CN103462940A - Huperzine A micro-emulsion type cataplasm - Google Patents
Huperzine A micro-emulsion type cataplasm Download PDFInfo
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- CN103462940A CN103462940A CN2013104237755A CN201310423775A CN103462940A CN 103462940 A CN103462940 A CN 103462940A CN 2013104237755 A CN2013104237755 A CN 2013104237755A CN 201310423775 A CN201310423775 A CN 201310423775A CN 103462940 A CN103462940 A CN 103462940A
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Abstract
The invention discloses huperzine A micro-emulsion type cataplasm which mainly consists of a medicament storage layer, a non-woven cloth back lining layer and an anti-adhesive layer, wherein the medicament storage layer is arranged between the non-woven cloth back lining layer and the anti-adhesive layer; and the medicament storage layer comprises huperzine A, oil, a surfactant, a cosurfactant, an absorption enhancer, a cataplasm aqueous matrix and distilled water. According to the huperzine A micro-emulsion type cataplasm, the huperzine A is uniformly dispersed in the cataplasm aqueous matrix in a micro-emulsion state and is matched with a skin penetration enhancer. Compared with a skeleton type huperzine A slow-release paster which takes polyacrylate as the matrix, the huperzine A micro-emulsion type cataplasm overcomes the following significant defects: firstly, the irritation is reduced, secondly, the toxicity is low, thirdly, the permeation rate is improved, and fourthly, the rare resource is saved; moreover, the exploration of rare plants is reduced.
Description
Technical field
The present invention relates to medical technical field, relate in particular to a kind of safe and efficient huperzine A micro-emulsion type of saving scarce resource cataplasma for the treatment of degenerative brain disorder.
Background technology
At first German doctor Alois Alzheimer is described degenerative brain disorder (AD): a kind of nervous system sexually transmitted disease (STD) of age-dependent becomes, it is feature that pathology be take neural inflammatory speckle, neurofibrillary tangle, neuronal death, and clinical main manifestations is dysmnesia, cognitive disorder, personality changes etc.
Current, world population has entered the aging stage, the sickness rate rising of AD, and the whole world approximately has 2,000 ten thousand people to be subject to the puzzlement of this disease.According to the update statistics, the mortality rate of AD is only second to heart disease, cancer and apoplexy, is listed as the 4th.Sickness rate and age that this is sick are proportionate, and according to China investigation, AD sickness rate 60-69 year is 1%-2%, and 70-79 year is 4%-8%.Therefore this has had a strong impact on old people's quality of life, clinically in the urgent need to safety, new drug effective, easy to use.
At present, clinical treatment AD main method is: (1) symptomatic treatment: the various mental symptoms that AD is caused, and as drowsiness, depressed, anxiety etc. treated.Normal antipsychotic drug, antidepressants and the antianxiety drugs selected, as chlorpromazine, diazepam etc.But this type of drug side effect is large, sometimes even make that sb.'s illness took a turn for the worse.(2) neurotrophic factor therapy: this trophic factors is some protein that promotes nervous system development and maintain nervous function, and it is by the synthetic necessary neurotransmitter generation effect of the cell that excites nerve.But, because neurotrophic factor is difficult for, by blood brain barrier, can't entering rapidly target site, affect the treatment.(3) acetylcholine alternative medicine: comprise acetylcholine precursor, cholinoceptor activator and cholinesterase inhibitor.The acetylcholine precursor is choline and acetylcholine esterase, and its main purpose is increase acetylcholine synthetic, but both curative effects are all not remarkable.The cholinoceptor activator, due to activation M1 and the M2 receptor of non-selectivity, activates M for a long time
2be subject to know from experience the inhibition that causes acetylcholine to discharge, its curative effect can not show a candle to cholinesterase inhibitor.Cholinesterase inhibitor is one of the most effective medicine of current treatment AD, and first generation cholinesterase inhibitor mainly contains physostigmine, tetrahydroaminoacridine, and wherein tetrahydroaminoacridine is unique cholinesterase inhibitor that is used for the treatment of AD by the U.S. FDA approval.But above-mentioned cholinesterase inhibitor side effect is larger, so the utmost point need select a kind of side effect less, and very easily by the high activity cholinesterase inhibitor of blood brain barrier.
Huperzine A is the efficient cholinesterase inhibitor of Zhejiang Academy of Medical Sciences and institute of materia medica, Shanghai cooperation R & D, for extracting the novel lycopodium alkaloid from the Chinese medicine Herba Lycopodii serrati.Chemistry is by name; (5R, 9R, 11E)-5-amino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (B) pyridine-2 (1H) ketone also, and relative molecular weight is 242.32, has advantages of and can penetrate blood brain barrier.Studies have shown that, the mechanism of action of huperzine A system is by suppressing acetylcholine esterase active in brain, improves levels of acetylcholine and plays a role.Its significant advantage is that the inhibition acetylcholine esterase effect to memory, having relevant cerebral cortex and a Hippocampus obviously is better than other brain district, and the persistent period is 6 hours.In recent years clinical practice proves, huperzine A has obvious effect to improving person in middle and old age's dysmnesia, is current treatment AD one of the most effective medicine.Its Tablet and Capsula has gone through to go on the market.
Because the AD treatment cycle is longer, Long-term Oral inconvenience, and liver function is had to certain influence.In addition, also often occurring that due to illness the people remembers decline heavily takes situation about missing.For this reason, the present inventor has developed huperzine A slow-release paster for AD treatment (clinical batch of piece number: 2004L04806), each administration has maintained 3-4 days.But, the huperzine A slow-release paster is matrix type percutaneous medicine-releasing system, medicine is dispersed in the gluing skeleton of macromolecule, be subject to the impact of stratum corneum barrier, the percutaneous penetration of drugs amount is limited, need add suitable overdose of medicine thing to drive, just can reach effective therapeutic dose, Herba Lycopodii serrati growing environment harshness in addition, wild resource is most deficient, and price is very expensive.Therefore,, high in cost of production shortcoming low in bioavailability that the huperzine A slow-release paster remains, therefore be badly in need of finding a kind of more outstanding drug-supplying system, improve the utilization rate of medicine, reduces the exploitation to scarce resource.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, the mode that adopts the medicine microemulsion technology to combine with cataplasma, provide a kind of huperzine A micro-emulsion type cataplasma.
The objective of the invention is to be achieved through the following technical solutions: a kind of huperzine A micro-emulsion type cataplasma, it mainly is comprised of medicine storing layer, non-woven fabrics backing layer and adherent layer; Wherein, drug depot is placed between non-woven fabrics backing layer and adherent layer, and medicine storing layer comprises huperzine A, oil, surfactant, cosurfactant, absorption enhancer, cataplasma aqueous matrix and distilled water; 0.01-0.1 mass parts huperzine A is dissolved in 1-20 mass parts oil, then add 1-10 mass parts surfactant and 0.1-10 mass parts cosurfactant, be uniformly mixed as phase in pastille; At room temperature, drip while stirring 5-50 mass parts distilled water in pastille mutually in, stir to clarify transparently, obtain the huperzine A microemulsion; Getting 5-20 mass parts absorption enhancer is the A phase, gets 20-60 mass parts cataplasma hydrophilic matrix and 20-40 mass parts distilled water is mixed into the B phase, and the A phase is mixed mutually with B, stirs after 10-30 minute, adds 0.05-20 mass parts huperzine A microemulsion, 100-300r.min
-1stir 1-3 hour, degassed, be coated on the non-woven fabrics backing layer, after covering with adherent layer, section, pack, and obtains huperzine A micro-emulsion type cataplasma.
The invention has the beneficial effects as follows, in huperzine A micro-emulsion type cataplasma of the present invention, huperzine A is dispersed in the cataplasma aqueous matrix with the form of microemulsion, and is aided with Percutaneous absorption enhancer.The matrix type huperzine A slow-release paster that is substrate with polyacrylate is compared, huperzine A micro-emulsion type cataplasma has overcome following great defect, and reduce the exploitation to rare plant: 1. reduce zest: presenile dementia patient needs long-term prescription, skin will be exposed to the framework material polyacrylate for a long time, the part human body skin can produce certain stimulation, cause the symptoms such as allergy, skin itching, and the excipient that the micro-emulsion type cataplasma adopts and the skin affinity is stronger is as substrate, zest is less; 2. reduction toxicity: in slow-release paster preparation, framework material need use organic solvent dissolution, though adopt baking oven volatilization major part, still has part residual, to skin and body, can produce toxicity, and the adding of micro-emulsion type cataplasma organic solvent-free; 3. raising infiltration rate: people's Skin permeation rate in vitro is from 300 μ g/10cm
2.d be increased to 400 μ g/10cm
2.d more than; 4. saving scarce resource: the former plant Herba Lycopodii serrati growing environment harshness of extracting huperzine A, wild resource is most deficient, cause expensive, the micro-emulsion type cataplasma is by increasing substantially transdermal penetration speed, reduce the consumption of huperzine A, reach therapeutic dose, thereby reduce the exploitation of rare wild resource.
The accompanying drawing explanation
The huperzine A micro-emulsion type cataplasma (implementing 1 prescription) of Fig. 1 same dose and slow-release paster people Skin permeation rate in vitro comparison diagram.
Specific embodiment
Huperzine A micro-emulsion type cataplasma of the present invention mainly is comprised of medicine storing layer, non-woven fabrics backing layer and adherent layer.Wherein, drug depot is placed between non-woven fabrics backing layer and adherent layer, and medicine storing layer comprises huperzine A, oil, surfactant, cosurfactant, absorption enhancer, cataplasma aqueous matrix and distilled water.0.01-0.1 mass parts huperzine A is dissolved in 1-20 mass parts oil, then add 1-10 mass parts surfactant and 0.1-10 mass parts cosurfactant, be uniformly mixed as phase in pastille; At room temperature, slowly drip while stirring 5-50 mass parts distilled water in pastille mutually in, stir to clarify transparently, obtain transparent huperzine A microemulsion; Getting 5-20 mass parts absorption enhancer is the A phase, gets 20-60 mass parts cataplasma hydrophilic matrix and 20-40 mass parts distilled water is mixed into the B phase, and the A phase is mixed mutually with B, stirs after 10-30 minute, adds 0.05-20 mass parts huperzine A microemulsion, 100-300r.min
-1stir 1-3 hour, degassed, be coated on the non-woven fabrics backing layer, with adherent layer (as separate paper), cover, cut into pieces, pack and obtain huperzine A micro-emulsion type cataplasma.
Described absorption enhancer is following one or more: laurocapram, 1-2-propylene glycol, oleic acid, PEG400, isopropyl myristate, n-dodecanol, n-octyl alcohol, glycerol, eucalyptole, Mentholum, Borneolum Syntheticum.
Described surfactant is following one or more: tween 80, Arlacel-20, lecithin, polyoxyethylene hydrogenated Oleum Ricini, fabaceous lecithin, pluronic F-68, Labraso.
Described cosurfactant is following one or more: ethanol, polyoxyethylene-8-caprylin, normal propyl alcohol, isobutanol, 1-capryl alcohol, polyglyceryl fatty acid ester.
Described cataplasma aqueous matrix is following one or more: carbomer, sodium polyacrylate, polyvinyl alcohol, gelatin, polyvinylpyrrolidone, tragakanta, sodium alginate, methylcellulose.Described carbomer is carbomer 934,940,941, U10.
Described oil is following one or more: Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil, oleate, Ethyl linoleate, isopropyl myristate, oleic acid, linoleic acid.
The particle diameter of described huperzine A microemulsion is 1-100nm, is preferably 10-70nm.
Illustrate this patent below with reference to embodiment, those skilled in the art understand, and embodiments of the invention are only for technical scheme of the present invention is described, and non-limiting the present invention.The improvement that any the present invention makes and variation, all within protection scope of the present invention.
Embodiment 1: prepare huperzine A micro-emulsion type cataplasma
Huperzine A 0.1g
Oleum Arachidis hypogaeae semen 10g
Polyoxyethylene hydrogenated Oleum Ricini 10g
Poloxamer 5g
Polyglycol distearate 5g
PEG400 5g
1-2 propylene glycol 5g
Glycerol 5g
Laurocapram 7g
Carbomer U10 30g
Polyvidone 8g
Sodium carboxymethyl cellulose 20g
Dihydroxyaluminum aminoacetate 5g
Distilled water 300ml
Huperzine A is dissolved in Oleum Arachidis hypogaeae semen, then add polyoxyethylene hydrogenated Oleum Ricini, poloxamer, polyglycol distearate, be uniformly mixed as phase in pastille.At room temperature adopt constant temperature blender with magnetic force slowly drip while stirring water in pastille mutually in, with 300r.min
-1constant speed stirs to clarify transparent, makes transparent huperzine A microemulsion 100g.Taking polyethylene glycol 400,1-2 propylene glycol, glycerol, laurocapram, mix as the A phase; Get carbomer U10, polyvidone, sodium carboxymethyl cellulose and mix with distilled water, as the B phase, A is mixed mutually with B, stir (200r.min
-1) after 15 minutes, add 10g huperzine A microemulsion, 200r.min
-1stir 2 hours, degassed, coating, cover with separate paper, is cut into the small pieces of 10cm * 10cm, and packing and obtain content is 20mg.100cm
-2cataplasma.
Embodiment 2: prepare huperzine A micro-emulsion type cataplasma
Huperzine A 0.1g
Oleum Ricini 20g
Poloxamer 10g
Lecithin 4g
Pluronic F-68 2g
Tween 80 8g
PEG400 5g
Laurocapram 10g
Oleic acid 10g
Glycerol 6g
Carbomer 934 25g
Sodium polyacrylate 15g
Tragakanta 10g
Dihydroxyaluminum aminoacetate 6g
Distilled water 350ml
By huperzine A, Oleum Ricini, poloxamer, lecithin, tween 80, pluronic F-68, be uniformly mixed as phase in pastille.At room temperature adopt constant temperature blender with magnetic force slowly drip while stirring water in pastille mutually in, with 300r.min
-1constant speed stirs to clarify transparent, makes transparent huperzine A microemulsion 150g.Taking polyethylene glycol 400, laurocapram, oleic acid, glycerol, mix as the A phase; Get carbomer 934, sodium polyacrylate, tragakanta mixing, as the B phase, A is mixed mutually with B, stir (200r.min
-1) after 20 minutes, add 5g huperzine A microemulsion, 200r.min
-1stir 2 hours, degassed, coating, cover with separate paper, is cut into the small pieces of 10cm * 10cm, and packing and obtain content is 3mg.100cm
-2cataplasma.
Embodiment 3: the research of huperzine A micro-emulsion type cataplasma people isolated skin transdermal penetration speed
Adopt the Franz diffusion cell to carry out the skin permeability test, skin is fixed on to diffusion cell Chi Kou, horny layer is outside, huperzine A micro-emulsion type cataplasma (implementing 1 prescription) or the slow-release paster of same dose are sticked on horny layer, accepting medium is that mass percent is 40% PEG400 normal saline solution, and pond mouth effective area is about 3.1cm
2, use the magnetic grain with 400r.min
-1speed stir, 37 ℃ of constant temperature of water-bath chuck for diffusion cell, respectively at the stipulated time sampling, add the acceptable solution of equivalent after sampling.Measure the concentration of huperzine A in penetrating fluid with HPLC.Accumulation infiltration capacity Q with different time maps to time t, calculates the Skin permeation of medicine.
The HPLC method is: chromatographic column Kromasil C
18(250mm * 4.6mm, 5 μ m); The triethanolamine solution that methanol is 0.02% with concentration of volume percent 60:40 by volume mixes, and forms mobile phase; Flow velocity 1ml.min
-1; Detect wavelength 313nm; 30 ℃ of column temperatures; Sample size 20 μ l.Theoretical cam curve is calculated and should be not less than 3000 by huperzine A, but huperzine A and other component baseline separation, interference measurement not, standard curve is: Y=19487X-973, r=0.9996, quantitatively be limited to 5ng.ml
-1.
Huperzine A is shown in Fig. 1 through the infiltration rate-time graph of people's isolated skin, as seen from Figure 1, after huperzine A micro-emulsion type cataplasma and slow-release paster administration, the Skin permeation rising of huperzine A, reach maximum in 12-24h, micro-emulsion type cataplasma transdermal penetration speed reaches 1.88 μ gcm
-2h
-1, obviously be greater than slow-release paster (1.3 μ gcm
-2h
-1), slow decreasing after 48h, but still comparatively steady in 72h.
Above-described embodiment is used for the present invention that explains, rather than limits the invention, and in the protection domain of spirit of the present invention and claim, any modification and change that the present invention is made, all fall into protection scope of the present invention.
Claims (8)
1. a huperzine A micro-emulsion type cataplasma, is characterized in that, it mainly is comprised of medicine storing layer, non-woven fabrics backing layer and adherent layer; Wherein, drug depot is placed between non-woven fabrics backing layer and adherent layer, and medicine storing layer comprises huperzine A, oil, surfactant, cosurfactant, absorption enhancer, cataplasma aqueous matrix and distilled water; 0.01-0.1 mass parts huperzine A is dissolved in 1-20 mass parts oil, then add 1-10 mass parts surfactant and 0.1-10 mass parts cosurfactant, be uniformly mixed as phase in pastille; At room temperature, drip while stirring 5-50 mass parts distilled water in pastille mutually in, stir to clarify transparently, obtain the huperzine A microemulsion; Getting 5-20 mass parts absorption enhancer is the A phase, gets 20-60 mass parts cataplasma hydrophilic matrix and 20-40 mass parts distilled water is mixed into the B phase, and the A phase is mixed mutually with B, stirs after 10-30 minute, adds 0.05-20 mass parts huperzine A microemulsion, 100-300r.min
-1stir about 1-3 hour, degassed, be coated on the non-woven fabrics backing layer, after covering with adherent layer, section, pack, and obtains huperzine A micro-emulsion type cataplasma.
2. according to the described cataplasma of claims 1, it is characterized in that, described absorption enhancer is following one or more: laurocapram, 1-2-propylene glycol, oleic acid, PEG400, isopropyl myristate, n-dodecanol, n-octyl alcohol, glycerol, eucalyptole, Mentholum, Borneolum Syntheticum.
3. according to the described cataplasma of claims 1, it is characterized in that, described surfactant is following one or more: tween 80, Arlacel-20, lecithin, polyoxyethylene hydrogenated Oleum Ricini, fabaceous lecithin, pluronic F-68, Labraso.
4. according to the described cataplasma of claims 1, it is characterized in that, described cosurfactant is following one or more: ethanol, polyoxyethylene-8-caprylin, normal propyl alcohol, isobutanol, 1-capryl alcohol, polyglyceryl fatty acid ester.
5. according to the described cataplasma of claims 1, it is characterized in that, described catablasm base material is following one or more: carbomer, sodium polyacrylate, polyvinyl alcohol, gelatin, polyvinylpyrrolidone, tragakanta, sodium alginate, methylcellulose.
6. according to the described cataplasma of claims 5, it is characterized in that, described carbomer is carbomer 934,940,941, U10.
7. according to the described cataplasma of claims 5, it is characterized in that, described oil is following one or more: Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil, oleate, Ethyl linoleate, isopropyl myristate, oleic acid, linoleic acid.
8. according to the described cataplasma of claims 1, it is characterized in that, described pastille microemulsion particle diameter is 1-100nm, is preferably 10-70nm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109528693A (en) * | 2018-12-20 | 2019-03-29 | 武汉科福新药有限责任公司 | A kind of rapamycin cataplasm and preparation method thereof |
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|---|---|---|---|---|
| CN1644208A (en) * | 2004-11-26 | 2005-07-27 | 谢德隆 | China fir extracts with lycopodine A and B composition and their preparing method |
| CN101396380A (en) * | 2007-09-28 | 2009-04-01 | 赵守明 | Huperzia serrata extract and preparation method thereof |
| CN102151268A (en) * | 2011-03-28 | 2011-08-17 | 王义明 | Compound preparation for treating Alzheimer's disease and preparation method thereof |
-
2013
- 2013-09-17 CN CN2013104237755A patent/CN103462940A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1644208A (en) * | 2004-11-26 | 2005-07-27 | 谢德隆 | China fir extracts with lycopodine A and B composition and their preparing method |
| CN101396380A (en) * | 2007-09-28 | 2009-04-01 | 赵守明 | Huperzia serrata extract and preparation method thereof |
| CN102151268A (en) * | 2011-03-28 | 2011-08-17 | 王义明 | Compound preparation for treating Alzheimer's disease and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109528693A (en) * | 2018-12-20 | 2019-03-29 | 武汉科福新药有限责任公司 | A kind of rapamycin cataplasm and preparation method thereof |
| CN109528693B (en) * | 2018-12-20 | 2022-03-01 | 武汉科福新药有限责任公司 | Rapamycin cataplasm and preparation method thereof |
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Application publication date: 20131225 |