the formula, n represents 1～4 integer.)
Background technology
Purinoceptor agonist DUP or its esters have the effect that promotes lacrimal secretion, and be as being recorded among the WO98/34593 for the useful medicine of treatment xerophthalmia, on the books in WO99/05155 about the preparation method of DUP or its esters.Also having put down in writing with DUP or its esters among the WO98/34593 is the preparation method of the general eye drop of effective ingredient, but as concrete gradation composition, only put down in writing and to be derivatives class, animal oil lipid, acrylate copolymer class, vegetable oil lipid, polysaccharide, glycosaminoglycan class, salt, but wherein not mention the clear and bright property or the stability of the eye drop of preparation at all to hydrous water, polyethers, polyethylene kind, cellulose derivative class, oil in the drug solns at ophthalmic.In addition,, do not narrate any antiseptic and be fit to, do not put down in writing the concrete Formulation Example that cooperates antiseptic yet about the antiseptic that cooperates in the eye drop.
Comprise the unit dose type of the type of once using up of enclosing ampoule (about 0.5mL) in the packaged configuration of eye drop, and enclose the multiple dose type that 5～10mL uses repeatedly.The unit dose type has the advantage that there is no need to cooperate antiseptic owing to once use up, and for eye drip repeatedly, container also must equate that with its number of times overall volume is big, is not easy to carry on the other hand.Therefore, like the patient of multiple dose type also a lot, thus not only urgent hope exploitation unit dose type, also urgent hope exploitation multiple dose type.The occasion of multiple dose type can not asepticly be preserved behind the Kaifeng, therefore is necessary to cooperate antiseptic, and exploitation multiple dose type eye drop is necessary the antiseptic that can cooperate is studied.Usually, as the antiseptic of eye drop, can use quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, parabens such as methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid or its esters, quaternary ammonium salt is good aspect antiseptic effect, is particularly suitable for using benzalkonium chloride.
Normally used benzalkonium chloride ((C
6H
5CH
2N (CH
3)
2R) be that alkyl R is C Cl)
8～C
18Mixture, similar record is also arranged in the pharmacopeia in Japan and the United States, Europe.
Japanese Pharmacopoeia: with (C
6H
5CH
2N (CH
3)
2R) Cl represents, R is C
8H
17～C
18H
37, mainly by C
12H
25And C
14H
29Constitute.
American Pharmacopeia: be (C
6H
5CH
2N (CH
3)
2R) Cl is the mixture of chlorination alkyl benzyl dimethyl ammonium, and R represents to compare C
8H
17The mixing of all of chain length or some alkyl, most of by C
12H
25, C
14H
29And C
16H
33Constitute.
European Pharmacopoeia: be the mixture of chlorination alkyl benzyl dimethyl ammonium, alkyl has C
8To C
18Chain length.
" benzalkonium chloride " is expressed as the benzalkonium chloride of mixture as mentioned above in this description.
Carbon number during in addition, with the carbon number specialization is represented the carbon chain lengths of the alkyl of " R " expression in the above-mentioned pharmacopeia.
DUP or its esters have the effect that promotes lacrimal secretion, for the treatment xerophthalmia is useful medicine, after it is applied to eye drop and studies, learns if benzalkonium chloride is coupled in the DUP eye drop, eye drop unexpectedly takes place to cooperate and changes, and produces white casse.
Summary of the invention
The inventor found that by cooperating BAK-C for keeping the clear and bright property of preparation and the preparationization of DUP eye drop of stability to carry out concentrated research simultaneously keeping antiseptic effect
12Can access the eye drop that can satisfy above-mentioned these conditions.
The present invention relates to a kind of eye drop, it is characterized in that, in the DUP or the clear and bright and stable eye drop of its esters that contain following general formula (1) expression, cooperate BAK-C as effective ingredient
12
(in the formula, n represents 1～4 integer.)
The salt of use therein DUP is represented the salt with alkali metal formation such as sodium, potassium, special particular certain cancers.
As DUP or its esters, preferred n is 4, the preferred especially sodium salt that uses following formula (2) expression.
It is said general because benzalkonium chloride has positive charge, therefore form insoluble complex with the medicine that has negative charge easily, cause to cooperate to change.But the similar substance of DUP is the negative charge that has phosphoric acid on the uridnine in conjunction with the chemical compounds such as uridine triphosphate of several phosphoric acid, but can not cooperate variation with benzalkonium chloride.Further combined with uridnine, DUP that negative charge is neutralized or its esters surely not take place to cooperate and change on the supposition phosphoric acid, so carried out cooperating the research of benzalkonium chloride as antiseptic.But, learn that unexpectedly DUP or its esters cooperate variation with benzalkonium chloride, produce white casse.Known BAK-C
12Have the effect (special fair 6-74212) that prevents with the incompatibility of medicine, but even the problems referred to above can not predict with reference to this known technology.
Therefore, the inventor has carried out concentrated research to the antiseptic that cooperates in the DUP eye drop.Found that if use BAK-C
12, then do not take place to cooperate to change, can obtain clear and bright and stable eye drop, finished the present invention.Detailed content describes in detail in following embodiment.
And, use the mixture of the different benzalkonium chloride of the carbon number of alkyl R in the above-mentioned formula, the carbon number that is R is that the carbon number of the mixture of 12 and 14 benzalkonium chloride and R is that the mixture of 12,14 and 16 benzalkonium chloride is tested, learn that these mixture all produce white casse, separately BAK-C
12Show special excellent characteristic.
The concentration of DUP or its esters can suitably be selected preferred 0.01～5% (W/V), more preferably 0.1～3% (W/V) (W/V represents w/v) according to object disease or symptom etc.
BAK-C
12Concentration so long as get final product, if concentration height then may cause the cornea obstacle is crossed and lowly then can not be brought into play antiseptic effect as the common concentration that adopts of the antiseptic of eye drop.Therefore, preferred 0.001～0.05% (W/V) of its concentration, more preferably 0.002～0.01% (W/V).
When preparing eye drop of the present invention, remove above-mentioned BAK-C
12In addition, can also cooperate widely used additive in the eye drop as required.As additive, isotonic agents such as sodium chloride, potassium chloride, calcium chloride, glycerol, propylene glycol for example, buffer agents such as boric acid, Borax, citric acid, sodium hydrogen phosphate, episilon amino caproic acid, pH regulator agent such as hydrochloric acid, sodium hydroxide etc.
The pH of eye drop of the present invention is preferably 3～8, is preferably 4～7 especially.
Eye drop of the present invention can be according to the method preparation of extensive employing.
Below in conjunction with embodiment the present invention is described, but these embodiment only are used for understanding the present invention better, not delimit the scope of the invention.
The specific embodiment
Embodiment
(formulation example)
Below list an example of the formulation example of eye drop of the present invention.
Prescription 1 (among the 100mL)
P
1, P
4-two (uridnine-5 ') four phosphatase 11 g
BAK-C
12 0.004g
Sodium chloride 0.63g
Potassium chloride 0.15g
Sodium hydrogen phosphate 12 hydrate 0.2g
The 1N sodium hydroxide is an amount of
1N hydrochloric acid is an amount of
Sterile purified water is an amount of
Above-mentioned eye drop is to keep clear and bright property, is suitable for the stable eye drop that uses as multiple dose type eye drop.
(preservation potency test)
Eye drop to the prescription 1 of above-mentioned formulation example record carries out following preservation potency test.In sterile purified water, add the gradation composition shown in the above-mentioned formulation example, according to conventional method preparation eye drop.PH regulator to 6.5.Preserving potency test carries out according to the preservation potency test method of the 13 edition Japanese Pharmacopoeia.
The result is as shown in table 1.Adding the bacterium number of bacterium after 4 weeks is that antibacterial is 0, and fungus is 0 or reduces than inoculation bacterium digital display work, given full play to antiseptic effect as can be known.
Table 1
Bacterium number in the 1mL preparation
| Inoculation bacterium number | Bacterium number after 4 weeks | ||
| Antibacterial | E.Coli | 7.9×10 5 | 0 |
| P.areruginosa | 4.6×10 5 | 0 | |
| S.aureus | 2.2×10 5 | 0 | |
| Fungus | C.albicans | 5.4×10 5 | 0 |
| A.niger | 2.8×10 5 | 3.1×10 1 | |
(preparation test)
1, the variation that cooperates of DUP and DUP similar substance and benzalkonium chloride
Use the similar substance of DUP or its esters and DUP, investigate the experiment whether insoluble complex that causes white casse when cooperating with benzalkonium chloride forms.DUP or its esters use the P of following formula (2) expression
1, P
4-two (uridnine-5 ') four tetrasodium phosphates (hereinafter referred to as DUTP-4Na).The similar substance of DUP uses uridnine (following formula (3)), uridine monophosphate disodium (UMP; Following formula (4)), uridine 5'-diphosphate disodium (UDP; Following formula (5)), uridine triphosphate trisodium (UTP; Following formula (6)).
(experimental technique)
1) prepares 1% aqueous solution respectively for DUTP-4Na, uridnine, UMP, UDP and UTP.This 1% aqueous solution is further diluted, prepare 0.1% aqueous solution.
2) in various solution 5mL, add 1% benzalkonium chloride aqueous solution, 50 μ L, obtain experimental liquid (benzalkonium chloride concentration reaches 0.0 1%).
3), measure the benzalkonium chloride concentration in the supernatant with after the experimental liquid centrifugal treating (3600rpm, 30 minutes).Add 1% benzalkonium chloride aqueous solution, 50 μ L in contrast in distilled water 5mL, the benzalkonium chloride in the supernatant is represented with the response rate (%) with respect to the amount of contrast.
(result)
The result is as shown in table 2, changes if take place to cooperate, and then forms insoluble complex with benzalkonium chloride, produces precipitation, and the response rate of benzalkonium chloride reduces.Similar substance uridnine, UMP, UDP and the UTP of DUP there is no the response rate to be reduced, and does not form insoluble complex.But the DUTP-4Na response rate reduces, and DUTP-4Na has formed insoluble complex as can be known.Thereby, although seeing to cooperate, the similar substance of DUP do not change, and as seen DUP or its esters cooperate variation, and it is specific that therefore this cooperation changes DUP or its esters.
Table 2
The response rate of benzalkonium chloride (%)
| Concentration | Uridnine | UMP | UDP | UTP | DUTP-4Na |
| 1％(W/V) | 101.6 | 101.6 | 97.9 | 96.0 | 80.3 |
| 0.1％(W/V) | 92.1 | 99.3 | 99.6 | 94.7 | 75.8 |
2, DUTP-4Na and BAK-C
12Cooperation
DUP or its esters use DUTP-4Na, and the benzalkonium chloride different with the carbon number of alkyl R in the above-mentioned formula cooperates, and observe whether producing white casse.The different benzalkonium chloride of the carbon number of R uses BAK-C
12, BAK-C
12,14(carbon number is the mixture of 12 and 14 benzalkonium chloride) or BAK
Mix(carbon number is the mixture of 12,14 and 16 benzalkonium chloride).
(experimental technique)
1) in the 1.0%DUTP-4Na aqueous solution, add sodium hydrate aqueous solution, be adjusted to pH7.4 after, used thickness is this aqueous solution of membrane filtration of 0.22 μ m.
2) inject 1.0%DUTP-4Na aqueous solution 4mL respectively, inject liquid to each and add BAK-C
12Aqueous solution, 0.1%BAK-C
12,14Aqueous solution, 1.0%BAK
MixAqueous solution 40 μ L (ultimate density 0.01%) or 80 μ L (ultimate density 0.02%) reach the concentration of table 3, test preparation liquid.
3) determination test liquid is at the permeability (%T) at 632.8nm place and observe outward appearance.
The concentration of each composition of table 3 (% (W/V))
| DUTP-4Na | BAK-C 12 | BAK-C 12、14 | BAK mix | |
| Preparation 1 | 1.0 | 0.01 | - | - |
| Preparation 2 | 1.0 | 0.02 | - | - |
| Reference preparation 1 | 1.0 | - | 0.01 | - |
| Reference preparation 2 | 1.0 | - | 0.02 | - |
| Reference preparation 3 | 1.0 | - | - | 0.01 |
| Reference preparation 4 | 1.0 | - | - | 0.02 |
(result)
The result is as shown in table 4.In DUP-4Na, cooperate BAK-C
12,14Or BAK
MixThe time, permeability all reduces under 0.01%, 0.02% any concentration, visible white casse.But, if cooperate BAK-C separately
12, then still be water white transparency, not owing to cooperate variation to produce white casse.
As mentioned above, if in the DUTP-4Na eye drop, cooperate BAK-C
12, can not produce white casse, obtain clear and bright eye drop.
Table 4 permeability (%T) and outward appearance
| Permeability (%T) | Outward appearance | |
| Preparation 1 | 99.6 | Water white transparency |
| Preparation 2 | 100.4 | Water white transparency |
| Reference preparation 1 | 88.3 | Adularescent muddiness slightly |
| Reference preparation 2 | 19.2 | White casse |
| Reference preparation 3 | 76.2 | Adularescent muddiness slightly |
| Reference preparation 4 | 15.6 | White casse |
Can obtain having cooperated BAK-C according to the present invention
12Clear and bright and stable DUP eye drop.
Claims (5)
1, a kind of eye drop is characterized in that, in containing diuridine phosphoric acid or its esters clear and bright and stable eye drop as effective ingredient, as antiseptic, the carbon number that cooperates alkyl R is 12 benzalkonium chloride (C
6H
5CH
2N (CH
3)
2R) Cl.
2, eye drop as claimed in claim 1, the concentration of diuridine phosphoric acid or its esters are 0.1～5.0% (W/V).
3, eye drop as claimed in claim 1, the concentration of benzalkonium chloride are 0.001～0.05% (W/V).
4, as any described eye drop in the claim 1～3, diuridine phosphoric acid is P
1, P
4-two (uridnine-5 ') four phosphoric acid.
5, contain diuridine phosphoric acid or its esters preparation method as the clear and bright and stable eye drop of effective ingredient, it is characterized in that, as antiseptic, the carbon number that cooperates alkyl R is 12 benzalkonium chloride (C
6H
5CH
2N (CH
3)
2R) Cl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001274882 | 2001-09-11 | ||
| JP274882/2001 | 2001-09-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1406586A CN1406586A (en) | 2003-04-02 |
| CN1228053C true CN1228053C (en) | 2005-11-23 |
Family
ID=19099844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021321000A Ceased CN1228053C (en) | 2001-09-11 | 2002-09-10 | Eye drop containing diuridine phosphoric acid |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20030022740A (en) |
| CN (1) | CN1228053C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100870104B1 (en) * | 2005-11-28 | 2008-11-26 | 주식회사 머젠스 | Composition Having Effect on Treatment and Prevention of Dry eye syndrome |
| TR201820073T4 (en) | 2012-03-26 | 2019-01-21 | Santen Pharmaceutical Co Ltd | Eye drops containing diquafosol. |
| BR112015017919A8 (en) * | 2013-01-31 | 2019-11-05 | Senju Pharma Co | aqueous liquid preparation and method for clarifying an aqueous liquid preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU499860B2 (en) * | 1975-04-24 | 1979-05-03 | Honda Giken Kogyo Kabushiki Kaisha | Deflector plate to equalise fuel distribution in induction gas flow |
| US5900407A (en) * | 1997-02-06 | 1999-05-04 | Inspire Pharmaceuticals, Inc. | Method of treating dry eye disease with uridine triphosphates and related compounds |
| BRPI9810436B1 (en) * | 1997-07-25 | 2015-12-29 | Inspire Pharmaceuticals Inc | large-scale production of uridine di (5'-tetraphosphate) and salts thereof |
-
2002
- 2002-09-10 CN CNB021321000A patent/CN1228053C/en not_active Ceased
- 2002-09-11 KR KR1020020054874A patent/KR20030022740A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1406586A (en) | 2003-04-02 |
| KR20030022740A (en) | 2003-03-17 |
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