CN101057839A - Tanshinone solid dispersion and its application - Google Patents
Tanshinone solid dispersion and its application Download PDFInfo
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- CN101057839A CN101057839A CN 200610021953 CN200610021953A CN101057839A CN 101057839 A CN101057839 A CN 101057839A CN 200610021953 CN200610021953 CN 200610021953 CN 200610021953 A CN200610021953 A CN 200610021953A CN 101057839 A CN101057839 A CN 101057839A
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Abstract
The invention relates to the solid dispersion of tanshinone monomer compounds and the use thereof, which comprises tanshinone monomer compound and water-soluble carrying agent by a ratio of 5-50% : 95-50%. The solid dispersion can be prepared into tablets, capsules, granules, oral liquids, creams, injections, freeze-dried powders for injection, sprays, externally used plasters or lotions.
Description
Technical field the present invention relates to medicine and uses thereof.Solid dispersion of TANSHINONES monomeric compound and uses thereof particularly.
The background technology Radix Salviae Miltiorrhizae is the dry root and rhizome of labiate Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bge.).TANSHINONES is a fat-soluble effective ingredient wherein, mainly is the chemical compound of some diterpene quinones, as Tanshinone I I A, II B, cryptotanshinone, miltirone etc.Clinical research shows that its curative effect mainly shows four following aspects: aspect cardiovascular, modern pharmacology shows, when fat soluble ingredient of red sage root acts on cardiovascular system, can coronary artery dilator, and the function that coronary flow is increased; Aspect anti-inflammation, TANSHINONES to gram positive bacteria particularly staphylococcus aureus stronger inhibitory action is arranged, golden Portugal bacterium in the treatment burn is infected and is promoting that effect is remarkable aspect the wound healing; Aspect digestive system, Radix Salviae Miltiorrhizae has the certain protection effect to the liver ischemia reperfusion injury; At anti-tumor aspect,, experiment showed, that more and more TANSHINONES has cytotoxicity to kinds of tumor cells along with the development of Celluar and Molecular Biology.The cell of acute promyelocytic leukemia (APL) patient's MR2 cell strain there is the effect of the differentiation of inducing as Tanshinone I I A.
Tanshinone compound is the non-water-soluble composition in the plant Radix Salviae Miltiorrhizae.Hydrophilic/hydrophobic index as Tanshinone I I A is 79/401=0.1971, and the hydrophilic/hydrophobic index of Tanshinone I is 80/377=0.2122.The dissolubility of this compounds in water both depended on the hydrophilic/hydrophobic index, the three dimensional structure that also depends on them, for being one, the Tanshinone I of aromatic ring approaches complete planar molecule as the A ring, so more be insoluble in water than Tanshinone I I A, in a single day these fat-soluble chemical compounds enter in the body, will be in body fluid produce hydrophobic interaction under the effect of hydrone (referring to J.Fisher﹠amp; J.R.P.Arnold (Li Yanmei translates) " chemistry in biology " pp86-89 Science Press 2000 Beijing).The fat-soluble effective ingredient of Radix Salviae Miltiorrhizae shows for the experiment of rat oral gavage, because of its hydrophilic index is low, causes absorption difference in the body, and therefore, pharmacological action is difficult for performance.Give animal successive administration one month respectively with Tanshinone I, Tanshinone I I A, the result does not see curative effect yet.Medicine has only dissolving to be absorbed, the dissolubility of most medicines and rate of dissolution and medicine be absorbed with tangible statistics dependency.Before this method is set up, once did the Caco-2 test cell line of tanshinone compound, the result proves that this compounds is permeate through cell membranes very smoothly.Therefore, its stripping from solid preparation, dissolving become the speed limit process of drug absorption.At this moment, rate of dissolution and dissolution degree directly influence speed, the power of drug effect appearance and hold time.Therefore, the dissolution of raising TANSHINONES and its dissolubility of increase are very necessary.In order to improve its dissolubility, pharmacy worker has adopted a lot of methods, mainly is divided into two big classes: a kind of is to add different proportion, different types of surfactant, as tween 20, Tween-40, tween 80, PEG-4000, dimethyl sulfoxine (DMSO) etc.Another kind of is sulfonating reaction, and existing researcher in the presence of acetic anhydride, with concentrated acid sulfonation, saltout, is reflected at Tanshinone I I A, Tanshinone I on the TANSHINONES molecule by Mannich and introduces sulfonic group, reuse methanol crystallization and getting.The effect of first method solubilising and not obvious wherein, there is the low problem of yield in the second method complexity, and fat-soluble constituent structure is modified into water miscible material, may decrease in the ability of the bimolecular lipid membrane that sees through cell.
Summary of the invention the present invention provides a kind of preparation that can increase tanshinone compound dissolubility and dissolution rate in order to overcome above-mentioned weak point of the prior art just.Change its poor solubility, dissolution rate is slow, is difficult for the character of absorption, improves the bioavailability of this compounds.
Task of the present invention is achieved in that by the monomeric compound of tanshinone and water miscible carrier forms tanshinone solid dispersion by 5%-50%: 95%-50%.The monomeric compound of described tanshinone comprises: Tanshinone I I A, Tanshinone I I B, cryptotanshinone, Tanshinone I, TANSHINONES V, TANSHINONES VI, iso tanshinone I, iso tanshinone II, iso tanshinone II B, dihydrotanshinone I, hydroxyl TANSHINONES, miltirone, Methyl tanshinoate monomeric compound.Described water-solubility carrier material comprises: PEG class: PEG4000, PEG6000, PEG12000, PEG20000; PVP class: PVPK15, PVPK90; Organic acid: succinic acid, citric acid, cholic acid, deoxycholic acid; Saccharide and alcohols: galactose, dextran, sucrose, mannitol, xylitol, sorbitol; Other: PGS (pregelatinized Starch), Poloxamer 188 (F-68), carbamide.
The purposes of tanshinone solid dispersion, tablet, capsule, granule, oral liquid, ointment, injection, Injectable sterile freeze-dried powder, spray, external use plaster, washing liquid that the tanshinone solid dispersion that obtains is made respectively.
Solid dispersion: adopting water miscible macromolecular material, surfactant is carrier, fusion method, solvent method, solvent fusion method, polishing and spray drying and cryodesiccated method, preparation tanshinone solid dispersion.Water-solubility carrier commonly used is water-soluble high-molecular compound, organic acid, saccharide etc.For the medicine of slightly solubility, utilize the solid dispersion of water-solubility carrier preparation, not only can keep the height dispersibility of medicine in carrier, and make medicine have good wettability.
Preparation solid dispersion body method commonly used has: solvent method, fusion method, solvent-fusion method, polishing, solvent-spray drying method, solvent-freeze-drying etc.The solid dispersion that different preparation methoies is prepared into, medicine dispersity therein is different.Such as: the dispersity of the solid dispersion that the employing fusion method makes mostly is eutectic mixture or solid solution, and mostly is glass solution or coprecipitate with the dispersity of solvent method preparation.The dispersity type of medicine in carrier is not individualism in the ordinary course of things.The polytype often mixture of a kind of solid dispersion.
The present invention compared with prior art has following advantage:
The dissolubility of tanshinone solid dispersion is about 100 times of TANSHINONES monomeric compound dissolubility, accumulative total stripping percentage rate in 60 minutes can reach more than 60%, TANSHINONES with form high degree of dispersion such as unformed shape, solid solution, coprecipitates in carrier material.
Below be the written explanation of Figure of description:
Fig. 1 is the comparison diagram of TANSHINONES V and tanshinone solid dispersion dissolution in vitro.Be TANSHINONES V and the stripping curve figure of TANSHINONES V PGS solid dispersion in the no enzyme simulated gastric fluid of pH=1.2 that press embodiment 1 preparation.As can be seen from the figure, solid dispersion has significantly improved the dissolution rate of TANSHINONES V, and 1 hour accumulation stripping percentage rate is 47.43%, is 5.16 times of TANSHINONES V crude drug.
Fig. 2 is the comparison diagram of the dissolution in vitro of TANSHINONES VI and TANSHINONES VI solid dispersion.Be TANSHINONES VI and the TANSHINONES VIPVPK that presses embodiment 2 preparation
15The stripping curve figure of solid dispersion in the no enzyme simulated gastric fluid of pH=1.2.As can be seen from the figure, solid dispersion has significantly improved the dissolution rate of TANSHINONES VI, and 1 hour accumulation stripping percentage rate is 67.84%, is 7.22 times of TANSHINONES VI crude drug.
Fig. 3 is the comparison diagram of the dissolution in vitro of Tanshinone I and Tanshinone I solid dispersion.Be Tanshinone I and the Tanshinone I PEG6000 and the stripping curve figure of tween 80 solid dispersion in the no enzyme simulated gastric fluid of pH=1.2 that press embodiment 3 preparation.As can be seen from the figure, solid dispersion has significantly improved the dissolution rate of Tanshinone I, and 1 hour accumulation stripping percentage rate is 52.93%, is 5.41 times of Tanshinone I crude drug.
Fig. 4 is the comparison diagram of the dissolution in vitro of miltirone and miltirone solid dispersion.Be miltirone and the stripping curve figure of miltirone galactose solid dispersion in the no enzyme simulated gastric fluid of pH=1.2 that press embodiment 4 preparation.As can be seen from the figure, solid dispersion has significantly improved the dissolution rate of miltirone, and 1 hour accumulation stripping percentage rate is 45.27%, is 4.42 times of miltirone crude drug.
Specific embodiments is further described related content of the present invention below with reference to embodiment and Figure of description.
1. 1 kinds of TANSHINONES V of embodiment solid dispersion, accurately take by weighing 2.5g PGS (pregelatinized Starch), place evaporating dish, other takes by weighing 2.5g TANSHINONES V powder, adds in the 330ml dehydrated alcohol, and water-bath is heated to for 60 ℃ dissolves fully and be incubated, both mixing are stirred evenly, continuation is heated in water-bath, under condition of stirring, boils off ethanol to there not being the alcohol flavor, subsequently mixture is placed vacuum desiccator, vacuum drying is 1 hour under 70 ℃ of conditions, takes out, and puts into exsiccator, after treating to cool down fully, pulverize, cross 120 mesh sieves, thereby obtain end product.
Table 1 is the comparison of the dissolubility of TANSHINONES V and above-mentioned TANSHINONES V solid dispersion.
The dissolubility of table 1 TANSHINONES V and TANSHINONES V solid dispersion (μ g/ml)
| Sample | Distilled water | Simulated gastric fluid | Phosphate buffered solution |
| TANSHINONES V TANSHINONES V PGS dispersion | 0.13 7.65 | 0.25 12.19 | 0.07 7.84 |
As can be seen from Table 1, solid dispersion has significantly increased the dissolubility of TANSHINONES V, and its dissolubility in simulated gastric fluid is 48.76 times of TANSHINONES V raw material.
2. 1 kinds of TANSHINONES VI of embodiment solid dispersion accurately takes by weighing 47.5gPVPK
15Place beaker, adding the 60ml absolute ethyl alcohol and stirring dissolves it fully, other takes by weighing 2.5g TANSHINONES VI powder, add in the 330ml dehydrated alcohol, water-bath is heated to for 60 ℃ dissolves fully and is incubated, with both mixings, be poured on the stainless steel dish, continuation is heated in water-bath, under condition of stirring, boils off ethanol fully as far as possible, because its surperficial hardening, therefore its inner ethanol can't steam fully, if residual a spot of solvent in the solid dispersion, easily causes the recrystallization of medicine and reduces its dispersion, therefore the dispersion with this hardening places the dry 3h of vacuum desiccator again, be placed on after the taking-up in the exsiccator, after treating to cool down fully, pulverize, cross 100 mesh sieves, thereby obtain end product.
Table 2 is the comparison of the dissolubility of TANSHINONES VI and above-mentioned TANSHINONES VI solid dispersion.
The dissolubility of table 2 TANSHINONES VI and TANSHINONES VI solid dispersion (μ g/ml)
| Sample | Distilled water | Simulated gastric fluid | Phosphate buffered solution |
| TANSHINONES VI TANSHINONES VI PVPK 15Dispersion | 0.21 9.24 | 0.19 14.17 | 0.09 10.7 |
As can be seen from Table 2, solid dispersion has significantly increased the dissolubility of TANSHINONES VI, and its dissolubility in simulated gastric fluid is 74.58 times of TANSHINONES VI raw material.
3. 1 kinds of Tanshinone I solid dispersion of embodiment, accurately take by weighing 4g PEG6000 and 8g tween 80, place evaporating dish, heating in water bath makes it fusion respectively, other takes by weighing 1.5g Tanshinone I powder, to wherein adding the 750ml dehydrated alcohol, water-bath is heated to for 60 ℃ dissolves fully and is incubated, and the three is stirred, continuation is heated in water-bath, under condition of stirring, boil off ethanol to there not being the alcohol flavor, pour fused mixture into place ice bath stainless steel disc subsequently, make straticulation, blow with cold wind,, place the exsiccator inner drying its rapid cooling curing, after treating to cool down fully, pulverize, cross 100 mesh sieves, thereby obtain end product.
Table 3 is the comparison of the dissolubility of Tanshinone I and above-mentioned Tanshinone I solid dispersion.
The dissolubility of table 3 Tanshinone I and Tanshinone I solid dispersion (μ g/ml)
| Sample | Distilled water | Simulated gastric fluid | Phosphate buffered solution |
| Tanshinone I Tanshinone I PEG6000 | 0.11 4.45 | 0.15 7.03 | 0.04 4.92 |
As can be seen from Table 3, solid dispersion has significantly increased the dissolubility of Tanshinone I, and its dissolubility in simulated gastric fluid is 46.87 times of Tanshinone I raw material.
4. 1 kinds of miltirone solid dispersion of embodiment accurately take by weighing the 8.1g galactose, place evaporating dish, add 10ml water and make it to dissolve fully, other takes by weighing 2.7g miltirone powder, to wherein adding the 250ml dehydrated alcohol, both are stirred,, boil off ethanol to there not being the alcohol flavor at 60 ℃ of heating of water-bath and stirring 3h, subsequently this mixture is poured in the beaker, place the vacuum desiccator inner drying, after treating to cool down fully, pulverize, cross 100 mesh sieves, thereby obtain end product.
Table 4 is the comparison of the dissolubility of miltirone and above-mentioned miltirone solid dispersion.
The dissolubility of table 4 miltirone and miltirone solid dispersion (μ g/ml)
| Sample | Distilled water | Simulated gastric fluid | Phosphate buffered solution |
| Miltirone miltirone galactose dispersion | 0.29 3.59 | 0.34 7.86 | 0.13 4.38 |
As can be seen from Table 4, solid dispersion has significantly increased the dissolubility of miltirone, and its dissolubility in simulated gastric fluid is 23.12 times of miltirone raw material.
Embodiment 5. is a raw material with iso tanshinone II-solid xylitol dispersion, adopts wet granulation, refills capsular method, preparation iso tanshinone II capsule.It is as follows to write out a prescription:
Iso tanshinone II solid dispersion 6g (principal agent)
10%PVPK
30Ethanol solution an amount of (binding agent)
Lactose 40g (filler)
Magnesium stearate 1g (lubricant, fluidizer)
100
Embodiment 6. is a raw material with iso tanshinone I-citric acid solid dispersion, with itself and microcrystalline Cellulose, pregelatinized Starch, magnesium stearate uniform mixing, adopts direct compression process, preparation TANSHINONES tablet.It is as follows to write out a prescription:
Iso tanshinone I solid dispersion 6g (principal agent)
Microcrystalline Cellulose 42g (filler, binding agent)
Pregelatinized Starch 20g (disintegrating agent, filler)
Magnesium stearate 2g (lubricant, fluidizer)
100
Embodiment 7. is a raw material with dihydrotanshinone I-PEG20000 solid dispersion, adopts wet granulation, preparation TANSHINONES granule.It is as follows to write out a prescription:
Dihydrotanshinone I solid dispersion 6g (principal agent)
10%PVPK
30Ethanol solution an amount of (binding agent)
Lactose 80g (filler)
Protein sugar 0.2g (sweeting agent)
Essence an amount of (aromatic)
100 bags
Methyl tanshinoate solid dispersion 6g (principal agent)
Glyceryl monostearate 70g (oil phase, auxiliary emulsifying)
Stearic acid 120g (oil phase)
Glycerol 85g (wetting agent)
White vaseline 85g (oil phase, adjusting denseness)
Lauryl alcohol sodium sulfovinate 10g (emulsifying agent)
Ethyl hydroxybenzoate 1g (antiseptic)
Distilled water adds to 1000g (water)
100
Dihydrotanshinone I solid dispersion 6g (principal agent)
Rubber 10g (excipient)
Zinc oxide 13g (opacifier)
White vaseline 2g (adjusting denseness)
Lanoline 3g (adjusting denseness)
Gasoline 30ml (solvent)
100.
Claims (2)
1. tanshinone solid dispersion, it is characterized in that: monomeric compound and water miscible carrier by tanshinone are pressed 5%-50%: 95%-50%, form tanshinone solid dispersion;
1.2 the monomeric compound of described tanshinone comprises: Tanshinone I I A, Tanshinone I I B, cryptotanshinone, Tanshinone I, TANSHINONES V, TANSHINONES VI, iso tanshinone I, iso tanshinone II, iso tanshinone II B, dihydrotanshinone I, hydroxyl TANSHINONES, miltirone, Methyl tanshinoate monomeric compound;
1.3 described water-solubility carrier material comprises: PEG class: PEG4000, PEG6000, PEG12000, PEG20000; PVP class: PVPK15, PVPK90; Organic acid: succinic acid, citric acid, cholic acid, deoxycholic acid; Saccharide and alcohols: galactose, dextran, sucrose, mannitol, xylitol, sorbitol; Other: PGS, Poloxamer 188, carbamide.
2. the purposes of tanshinone solid dispersion according to claim 1 is made tablet, capsule, granule, oral liquid, ointment, injection, Injectable sterile freeze-dried powder, spray, external use plaster, washing liquid with the tanshinone solid dispersion that obtains.
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| CN 200610021953 CN101057839A (en) | 2005-04-12 | 2005-04-12 | Tanshinone solid dispersion and its application |
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| CN 200610021953 CN101057839A (en) | 2005-04-12 | 2005-04-12 | Tanshinone solid dispersion and its application |
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| CN 200510020698 Division CN1686104A (en) | 2005-04-12 | 2005-04-12 | Tanshinone solid dispersion, inclusion compound and its use |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552236A (en) * | 2012-02-13 | 2012-07-11 | 天津中医药大学 | Application of tanshinone I to treatment of microglia-mediated disease |
| CN104940148A (en) * | 2015-07-11 | 2015-09-30 | 鲁南制药集团股份有限公司 | Mosapride citrate granules and preparation method thereof |
| CN105030691A (en) * | 2015-07-11 | 2015-11-11 | 鲁南贝特制药有限公司 | Loratadine granules |
| CN107375219A (en) * | 2017-09-11 | 2017-11-24 | 青海七彩花生物科技有限公司 | A kind of tanshinone IIA hydroxyapatite solid dispersions and preparation method thereof |
| CN108744583A (en) * | 2018-07-12 | 2018-11-06 | 吉林龙鑫药业有限公司 | A kind of drug extraction tank and its application |
| CN111035628A (en) * | 2020-01-19 | 2020-04-21 | 广东药科大学 | Self-dissolving microneedle for treating scar |
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2005
- 2005-04-12 CN CN 200610021953 patent/CN101057839A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552236A (en) * | 2012-02-13 | 2012-07-11 | 天津中医药大学 | Application of tanshinone I to treatment of microglia-mediated disease |
| CN104940148A (en) * | 2015-07-11 | 2015-09-30 | 鲁南制药集团股份有限公司 | Mosapride citrate granules and preparation method thereof |
| CN105030691A (en) * | 2015-07-11 | 2015-11-11 | 鲁南贝特制药有限公司 | Loratadine granules |
| CN105030691B (en) * | 2015-07-11 | 2018-04-13 | 鲁南贝特制药有限公司 | A kind of Loratadine granule |
| CN104940148B (en) * | 2015-07-11 | 2018-12-28 | 鲁南制药集团股份有限公司 | A kind of mosapride citrate particle and preparation method thereof |
| CN107375219A (en) * | 2017-09-11 | 2017-11-24 | 青海七彩花生物科技有限公司 | A kind of tanshinone IIA hydroxyapatite solid dispersions and preparation method thereof |
| CN107375219B (en) * | 2017-09-11 | 2019-01-15 | 奉节县人民医院 | A kind of tanshinone IIA-hydroxyapatite solid dispersions and preparation method thereof |
| CN108744583A (en) * | 2018-07-12 | 2018-11-06 | 吉林龙鑫药业有限公司 | A kind of drug extraction tank and its application |
| CN108744583B (en) * | 2018-07-12 | 2019-03-29 | 吉林龙鑫药业有限公司 | Danshensu and the method for being prepared into Sodium Danshensu in a kind of extraction Radix Salviae Miltiorrhizae |
| CN111035628A (en) * | 2020-01-19 | 2020-04-21 | 广东药科大学 | Self-dissolving microneedle for treating scar |
| CN111035628B (en) * | 2020-01-19 | 2022-12-30 | 广东药科大学 | Self-dissolving microneedle for treating scar |
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