CN1049358C - Carboxybinil polymer which shows newtonian viscosity - Google Patents
Carboxybinil polymer which shows newtonian viscosity Download PDFInfo
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- CN1049358C CN1049358C CN93100155A CN93100155A CN1049358C CN 1049358 C CN1049358 C CN 1049358C CN 93100155 A CN93100155 A CN 93100155A CN 93100155 A CN93100155 A CN 93100155A CN 1049358 C CN1049358 C CN 1049358C
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- eye drop
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Abstract
The present invention discloses a vinyl carboxylate polymer which shows newtonian viscosity, a preparing method thereof and eye drops mixing with the polymers. An ultrasonic irradiation device is used for shearing a water solution of vinyl carboxylate polymers indicating non-Newtonian viscosity to obtain a vinyl carboxylate polymer which indicates the newtonian viscosity, has a low yield point and has an approximately linear relation between shearing stress and a shearing speed. The polymer is mixed with the eye drops, which can obtain eye drops with low viscosity of below 1000 cp and an excellent promoting effect of drug absorption.
Description
The present invention relates to a kind of eye drop and manufacture method thereof that contains carboxylic ethylene polymer, the carboxylic ethylene polymer in the described eye drop shows newtonian viscous.
Carboxylic ethylene polymer is for based on acrylic acid, to this again with various crosslinked water solubility copolymers of cross-linking agent such as a spot of polyene third sucrose.Its molecular weight ranges from 1,000,000 to 3,000,000, its range of viscosities from as 1% low viscosity aqueous solution, 3000-7000cp (the viscosity specification of the power of U.S. officina side-ボ ス-910), to showing as 0.2% high viscosity aqueous solution, 1500-50000cp (the viscosity specification of the outer pharmaceuticals composition specification of Pharmacopeia of Japan), various carboxylic ethylene polymers are used to make up, each field of medicine, chemical industry etc.
These carboxylic ethylene polymers are characterised in that, have shown the non-Newtonian viscosity with high yield strength.That is, even if addition seldom also can obtain very high viscosity.Here, when yield point (intensity) refers to the viscosity of rotary viscosity measuring solution, the shear stress values when shear rate is zero.
As the example that carboxylic ethylene polymer is applied to field of ophthalmology, known to have with slow release medicine be that purpose is mixed in eye drop (spy opens clear 54-67021, and the spy opens clear 54-110312, and the spy opens flat 2-503201).Carboxylic ethylene polymer is made aqueous solution, and then gel has high viscosity.Can think that because high viscosity, gel can be stranded on the cornea for a long time; This gelinite again since progressively a spot of disintegration medicine is slowly released.Therefore, above-mentioned prior art also is limited to its viscosity more than the 1000cp, and can think, this high viscosity is necessary to the slow release of medicine.
As mentioned above, prior art is characterised in that, effectively uses the characteristic that also can obtain full-bodied, as to have non-Newtonian viscosity carboxylic ethylene polymer with addition seldom.
With show non-Newtonian viscosity, existing carboxylic ethylene polymer is applied to eye drop, its advantage is for obtaining the effect of slow release drug effect.But its shortcoming is, viscosity is too high, and eye drop is increased because of its viscosity, then can produce foreign body sensation, so its viscosity is preferably low as far as possible.Special when viscosity when 10000cp is above, medicament becomes an eye ointment shape, much less makes quantitative eye drop by eye-drop liquid bottle, the own eye drop of patient also becomes difficulty, need be by the doctor to the coating of doing in the conjunctival sac.
In addition, more than manufacturing 10000cp, during full-bodied eye drop,, also produced many difficulties in the manufacturing because of containing in the solution that bubble is difficult to remove and can't filtration sterilization etc.
Therefore, the convenience of considering use and the problem of making, the viscosity of eye drop is being ideal less than 1000cp.
As one of this way to solve the problem, can consider significantly to lower the amount of the carboxylic ethylene polymer of mixing, make its viscosity less than 1000cp.The concentration of known carboxylic ethylene polymer and the relation of viscosity are shown in Fig. 1.Yet although the method has solved the problem of viscosity, from Fig. 1 clear expression, carboxylic ethylene polymer can only be with extremely low concentration fusion, and it is mixed effect and also disappears.
In addition, although in known technology, disclose, people's promotion assimilation effect of a kind of medicine as the carboxylic ethylene polymer effect of exploitation that still waits in expectation, and wish that the new Research on effect of relevant carboxylic ethylene polymer carries out.Yet its Expected Results can't obtain when known this polymer was mixed with extremely low use level, and the exploitation of the carboxylic ethylene polymer of newtype is paid attention to and studied.
For this reason, even just reducing the carboxylic ethylene polymer that blended amount also can obtain low viscous eye drop not significantly, present inventors done painstakingly research.The result, successfully found the carboxylic ethylene polymer that has little yield point (intensity), demonstrate newtonian viscous, and find: the carboxylic ethylene polymer that demonstrates this newtonian viscous by use, can make when keeping to bring into play the concentration of fiting effect, have low viscous eye drop less than 1000cp.
One of purpose of the present invention is, a kind of eye drop substrate that contains carboxylic ethylene polymer is provided, and described eye drop comprises medicated disinfecting Purified Water, pH regulator agent etc., and described carboxylic ethylene polymer shows newtonian viscous.
At first, when present inventors do research in the manufacture method of the carboxylic ethylene polymer that just shows newtonian viscous, find, the carboxylic ethylene polymer aqueous solution that shows non-Newtonian viscosity is made shear treatment, can obtain showing the carboxylic ethylene polymer of newtonian viscous by the ultrasonic irradiation device.
Secondly, the carboxylic ethylene polymer fusion of the demonstration newtonian viscous of gained like this in eye drop, is investigated with regard to its drug absorption, see that this eye drop has the effect of excellent promotion drug absorption.
Another object of the present invention is to provide a kind of manufacture method that contains the eye drop of the carboxylic ethylene polymer (following note is made N-CVP) that shows newtonian viscous, compare with the eye drop manufacture method of known fusion carboxylic ethylene polymer, eye drop manufacture method of the present invention is simple, easy.
N-CVP used among the present invention refers to, with allyl sucrose, the poly-chain base polyethers of polypentaerythritol etc., the crosslinked acrylic copolymer of cross-linking agent of the difunctionality cross-linking agent of diethanol and divinylbenzene etc., diene hydrophobic polymer etc., when with rotary viscosity design determining viscosity, have little yield point, be preferably 0.5dyn/cm
2Following little yield point (intensity), it has relation slightly linearly between shear stress and shear rate.
The feature of N-CVP of the present invention promptly is to have little yield point, and linearly relation roughly between shear stress and shear rate though there is not direct relation on molecular weight, as a reference, also can be extrapolated its molecular weight from the limiting viscosity value.The scope of the molecular weight of N-CVP of the present invention can extrapolate into the carboxylic ethylene polymer of known non newtonian type as raw material about 1/5th to about scope of 1/50th, promptly about 20,000 to about 500,000.
The eye drop substrate of fusion N-CVP can be applicable to antibacterial, therapeutic agent for glaucoma, anti-cataract agent, anti-inflammatory agent, antiallergic medicament, and nearly all fields such as agent are used in diagnosis.In addition, this eye drop is not subjected to the restriction of medicine yet, and is the same with the carboxylic ethylene polymer of known demonstration non-Newtonian viscosity, can be widely used in the medicine that uses in the field of ophthalmology.
Compound method as N-CVP of the present invention, can enumerate: use the ultrasonic irradiation device, as the high pressure homogenizer of マ Application ト Application go-リ Application and micro fluidizer (マ ィ Network ロ Off Le ィ ダ ィ ザ-) etc. or the machine the homogenizer with shearing force, in aqueous solution, the carboxylic ethylene polymer of processes and displays non-Newtonian viscosity becomes the polymer of newtonian viscous with it.
The carboxylic ethylene polymer of used demonstration newtonian viscous also can be purchased from グ Star De リ Star チ chemical company and Wako Pure Chemical Industries, Ltd., and its commodity are called カ-ボ ボ-Le 910,934,934P, 940,941,976; Ha ィ PVC ス ヮ コ-130,104,105,204,304 etc.
Detailed will illustrate in the mensuration item of viscosity, show its big yield point as feature with respect to the carboxylic ethylene polymer that shows non-Newtonian viscosity, and N-CVP of the present invention then gets very little yield strength value, and the viscosity of its solution significantly reduces.
With this N-CVP preparation eye drop, the bubble in the solution is few, can filtration sterilization, and this is impossible fully with existing carboxylic ethylene polymer, thereby, to compare with existing fusion carboxylic ethylene polymer eye drop, the manufacturing of eye drop of the present invention is very easy to.
In addition, the eye drop that forms with fusion N-CVP of the present invention, because of its viscosity is low, patient self is eye drip easily also, and available eye drops bottle is made quantitative eye drip.
Then, effect for investigation N-CVP, the preparation of the present invention of N-CVP will have been used, from preparation, remove the effect of N-CVP in contrast, the preparation of the present invention of N-CVP will have been used, the medicament of removing N-CVP in contrast from preparation is given the rabbit eye drip respectively, relatively its two drug absorption situation.Detailed data are represented in the absorption experiment item, yet the apparent in view ground of the tissue concentration area under curve of preparation of the present invention and control formulation is big, also can understand the absorption facilitation of N-CVP tool excellence of the present invention thus.
That is, N-CVP not only can provide the interior concentration of tissue of medicine owing to promoted the absorption of medicine, and the medicine that improves the absorbability difference is absorbed situation, also has the effect that reduces medicine dosage and medication number of times.
As the compound method of eye drop of the present invention, use N-CVP to prepare by usual method.For example, medicine and N-CVP are added in the sterile purified water, last, use the pH regulator agent, as, sodium hydroxide and dilute hydrochloric acid are regulated pH, thereby are obtained preparation of the present invention.
During preparation, on demand whether, also can add osmotic pressure regulator as sodium chloride, potassium chloride, glycerol etc.; Buffer agent as sodium phosphate, potassium phosphate; Stabilizing agent as sodium ethylene diamine tetracetate (エ デ ト acid Na ト リ ゥ system) etc.; Antiseptic as ethylparaben, butyl p-hydroxybenzoate, sorbic acid etc.
In addition, make shear treatment, make after the N-CVP at the aqueous solution of the carboxylic ethylene polymer that will show non-Newtonian viscosity, the N-CVP that also can not emanate, and this is added various additives.
The pH value of preparation of the present invention in the scope of using as common eye drop, does not have restriction especially, but with the 3-8 ideal.Again, reach below the 1000cp,, be more preferably 0.1-2% though its doping level is preferably 0.1-5% also because of pH and the different more or less differences of manufacture method as long as the amount of the N-CVP that uses in preparation of the present invention is mixed to the viscosity of eye drop it.
Figure 1 shows that and the concentration of the pure pharmaceutical worker's industry of light various carboxylic ethylene polymers that company sells and the relation of viscosity (being reprinted from and the pure pharmaceutical worker's industry of light handbook).Wherein the longitudinal axis represent viscosity (unit: cp), transverse axis indicated concentration (unit: %).
Figure 2 shows that with rotary viscosity and record the shear stress of 0.2% aqueous solution (pH7.0) of Ha ィ PVC ス ヮ コ-105 and the result of shear rate.
The longitudinal axis is represented shear stress (unit: dyn/cm
2), transverse axis is represented shear rate (l/s).
Figure 3 shows that the use rotating cylinder viscometer, measure the shear stress of 0.2% aqueous solution (pH7.0) of the N-CVP of gained in the formulation example 1 and the result of shear rate.
The longitudinal axis is represented shear stress (unit: dyn/cm
2), transverse axis is represented shear rate (l/s).
Fig. 4 is for to drip each time behind lagophthalmos with preparation of the present invention and control formulation, the luciferin concentration in the rabbit aqueous humor.The longitudinal axis is represented the luciferin concentration (ng/ml) in the aqueous humor, transverse axis express time (hr)-■-expression preparation measured result, the measurement result of--expression control formulation.
Below, in conjunction with the accompanying drawings with the manufacturing example of the compound method of N-CVP and eye drop as embodiment.
Embodiment
1.N-CVP compound method
Formulation example 1
The Ha ィ PVC ス ヮ コ-105 (1.0g) that produces with the pure pharmaceutical worker of light industry (strain) company is added entry (100ml), make aqueous solution after, with プ Le-Block type ultrasonic generator (frequency of oscillation: 20KHz) make 9 minutes ultrasonic Treatment.
Then, this solution of lyophilizing, (quantitatively) obtains N-CVP.
By with above-mentioned same method, use commercially available carboxylic ethylene polymer, by changing the ultrasonic irradiation time, obtain possessing the N-CVP of each yield point.
Formulation example 2
After the カ-ボ ボ-リ 976 (1.0g) of Block Star De リ Star チ chemical company added entry (100ml) and make aqueous solution, with homogenizer (rotating speed: 10000rpm) stirred 30 minutes.
Secondly, this solution of lyophilizing, (quantitatively) obtains N-CVP.
With with above-mentioned same method, use commercially available carboxylic ethylene polymer, by changing mixing time, the N-CVP of each yield point of tool.
2. the mensuration of viscosity
For the character of N-CVP of explanation formulation example 1, regulate 0.2% aqueous solution to pH7.0, under 25 ℃, make the mensuration of viscosity with the Rotovisco CV20 type viscometer (HAAKE company product) of rotating cylinder viscometer.In order to compare, the Ha ィ PVC ス ヮ コ-105 that the pure pharmaceutical worker's industry of use and light (strain) company produces tests under similarity condition as existing representational carboxylic ethylene polymer.
As shown in Figure 2, in the test of Ha ィ PVC ス ヮ コ-105, show that it has about 52dyn/cm
2High-yield strength (shear rate is 0 o'clock a shear stress values), and its non-Newtonian viscosity has been represented the curve linear relationship between shear stress and the shear rate.
On the other hand, as shown in Figure 3, in the test of the N-CVP of formulation example 1, can see that its yield strength is 0.02dyn/cm
2Less value obtains line relationship between its shear stress and shear rate, illustrate that thus N-CVP is a newtonian viscous.Viscosity number when shear rate is 1.92 (l/s) again is 6cp in the test of the N-CVP of formulation example 1, compares low significantly with Ha ィ PVC ス ヮ コ-105 4700cp that is surveyed.
So, become newtonian viscous, can make high-yield strength reduction, and can significantly reduce solution viscosity as the characteristic of non newtonian type carboxylic ethylene polymer by carboxylic ethylene polymer with non-Newtonian viscosity.
3. the mensuration of molecular weight
Between high molecular limiting viscosity ([η]) and molecular weight (M), exist as shown in the formula the relation shown in 1.
[formula 1] [η])=Km
α
(in the formula, K and α are empirical)
So available following formula is tried to achieve the molecular weight of N-CVP.
At first, the N-CVP of formulation example 1 is dissolved in 0.9% sodium-chloride water solution, making its concentration is 0.08% (w/v).
Secondly, record the viscosity (η of this solution with ゥ ベ ロ-デ type viscometer
1).Equally also record viscosity (η as 0.9% sodium-chloride water solution of solvent
2).By these values, try to achieve specific viscosity η
3=(η
1/ η
2Then, remove in specific viscosity with solute concentration)-1, and the reduced viscosity of income value for relatively, is also done same experiment to Ha ィ PVC ス ヮ コ-105 as limiting viscosity, tries to achieve limiting viscosity.
From the above-mentioned limiting viscosity of trying to achieve and constant (K=9.00 * 10 of trying to achieve with glucosan
-4, α=0.50, the molecular weight that polymer chemistry 13,20 (1956) calculates gained is: N-CVP11 11,000, and Ha ィ PVC ス ヮ コ-105 is 1,600,000.
The result can understand thus, is about 1/14th of Ha ィ PVC ス ヮ コ-105 by formulation example 1 by the molecular weight of the N-CVP of shear treatment Ha ィ PVC ス ヮ コ-105 gained.
4. the Production Example of eye drop
Production Example 1
Prescription 1-1, in every 100ml,
カ-ボ ボ-Le 976 (グ Star De リ Star チ chemical company) 1.3g
Uranine 0.01g
Sodium chloride 0.9g
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Manufacture method
After カ-ボ ボ-Le 976 is dissolved in sterile purified water, regulate pH to 4.3 with sodium hydroxide.Then, (frequency of oscillation=20KHz) is made 5 minutes ultrasonic Treatment, makes newtonian viscous thus to use プ Le-プ type ultrasonic irradiation device.At last, add uranine and sodium chloride preparaton.Under surveying 25 ℃ with Rotovisco CV20 type viscometer (HAAKE company product), shear rate is that the viscosity number under the condition of 1.92 (l/s) is 260cp.The viscosity of preparation shown below all records with this condition.
Same with Production Example 1, the eye drop of following prescription.
Among the every 100ml of prescription 1-2 (viscosity 20cp)
カ-ボ ボ-Le 976 (グ Star De リ Star チ chemical company)
Uranine
Sodium chloride 0.9g
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Among the every 100ml of prescription 1-3 (viscosity 400cp)
カ-ボ ボ-Le 976 (グ Star De リ Star チ chemical company) 2.0g
Uranine 0.01g
Sodium chloride 0.9g
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Production Example 2
Among the every 100ml of prescription 2-1 (viscosity 500cp)
Ha ィ PVC ス ヮ コ-105 (with the pure pharmaceutical worker's industry of light (strain)) 1.5g
Phosphorus carboxylic betamethasone (phosphoric acid ベ メ ゾ Application) 0.1g
Sodium chloride 0.9g
To hydroxy-methylbenzene acetoacetic ester 0.008g
To hydroxy-methylbenzene acid butyl ester 0.004g
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Manufacture method
After being dissolved in Ha ィ PVC ス ヮ コ-105 in the sterile purified water, make newton-type viscosity with homogenizer (rotating speed: 10000rpm, 10 minutes).This solution is added Betamethasone phosphate (phosphoric acid ベ メ ゾ Application), and sodium chloride to the hydroxy-methylbenzene acetoacetic ester, behind the hydroxy-methylbenzene acid butyl ester, adds sodium hydroxide, regulates pH to 6.0.
Production Example 3
Among the every 100ml of prescription 3-1 (viscosity 15cp)
N-CVP
Pyrenyl oxine (ピ レ ノ ギ シ Application)
Sodium chloride 0.9g
To hydroxy-methylbenzene acetoacetic ester 0.008g
To hydroxy-methylbenzene acid butyl ester 0.004g
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Manufacture method
To be dissolved in the sterile purified water by gained N-CVP in formulation example 1, behind adding pyrenyl oxine (ピ レ ノ キ シ Application), sodium chloride, ethylparaben, the butyl p-hydroxybenzoate, the chlorination sodium oxide is regulated pH to 6.0.
With the method same, can make the eye drop of following prescription with Production Example 3.
Among the every 100ml of prescription 3-2 (viscosity 5cp)
N-CVP 0.2g
Hydrochloric acid comospore alkali 1.0g
Sodium chloride 0.6g
Sorbic acid 0.1g
Dibastic sodium phosphate is an amount of
Sodium hydroxide is an amount of
Sterile purified water is an amount of
Absorption experiment
For illustrating the effect of N-CVP of the present invention, with the drug absorption experiment of rabbit effect eye drip.
(1 group 5) were after 1,2,3,4,6 and 8 hour, with the luciferin concentration in the fluorophotometer survey rabbit aqueous humor after the prescription 1-1 eye drop of example formulations of the present invention dripped people rabbit ophthalmic.In contrast, removing carboxylic ethylene polymer from the eye drop of Production Example 1 opposes as a rule.
In each time, the luciferin concentration in the aqueous humor is shown in Fig. 4.Be shown in table 1 from these tissue concentration areas under a curve (AUC) of trying to achieve again.
Table 1
AUC(mg·hr/ml)
Preparation of the present invention (prescription 1-1) 282.9 ± 47.6
Control formulation 54.4 ± 5.2
As from Fig. 4 and table 1 obvious, the control formulation that is not contained N-CVP by the absorptance of the medicine of fusion N-CVP wants superior more than 5 times.
To show with the result, N-CVP of the present invention has the effect of excellent promotion drug absorption.
Effect of the present invention namely is, by using according to the present invention prepared N-CVP, and can So that the eye drops that viscosity is low, drug absorption is good to be provided.
Claims (7)
1. an eye drop that contains medicine, sterile purified water, pH regulator agent and carboxylic ethylene polymer is characterized in that, described carboxylic ethylene polymer shows newtonian viscous.
2. eye drop as claimed in claim 1 is characterized in that, wherein, the content of the carboxylic ethylene polymer of described demonstration newtonian viscous is 0.1-5% (w/v).
3. eye drop as claimed in claim 1 is characterized in that, described eye drop viscosity is less than 1000cp.
4. the manufacture method of an eye drop as claimed in claim 1, described method ties up in the aqueous solvent, the carboxylic ethylene polymer that shows non-Newtonian viscosity is done after the shear treatment, the carboxylic ethylene polymer and the medicine of the demonstration newtonian viscous of described processing are added in the sterile purified water, regulate with the pH regulator agent, preparation obtains described eye drop.
5. the manufacture method of eye drop as claimed in claim 4 is characterized in that, the described shear treatment system that the carboxylic ethylene polymer that shows non-Newtonian viscosity is done carries out with the ultrasonic irradiation device.
6. the manufacture method of eye drop as claimed in claim 4 is characterized in that, the described shear treatment system that the carboxylic ethylene polymer that shows non-Newtonian viscosity is done carries out with the high pressure homogenizer.
7. the manufacture method of eye drop as claimed in claim 4 is characterized in that, the described shear treatment system that the carboxylic ethylene polymer that shows non-Newtonian viscosity is done carries out with homogenizer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93100155A CN1049358C (en) | 1993-01-01 | 1993-01-01 | Carboxybinil polymer which shows newtonian viscosity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93100155A CN1049358C (en) | 1993-01-01 | 1993-01-01 | Carboxybinil polymer which shows newtonian viscosity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1089624A CN1089624A (en) | 1994-07-20 |
| CN1049358C true CN1049358C (en) | 2000-02-16 |
Family
ID=4982840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100155A Expired - Fee Related CN1049358C (en) | 1993-01-01 | 1993-01-01 | Carboxybinil polymer which shows newtonian viscosity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1049358C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2013084A (en) * | 1978-01-25 | 1979-08-08 | Alcon Lab Inc | Ophthalmic compositions |
| JPS60235815A (en) * | 1984-05-08 | 1985-11-22 | Sansui Kk | Copolymer having thickening effect |
-
1993
- 1993-01-01 CN CN93100155A patent/CN1049358C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2013084A (en) * | 1978-01-25 | 1979-08-08 | Alcon Lab Inc | Ophthalmic compositions |
| JPS60235815A (en) * | 1984-05-08 | 1985-11-22 | Sansui Kk | Copolymer having thickening effect |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1089624A (en) | 1994-07-20 |
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