CN104586762A - Rebamipide-containing drug composition and preparation method thereof - Google Patents
Rebamipide-containing drug composition and preparation method thereof Download PDFInfo
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- CN104586762A CN104586762A CN201410147713.0A CN201410147713A CN104586762A CN 104586762 A CN104586762 A CN 104586762A CN 201410147713 A CN201410147713 A CN 201410147713A CN 104586762 A CN104586762 A CN 104586762A
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- rebamipide
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Abstract
The present invention provides a rebamipide-containing drug composition, which can be prepared through a simple method while the stable fine particle dispersion state of the rebamipide can be maintained and the fine particle can not be subjected to cementing. The aqueous rebamipide-containing drug suspension of the present invention is prepared by mixing poloxamer 407, a sodium salt compound and the rebamipide.
Description
Technical field:
The present invention relates to the pharmaceutical composition containing rebamipide, it is prepared by simple method and makes the rebamipide fine particle of dispersion keep steady statue; With and preparation method thereof.
Background of invention:
Rebamipide shows the effect of anti-inflammatory and ulcer in the gastrointestinal tract and is used as medicine.In addition, rebamipide has the effect increasing goblet cell density in cornea and conjunctiva, a kind of effect increasing mucus in eye, and increase the effect of tear, and it is known to treatment xerophthalmia, that is, the medicament (JP-A-9-301866) of dry eye syndrome.
But, rebamipide is not having solubility enough and steady in a long-term in eyes and mucosal tissue irritating little and physiological neutral pH value range that malfunction shortcoming is few, and therefore can not prepare the rebamipide-formulation of aqueous solution form, because rebamipide is acid compound.On the other hand, surfactant such as ionic surfactant and nonionic surfactant or solubilizing agent such as cyclodextrin derivative is likely adopted to prepare rebamipide aqueous solution.But when administration said preparation, this kind of surfactant and this kind of solubilizing agent may have biotic component in the mucosa that is dissolved in this solution and may hinder the activity of rebamipide, this kind ofly makes mucosa stabilisation and protect the effect of mucosa.
On the contrary, adopt the aqueous pharmaceutical suspensions of the rebamipide containing dispersion, the above-mentioned low solubility shortcoming about rebamipide will be overcome and therefore likely prepare a kind of rebamipide-formulation.But, rebamipide is normally with by making needle crystal of rebamipide (primary granule, particle mean size: short gauge length 0.1-0.5 μm, long gauge length 0.2-4 μm) powder form of its secondary granule of cementing formation (particle mean size: 10-50 μm) and preparation exists, and is therefore considered to be difficult to prepare rebamipide suspension by rebamipide fine particle.Therefore, under prior art, particulate is separated into comparably in order to make agglutinated rebamipide and secondary granule, namely cellulose derivative must be called in the mixture that the water-soluble polymer of suspending agent, surfactant etc. adds to containing rebamipide, and utilize special dispersion/levitation device such as high pressure homogenizer, colloid mill, turbine-type stirring device, high-speed revolution shearing agitating device and this mixture of ultrasonic generator strong stirring further.
In addition, even if likely by rebamipide with fine particle in aqueous, prior art also also has some problems; namely; along with the past of holding time, rebamipide fine particle will be cementing to form secondary granule again or to increase crystal grain again, and it is particulate that the particle of precipitation is not easy redispersion.
And in patent CN101528229B, it to mix with rebamipide with water miscible polyvinyl alcohol and overcomes previous technical problem, but is only limitted to the aqueous pharmaceutical suspensions that could realize producing desirable rebamipide with polyvinyl alcohol.
Under such Background prior art, it is desirable to research and develop a kind of aqueous pharmaceutical suspensions containing rebamipide to adopt simple method to be separated into particulate with just can enabling rebamipide stable and particulate is no longer cementing, and be not limited to the aqueous pharmaceutical suspensions that only just can obtain desirable rebamipide with polyvinyl alcohol.
Of the present invention open
(the problem to be solved in the present invention)
In order to overcome the problem of above-mentioned prior art, obtain the present invention.The invention provides a kind of aqueous pharmaceutical suspensions containing rebamipide, it is prepared by simple method and keeps the dispersed fine-particle state of rebamipide stable and particulate can not be made cementing.This is one object of the present invention.
(means of dealing with problems)
The present inventor has conducted extensive research to achieve the above object, then having been found that must mixed solution by be selected from aqueous solution that block copolymer (preferred poloxamer188) that polyoxypropylene ethylene glycol and oxirane formed joins containing rebamipide water soluble salt under specific dispersion or levitation device, then acidic aqueous solution is dripped as in above-mentioned mixed solution, thus the rebamipide fine particle be scattered in comparably in aqueous solution and gained suspension can store with stable suspended state and not have rebamipide fine particle cementing again.According to this new discovery and further improvement in addition, complete the present invention.
The invention provides pharmaceutical composition containing rebamipide as described below and preparation method thereof.
Containing rebamipide with comprise the water slurry that at least one is selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane are formed.
[1] water slurry, it also comprises sodium salt compound.
[1] water slurry or its sodium salt compound, wherein rebamipide is 0.1-30w/v%, and comprising at least one, to be selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed be 0.01-4w/v%.
[1], [4], any one water slurry in [5], it is ophthalmic preparation.
A preparation method for water slurry containing rebamipide, the method comprises:
(1) first step: the aqueous peracid solution preparing suitable solubility, and
(2) second step: rebamipide fine particle is made the aqueous solution containing rebamipide water soluble salt and adds at least one and be selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed,
(3) the 3rd steps: first step gained aqueous peracid solution is joined in second step gained solution, both are obtained by mixing the water slurry containing rebamipide.
(effect of the present invention)
According to aqueous pharmaceutical suspensions of the present invention, rebamipide comparably with fine-particle state dispersion and gained suspension can be stored with the state of stable dispersion, even if will rebamipide fine particle also can not be made during its long term storage cementing and make crystal grain increase again.Even if when rebamipide precipitates, also likely easily again obtain compact grained dispersity comparably with hand moving.
In addition, aqueous pharmaceutical suspensions of the present invention contains at least one and is selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed, and therefore need not adopt the dispersion/levitation device for strong stirring, and adopt common stirring just enough, namely only carry out mixing to make the rebamipide of cementing formation secondary granule disperse to become fine-particle state.Therefore, aqueous pharmaceutical suspensions of the present invention is by also having advantage in simple method formulated.
The detailed description of preferred implementation:
Aqueous pharmaceutical suspensions of the present invention contains rebamipide as active constituents of medicine.
Usually there is (particle mean size: 10-50 μm) with secondary particle state in the rebamipide active ingredient powder used in the present invention, about it is by rebamipide primary granule (acicular crystal, particle mean size: short gauge length 0.1-0.5 μm, long gauge length 0.2-4 μm) cementing formation.In aqueous pharmaceutical suspensions of the present invention, the existence of poloxamer188 enables rebamipide retain with the state of stably disperseing, and wherein rebamipide is broken up into particulate, and its particle mean size is 0.1-10 μm, is preferably 0.2-5 μm.
The rebamipide content that can suitably adjust in aqueous pharmaceutical suspensions of the present invention treats position, administering mode etc. to respond; Such as be preferably 0.1-30w/v%, be more preferably 0.3-10w/v%.
In addition, aqueous pharmaceutical suspensions of the present invention comprises poloxamer188 to be separated into fine-particle state with making above-mentioned rebamipide stable.
During use, the kind of the block copolymer that the mixing ratio comprising poloxamer188 at aqueous pharmaceutical suspensions of the present invention can be formed according to the mixing ratio of rebamipide or polyoxypropylene ethylene glycol and oxirane is come suitably to change, such as be preferably 0.01-4w/v%, be more preferably 0.1-2w/v%.
In order to by rebamipide evenly and be stably separated into fine-particle state, mixing ratio wherein between the block copolymer that formed of rebamipide and polyoxypropylene ethylene glycol and oxirane applies above-mentioned mixing ratio, and the 2-4000 by weight of mixing ratio in addition, is preferably the aqueous pharmaceutical suspensions of the present invention example preferably of 10-1000 (rebamipide for being 100 by weight) by weight.
In aqueous pharmaceutical suspensions of the present invention, when the block copolymerization beyond the region of objective existence that this suspension is formed except rebamipide and polyoxypropylene ethylene glycol and oxirane, when also comprising the metal salt compound in water soluble solution, can more effectively prevent the rebamipide of primary particle state cementing again.
Here, with regard to its pharmaceutically acceptable property, metal salt compound in water soluble solution is not limited, comprise such as sodium salt compound as sodium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium succinate, sodium tartrate, sodium hydroxide, sodium acetate, sodium carbonate and sodium citrate; Potassium salt compound is as potassium chloride, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, Potassium Suceinate, Soluble tartar., potassium hydroxide, potassium acetate, potassium carbonate and potassium citrate; Calcium salt compound is as calcium chloride, calcium hydroxide, calcium carbonate and calcium citrate; And magnesium salt compound is as magnesium chloride, magnesium hydroxide, magnesium carbonate and magnesium citrate.
Osmotic pressure for aqueous suspension preparation of the present invention does not limit, and it to be that physiology is upper acceptable.Such as, be used in the situation of ophthalmic preparation at aqueous suspension preparation of the present invention, institute adopts the osmotic pressure of preparation to be generally 150-600m0sm/kg, preferably 200-400m0sm/kg, is more preferably 245-365m0sm/kg.Above-mentioned metal salt compound and/or three salt compounds are utilized by methods known in the art; Or sugar, sugar alcohol, polyhydric alcohol etc., scalable osmotic pressure.
PH value for aqueous suspension preparation of the present invention does not limit, as long as it is pharmaceutically acceptable, and comprises such as 3.0-9.0, is preferably 5.0-7.0.PH value regulator such as citric acid, phosphoric acid, acetic acid and salt thereof, hydrochloric acid and sodium hydroxide scalable pH value is utilized by methods known in the art.
Except mentioned component, aqueous suspension preparation of the present invention also can comprise other active pharmaceutical ingredient, antiseptic, surfactant, flavoring agent, coloring agent, chelating agen, buffer agent, thickening agent etc., as long as it does not hinder effect of the present invention.
In aqueous suspension preparation of the present invention, acceptable exemplary preservatives comprises parabens such as methyl parahydroxybenzoate, ethylparaben, butyl p-hydroxybenzoate; Quaternary ammonium salt such as benzalkonium chloride and benzethonium chloride; Guanidine bactericide is chlorhexidine gluconate such as; EDETATE SODIUM etc.
Aqueous suspension preparation of the present invention is more suitable for pismucosal formulations such as ophthalmic preparation, nasal mist and inhalant preparation, and it is the atomization preparation for lung administration utilizing inhalation sprayer unit to spray, and is also more suitable for oral formulations, injection etc.More preferably aqueous suspension preparation of the present invention is used as ophthalmic preparation.
By the rebamipide of scheduled volume, poloxamer188 and other optional composition are mixed can prepare aqueous suspension preparation of the present invention with pharmaceutically acceptable waters (preferred pure water or injectable water).As the preferred preparation method of aqueous suspension preparation of the present invention, the following methods comprising the first step and second step is exemplified as follows:
(1) first step: the aqueous peracid solution preparing suitable solubility, and
(2) second step: rebamipide fine particle is made the aqueous solution containing rebamipide water soluble salt and adds at least one and be selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed,
(3) the 3rd steps: first step gained aqueous peracid solution is joined in second step gained solution, both are obtained by mixing the water slurry containing rebamipide.
The composition except rebamipide and polyvinyl alcohol can be added in the first step or second step.In second step and the 3rd step, likely (special strong stirring need not be adopted) under the weak stirring of general propeller stirrer and just rebamipide is separated into fine-particle state comparably only using, because wherein form the powdery rebamipide in cementing status of secondary granule, because the effect of poloxamer188 is very easily separated into fine-particle state.
Embodiment
Hereinafter, illustrate the present invention further by following examples, but should not be interpreted as the present invention and be only limitted to this.
Embodiment 1: ophthalmic preparation
| Rebamipide | 1.0g |
| Poloxamer188 | 0.05g |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
First rebamipide is dissolved in alkaline aqueous solution, adds poloxamer188 afterwards and aseptic process; Sodium citrate, potassium chloride, hydrochloric acid and pure water are made acidic aqueous solution and aseptic process; Then under magnetic stirring acidic aqueous solution is joined in alkaline aqueous solution, after stirring, obtain aqueous pharmaceutical suspensions.This aqueous pharmaceutical suspensions is sterilely dispensed into 5-15mL and has only prepared ophthalmic preparation in nonrecoverable plastic containers.
| Rebamipide | 1.0g |
| Poloxamer188 | 0.05g |
| Benzalkonium bromide solution (10w/w%) | 0.1mL |
| Sodium citrate | 0.15g |
| Potassium chloride | 0.2g |
| Sodium chloride | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount |
| Total amount | 100mL |
First rebamipide is dissolved in alkaline aqueous solution, adds poloxamer188 afterwards and aseptic process; Sodium citrate, benzalkonium bromide solution, potassium chloride, hydrochloric acid and pure water are made acidic aqueous solution and aseptic process; Then under magnetic stirring acidic aqueous solution is joined in alkaline aqueous solution, after stirring, obtain aqueous pharmaceutical suspensions.This aqueous pharmaceutical suspensions is sterilely dispensed in 5-15mL plastic containers and has prepared ophthalmic preparation.
Embodiment 3: inhalant preparation
First rebamipide is dissolved in alkaline aqueous solution, adds poloxamer188 afterwards and aseptic process; Sodium citrate, chlorhexidine gluconate, potassium chloride, hydrochloric acid and pure water are made acidic aqueous solution and aseptic process; Then under magnetic stirring acidic aqueous solution is joined in alkaline aqueous solution, after stirring, obtain aqueous pharmaceutical suspensions.What this aqueous pharmaceutical suspensions is sterilely dispensed into 0.3-5mL only sucks neat preparation for preparing in nonrecoverable plastic containers.
Test 1: long-term stable experiment
The ophthalmic preparation of embodiment 1 and 2 obtained is above stored 36 months under the condition of 25 DEG C/60%RH, and measures the particle mean size of the survival rate of rebamipide, osmotic pressure, pH and rebamipide in proper order.The granularity of rebamipide utilizes Laser Diffraction meter (ShimadzuSALD-3000J) to measure.
As a result, all Measuring Time points (before namely storing and after storing 12,24 and 36 months), whole results of the survival rate of rebamipide, osmotic pressure and particle mean size all meet standard-required, and (survival rate of rebamipide is 95% or higher, osmotic pressure is 255-320m0m, pH is 5-7, and particle mean size is 0.5-5 μm).Therefore, under long-term stable experiment, confirmed that the rebamipide of fine-particle state can be stored and not decomposed for stable rebamipide fine particle suspension or cementing.
Test 2: measure particle mean size
The suspension (embodiment 1 and comparing embodiment 1) be shown in Table 1 is prepared according to following steps.First rebamipide is dissolved in alkaline aqueous solution, adds poloxamer188 afterwards and aseptic process; Sodium citrate, potassium chloride, hydrochloric acid and pure water are made acidic aqueous solution and aseptic process; Then under magnetic stirring acidic aqueous solution is joined in alkaline aqueous solution, with magnetic stirring apparatus, this mixture is at room temperature stirred 1 hour (conventional general mixer 30mm, about 500rpm) and prepare about its suspension.Laser Diffraction meter (ShimadzuSALD-3000J) is utilized to measure rebamipide granularity in obtained suspension.
Table 1
Formulation ingredients embodiment 1 comparing embodiment 1
| Formulation ingredients | Embodiment 1 | Comparing embodiment 1 |
| Rebamipide | 1.0g | 1.0g |
| Poloxamer188 | 0.05g | - |
| Sodium citrate | 0.15g | 0.15g |
| Potassium chloride | 0.2g | 0.2g |
| Sodium chloride | 0.7g | 0.7g |
| Hydrochloric acid | (pH value is adjusted to 6) in right amount | (pH value is adjusted to 6) in right amount |
| Sodium hydroxide | (pH value is adjusted to 6) in right amount | (pH value is adjusted to 6) in right amount |
| Pure water | In right amount | In right amount |
| Total amount | 100mL | 100mL |
Result: be 1 μm or less with the fineness of dispersion of rebamipide during magnetic stirring apparatus under poloxamer188 existent condition in embodiment 1, the rebamipide then in suspension is separated into fine-particle state.In comparing embodiment 1, be 30 μm or larger not having under poloxamer188 existent condition with the fineness of dispersion of rebamipide during magnetic stirrer, the rebamipide then in suspension is cementing status and forms its secondary granule.
According to the above result, it is evident that, do not use special dispersion/levitation device to carry out strong stirring when have employed poloxamer188, rebamipide just dispersibles as fine-particle state.
Claims (8)
1. one kind contains the pharmaceutical composition that particle mean size is the rebamipide fine particle of 0.2-5 μm, it is characterized by and comprise the mixture that at least one is selected from the compound of the block copolymer that polyoxypropylene ethylene glycol and oxirane are formed, aqueous peracid solution and the aqueous solution containing rebamipide water soluble salt, this mixture is waterborne suspension.
2. waterborne suspension according to claim 1, wherein said to be selected from the block copolymer weight range that polyoxypropylene ethylene glycol and oxirane formed be 500-50000.
3. waterborne suspension according to claim 1, wherein said be selected from the block copolymer weight range that polyoxypropylene ethylene glycol and oxirane formed and be preferably 2090-17400.
4. waterborne suspension according to claim 1, wherein said to be selected from the block copolymer weight range that polyoxypropylene ethylene glycol and oxirane formed be 9840-14600 (poloxamer188).
5. water slurry according to claim 1, wherein said rebamipide is 0.1-30% (w/v) and to be selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed be 0.01-4% (w/v).
6. the water slurry described in claim 1,4, it is a kind of ophthalmic preparation.
7. water slurry according to claim 5, it is a kind of ophthalmic preparation.
8. prepare a new method for the water slurry containing rebamipide, the method comprises:
(1) first step: the aqueous peracid solution preparing suitable solubility, and
(2) second step: rebamipide fine particle is made the aqueous solution containing rebamipide water soluble salt and adds at least one and be selected from the block copolymer that polyoxypropylene ethylene glycol and oxirane formed,
(3) the 3rd steps: first step gained aqueous peracid solution is joined in second step gained solution, both are obtained by mixing the water slurry containing rebamipide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108136036A (en) * | 2015-10-01 | 2018-06-08 | 三进制药株式会社 | Novel ophthalmic composition comprising Rebamipide and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101056636A (en) * | 2004-11-15 | 2007-10-17 | 大塚制药株式会社 | Aqueous ophthalmic suspension of crystalline rebamipide |
| CN101528229A (en) * | 2006-10-26 | 2009-09-09 | 大塚制药株式会社 | Aqueous pharmaceutical suspensions containing rebamipide and manufacturing process thereof |
| CN103429224A (en) * | 2011-03-24 | 2013-12-04 | 大塚制药株式会社 | Pharmaceutical composition for treating disease in oral cavity comprising rebamipide |
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2014
- 2014-04-11 CN CN201410147713.0A patent/CN104586762A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101056636A (en) * | 2004-11-15 | 2007-10-17 | 大塚制药株式会社 | Aqueous ophthalmic suspension of crystalline rebamipide |
| CN101528229A (en) * | 2006-10-26 | 2009-09-09 | 大塚制药株式会社 | Aqueous pharmaceutical suspensions containing rebamipide and manufacturing process thereof |
| CN103429224A (en) * | 2011-03-24 | 2013-12-04 | 大塚制药株式会社 | Pharmaceutical composition for treating disease in oral cavity comprising rebamipide |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108136036A (en) * | 2015-10-01 | 2018-06-08 | 三进制药株式会社 | Novel ophthalmic composition comprising Rebamipide and preparation method thereof |
| US10918725B2 (en) | 2015-10-01 | 2021-02-16 | Samjin Pharmaceutical Co., Ltd. | Ophthalmic composition comprising rebamipide and method for preparing the same |
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