CN100388915C - Eye drop containing tranilast and its preparing process - Google Patents
Eye drop containing tranilast and its preparing process Download PDFInfo
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- CN100388915C CN100388915C CNB2006100407884A CN200610040788A CN100388915C CN 100388915 C CN100388915 C CN 100388915C CN B2006100407884 A CNB2006100407884 A CN B2006100407884A CN 200610040788 A CN200610040788 A CN 200610040788A CN 100388915 C CN100388915 C CN 100388915C
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- tranilast
- eye drop
- citric acid
- injection
- polyvinylpyrrolidone
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Abstract
The present invention discloses a formula for eye drops containing tranilast for treating allergic conjunctivitis and a preparation method thereof. More specifically, all auxiliary materials in the formula conform to medicinal specifications, and the auxiliary materials comprise meglumine, citric acid, polyvinylpyrrolidone K30 and nipagin ester. The preparation method has the advantages of simple process and controllable quality, and the eye drops have the advantages of high stability and convenience for transportation, storage and carrying. Study on the stimulation of the eye drops shows that the eye drops can not cause stimulation reactions on eyes if the medicine is used on eyes continuously.
Description
Technical field
The present invention relates to prescription of a kind of eye drop that contains tranilast for the treatment of anaphylaxis conjunctivitis and preparation method thereof.
Background technology
Tranilast (Tranilast) chemistry N-(3,4-dimethoxy cinnamoyl) anthranilic acid by name is a kind of novel sensitive media sustained-release agent of crossing, and can suppress allergy effectively, is mainly used in control allergic asthma and other anaphylactic disease.
Japan KISSEI pharmaceutical Co. Ltd in nineteen ninety-five at Japan's tranilast eye drop that gone on the market
Be applicable to anaphylaxis conjunctivitis.
Tranilast is soluble in organic solvents such as dimethyl formamide, pyridine, but utmost point indissoluble is separated in water.How tranilast is dissolved in the aqueous solution, the tranilast solution of the concentration that obtains medical treatment is the key point of preparation tranilast eye drop.
Japan's tranilast eye drop description has been announced its prescription composition, except that the principal agent tranilast, also contains boric acid, Borax, polyvinylpyrrolidone K
25, adjuvant such as polysorbate80, benzalkonium chloride and edetate sodium.Analyze the prescription of Japanese tranilast eye drop and form, its mesoboric acid and Borax are formed buffer solution, are used to the pH scope that provides suitable; Polyvinylpyrrolidone K
25Be viscosity modifier, be used to reduce the zest of preparation; Polysorbate80 is a surfactant, is used to increase the dissolubility of medicine; Benzalkonium chloride is an antibacterial: edetate sodium is a stabilizing agent.
But when carrying out the development of tranilast eye drop with reference to Japan's prescription, we find with boric acid and borax buffer solution is the prescription of solvent preparation, unstable under cryogenic conditions, is easy to generate precipitation.Polyvinylpyrrolidone K
25Also there is not medicinal standard at home, so can't be applied to preparation.Benzalkonium chloride also is easy to cause precipitate and separates out.In a word, with reference to Japan's prescription development tranilast eye drop, manufacturing condition requires harsh, to cryogenic poor stability, owing to separate out precipitation easily, untoward reaction such as twinge can take place in use.
Summary of the invention
The present invention is directed to the problem that above-mentioned prior art exists, we have developed a kind of eye drop that contains tranilast, and the adjuvant that uses in the prescription is the adjuvant that meets medicinal standard entirely, and preparation process is simple, control easily, and good stability, zest is little.
The purpose of this invention is to provide a kind of eye drop prescription that contains tranilast.The polyvinylpyrrolidone K that uses in Japan's prescription
25, also do not have medicinal specification at home, thereby must screen new viscosity modifier: the buffer system of its use, surfactant, antibacterial have considerable influence to the stability of principal agent, also must screen again.
Another object of the present invention provides the preparation method of tranilast eye drop.Tranilast minimum dissolubility in water has caused great difficulty for the preparation technology of tranilast eye drop, and the minor variations of conditions such as pH value of solution, polarity or ionic strength all may cause separating out of tranilast, causes the preparation failure.So the production technology that convenience is feasible, be convenient to large-scale production and quality control is the key that realizes that the tranilast eye drop is used widely.
The present invention is by the following technical solutions:
A kind of eye drop that contains tranilast that is used for the treatment of anaphylaxis conjunctivitis, the weight proportion of each component is in the prescription: tranilast 25, meglumine 100-300, citric acid 30-400, Nipagin ester 0.1-4, polyvinylpyrrolidone K
30(PVPK
30) 10-200, water for injection 4000-5000.
Wherein, more excellent weight proportion is: tranilast 25, meglumine 150-250, citric acid 50-100, Nipagin ester 0.5-1.5, polyvinylpyrrolidone K
30(PVPK
30) 30-60, water for injection 4000-5000.
Above-mentioned parabens ester can be methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben or butoben.
Prepare the method for above-mentioned tranilast eye drop, be specially: get above-mentioned recipe quantity tranilast and meglumine and add injection and blunge, slowly add citric acid, regulate pH value, add Nipagin ester and polyvinylpyrrolidone K again to 6.5-9.0 to dissolving
30(PVPK
30) solution, stir, add adding to the full amount of water for injection, aseptic filtration is sub-packed in the eye drop bottle.
The more excellent scope of above-mentioned pH value is 7.0-8.5.
Wherein, before the dissolving tranilast, Nipagin ester is mixed with 0.1% aqueous solution, or the alcoholic solution of 1-6% is standby; Polyvinylpyrrolidone K
30(PVP K
30) be mixed with 5-10% aqueous solution standby; It is standby that citric acid is mixed with the aqueous solution of 5-20%.
The present invention adopts meglumine aqueous solution dissolving tranilast, and is extremely neutral with the citron acid for adjusting pH then; With the Nipagin ester is antibacterial, with polyvinylpyrrolidone K
30Be viscosity modifier.Because of tranilast in this prescription dissolves well, so do not use surfactant.
Tranilast eye drop provided by the invention and method have following advantage:
1) preparation stability height of the present invention, zest is little;
2) preparation process of the present invention is simple, convenient, and large-scale production and quality control are convenient in control easily;
3) preparation prescription of the present invention can be practical, is adapted at domestic application.
The specific embodiment
Embodiment 1
Prescription:
Tranilast 25g
Meglumine 175g
Citric acid 55g
4% butoben alcoholic solution 25ml
PVP?K
30 50g
Water for injection adds to 5000ml
Make 1000
Technology:
After getting tranilast, meglumine and adding injection water 2500ml stirring and dissolving, gradation slowly adds dissolved 10% citric acid soln, regulates pH value to 7.5, adds Metagin ester solution and PVP K again
30, stir, filter, on filter, add adding to the full amount of water for injection, under aseptic condition,, after mensuration semi-finished product content is qualified, be sub-packed in the eye drop bottle with 0.22 μ m microporous filter membrane fine straining.
Embodiment 2
Prescription:
Tranilast 25g
Meglumine 225g
Citric acid 77.5g
Methyl hydroxybenzoate 1g
PVP?K
30 50g
Water for injection adds to 5000ml
Make 1000
Technology:
After the about 1000ml water heating for dissolving of methyl hydroxybenzoate usefulness with recipe quantity, standby; Behind the about 500ml water dissolution of citric acid usefulness with recipe quantity, standby; PVP K with recipe quantity
30Behind about 500ml water dissolution, standby; Get the tranilast and the meglumine of recipe quantity, stirring is dissolved in about 2500ml water; Citric acid soln is slowly added in the above-mentioned tranilast solution while stirring, and the control pH value is about 7.5.Add Metagin ester solution and PVP K again
30Solution, and add water to full dose, behind the mixing, aseptic filtration, fill are promptly.
Embodiment 3
Prescription:
Tranilast 25g
Meglumine 300g
Citric acid 150g
2% propylparaben alcoholic solution 50ml
PVP?K
30 200g
Water for injection adds to 5000ml
Make 1000
Technology:
After getting tranilast, meglumine and adding injection water 2500ml stirring and dissolving, gradation slowly adds dissolved 20% citric acid soln, regulates pH value to 7.5, adds propylparaben solution and PVP K again
30, stir, filter, on filter, add adding to the full amount of water for injection, under aseptic condition,, after mensuration semi-finished product content is qualified, be sub-packed in the eye drop bottle with 0.22 μ m microporous filter membrane fine straining.
Embodiment 4
Prescription:
Tranilast 25g
Meglumine 100g
Citric acid 30g
Ethyl hydroxybenzoate 0.5g
PVP?K
30 200g
Water for injection adds to 5000ml
Make 1000
Technology:
After getting tranilast, meglumine and adding injection water 2500ml stirring and dissolving, gradation slowly adds dissolved 5% citric acid soln, regulates pH value to 7.5, adds ethyl hydroxybenzoate and PVP K again
30, stir, filter, on filter, add adding to the full amount of water for injection, under aseptic condition,, after mensuration semi-finished product content is qualified, be sub-packed in the eye drop bottle with 0.22 μ m microporous filter membrane fine straining.
Embodiment 5
Prescription constituent screening
1), solubility test screening
Tranilast is almost insoluble in water, according to the eye drop requirement, needs to increase the dissolubility of medicine.From the physicochemical property of tranilast as can be known, this product is dissolved in alkaline aqueous solution well, still select different basic auxiliary to make tranilast solution, placed 10 days at low temperature (0-4 ℃) respectively, observe its dissolving situation, measurement result sees Table 1.
Table 1 solubility test result
The result shows: this product is investigated after low temperature (0-4 ℃) is placed 10 days, and is good with the prescription dissolving that adds meglumine, do not separate out precipitation, is cosolvent so select meglumine for use.
2), the pH value scope is selected experiment sieving
The pH value of eye drop requires between 5.0-9.0, can not peracid or cross alkali, because people's pH of tears is between 7.3-7.5, the oculomucous protein of peracid solidifiable is crossed alkali and oculomucous epithelial cell is corroded expand and damages.PH value can tolerate in the 5.0-9.0 scope, and can guarantee medicine effectiveness, safety and stability; PH value is between 6.0-8.5, and eyes are pleasant.In sum, we prepare tranilast solution, regulate different pH value with citric acid, and scope is placed through low temperature (0-4 ℃) respectively and observed the pH value situation of change in 10 days between 5.0-9.0, and measurement result sees Table 2.
Table 2pH value selection result
The result shows: this product was investigated through low temperature (0-4 ℃) in 10 days, and is more stable between 6.5-9.0 with the citron acid for adjusting pH value.
3), antibacterial is selected test
Eye drop is the multiple dose preparation, can't keep aseptic after once using, and therefore needs to add antibacterial and guarantees that this product is still stable after opening, the general requirement of antibacterial is that bacteriostasis is rapid, non-stimulated to eyes, stable in properties is not with principal agent and additives generation incompatibility.We prepare the tranilast eye drop with different antibacterial.Placed 10 days through low temperature (0-4 ℃) respectively, observe its situation of change, measurement result sees Table 3.
Table 3 antibacterial selection result
The result shows: this product selects for use different antibacterial to investigate in following 10 days through low temperature (0-4 ℃) condition, has only prescription 3 and prescription 6-prescription 9 not to separate out and does not have precipitation.It is reported that thimerosal toxicity is bigger, thus do not select for use, and select for use Nipagin ester as this product antibacterial.
4), viscosity modifier is selected test
Eye drop increases suitable viscosity, and the time of staying prolongs also abirritate within the eye can to make medicine.Prepared the tranilast eye drop with different viscosity modifiers, and observed its situation of change, measurement result sees Table 4.
Table 4 viscosity modifier selection result
The result shows: this product viscosity modifier is with PVP K
30For good.
Embodiment 6
Stability study test of the present invention
Get embodiment 1 prepared sample, in intensity of illumination (4500 ± 500L
x), placed 10 days under the high temperature (60 ± 2 ℃), low temperature (4 ± 2 ℃) condition, respectively at 5 days and sampling in 10 days, measure every index, the results are shown in Table 5.
Table 5 tranilast eye drop influence factor result of the test
Conclusion:
This product was tested 10 days the influence factor, removed under the illumination condition related substance and slightly degraded, every index that other are relevant and relatively having no significant change in 0 day.
Embodiment 7
Stability study test of the present invention
Get embodiment 2 prepared samples, the simulation commercially available back is placed under 40 ± 2 ℃ of temperature, relative humidity RH20 ± 5% condition, respectively at 0,1,2,3, June pick test, measurement result sees Table 6.
Table 6 tranilast eye drop accelerated test result
Get embodiment 2 prepared samples, the simulation commercially available back is placed under 25 ± 2 ℃ of conditions of temperature, and respectively at 0,3,6,9,12,18,24 month pick test, measurement result the results are shown in Table 7.
Table 7 tranilast eye drop long-term test results
Conclusion:
This product is the condition long term test of 25 ± 2 ℃ of the condition accelerated test 6 months of 40 ± 2 ℃ of temperature, relative humidity RH20 ± 5% and temperature 24 months, every index and relatively having no significant change in 0 day.
Embodiment 8
The test of tranilast eye drop eye irritation
Be subjected to reagent thing: embodiment 2 prepared samples.
Animal: white rabbit, 2.0～2.5kg, male and female dual-purpose.
Test divides negative matched group and is tried the administration group, and the self administration of consubstantiality left and right sides relatively.The negative control group eye drip gives 0.9% sodium chloride injection, every 0.1ml/ time; Be subjected to examination group eye drip to give the tranilast eye drop, every 0.1ml/ time, carry out successive administration 14 days every day 4 times.
Eye is observed: during the administration, embrocated the animal eyeball surface with the phosphor strip of the moistening mistake of water for injection earlier in 1,2,4,24,48 and 72 hour after the preceding and last administration of administration every day, then eye is checked that the line number of going forward side by side sign indicating number is taken a picture.If do not see any irritation at 72 hours, test then can finish.As have the persistency damage, be necessary to prolong and observe the time limit.Wherein, used slit lamp observation, other point of observation all to use magnifier direct observation eye in 1 hour after the last administration.
The each inspection all write down the score value of eye reaction by the requirement of guideline.Except observing conjunctiva, cornea and iris, other viewed damages also should write down and report.
Be recorded in the different dosing time point according to relevant standards of grading, the tranilast eye drop is to the irritant reaction score value of tame rabbit cornea, iris and conjunctiva, and concrete data see Table 8-table 11:
The irritative response record of table 8. tranilast eye drop dosing eyes corneal
Table 9. tranilast eye drop dosing eyes is to the irritative response record of iris
Table 10. tranilast eye drop dosing eyes is to the irritative response record of conjunctiva
Table 11. tranilast eye drop dosing eyes is to eye secretions record
Annotate: the highest every group of mean scores of discharge of eye normal saline group is 1/3, and tranilast eye drop high average value is 2/3, belongs to nonirritant.
Related data from above-mentioned each index: the tranilast eye drop is evaluated as nonirritant to the eye irritation of rabbit.
Conclusion:
According to clinical using method, 3 rabbit are administered four times with tranilast eye drop eye drip respectively every day, and each dosage is 0.1ml, successive administration 14 days.Result of the test shows: do not finding all that the tranilast eye drop had irritative response to the rabbit eye in 24 hours, 48 hours, 72 hours after 1,2,4 hour and the drug withdrawal during the administration and after the last administration.Evaluation of result is a nonirritant.Result of the test shows that the continuous dosing eyes of tranilast eye drop can not cause the irritative response of eye.
Claims (8)
1. an eye drop that contains tranilast that is used for the treatment of anaphylaxis conjunctivitis is characterized in that the weight proportion of each component in the described tranilast eye drop is: tranilast 25, meglumine 100-300, citric acid 30-400, Nipagin ester 0.1-4, polyvinylpyrrolidone K
3010-200, water for injection 4000-5000.
2. tranilast eye drop as claimed in claim 1 is characterized in that the weight proportion of each component in the described tranilast eye drop is: tranilast 25, meglumine 150-250, citric acid 50-100, Nipagin ester 0.5-1.5, polyvinylpyrrolidone K
3030-60, water for injection 4000-5000.
3. tranilast eye drop as claimed in claim 1 or 2 is characterized in that described Nipagin ester is methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben or butoben.
4. method for preparing the tranilast eye drop, it is characterized in that: according to the weight proportion of each component in the described eye drop of claim 1, tranilast and meglumine add injection and blunge to dissolving, slowly add citric acid, regulate pH value to 6.5-9.0, add Nipagin ester and polyvinylpyrrolidone K again
30Solution stirs, and adds adding to the full amount of water for injection, and aseptic filtration is sub-packed in the eye drop.
5. the method for preparing the tranilast eye drop as claimed in claim 4 is characterized in that regulating pH value to 7.0-8.5.
6. the method for preparing the tranilast eye drop as claimed in claim 4 is characterized in that Nipagin ester is mixed with 0.1% aqueous solution, or the alcoholic solution of 1-6% being standby before the dissolving tranilast.
7. the method for preparing the tranilast eye drop as claimed in claim 4 is characterized in that before the dissolving tranilast, with polyvinylpyrrolidone K
30The aqueous solution that is mixed with 5-10% is standby.
8. the method for preparing the tranilast eye drop as claimed in claim 4 is characterized in that the aqueous solution that citric acid is mixed with 5-20% is standby before the dissolving tranilast.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100407884A CN100388915C (en) | 2006-06-01 | 2006-06-01 | Eye drop containing tranilast and its preparing process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100407884A CN100388915C (en) | 2006-06-01 | 2006-06-01 | Eye drop containing tranilast and its preparing process |
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| Publication Number | Publication Date |
|---|---|
| CN1857199A CN1857199A (en) | 2006-11-08 |
| CN100388915C true CN100388915C (en) | 2008-05-21 |
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|---|---|---|---|
| CNB2006100407884A Active CN100388915C (en) | 2006-06-01 | 2006-06-01 | Eye drop containing tranilast and its preparing process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7191515B2 (en) * | 2017-01-17 | 2022-12-19 | ロート製薬株式会社 | ophthalmic composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001122776A (en) * | 1999-10-26 | 2001-05-08 | Toa Yakuhin Kk | Pharmaceutical preparation including tranilast |
| JP2004238346A (en) * | 2003-02-07 | 2004-08-26 | Shiono Chemical Co Ltd | Stable aqueous solution preparation of tranilast |
| WO2005094811A1 (en) * | 2004-03-30 | 2005-10-13 | Rohto Pharmaceutical Co., Ltd. | Pharmaceutical product containing tranilast |
-
2006
- 2006-06-01 CN CNB2006100407884A patent/CN100388915C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001122776A (en) * | 1999-10-26 | 2001-05-08 | Toa Yakuhin Kk | Pharmaceutical preparation including tranilast |
| JP2004238346A (en) * | 2003-02-07 | 2004-08-26 | Shiono Chemical Co Ltd | Stable aqueous solution preparation of tranilast |
| WO2005094811A1 (en) * | 2004-03-30 | 2005-10-13 | Rohto Pharmaceutical Co., Ltd. | Pharmaceutical product containing tranilast |
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|---|---|
| CN1857199A (en) | 2006-11-08 |
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Address after: 210009 No. 50 Majia Street, Gulou District, Nanjing City, Jiangsu Province Patentee after: Pharmaceutical Co., Ltd. Address before: 210009 No. 50 Majia Street, Gulou District, Nanjing City, Jiangsu Province Patentee before: Pharmaceutical Co., Ltd., China Univ. of Pharmacy |
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