CN105906497A - A venlafaxine hydrochloride pharmaceutical composition and biological medicine uses thereof - Google Patents
A venlafaxine hydrochloride pharmaceutical composition and biological medicine uses thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/757—Unsaturated compounds containing a keto groups being part of a ring containing —CHO groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/484—Glycyrrhiza (licorice)
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Abstract
A venlafaxine hydrochloride pharmaceutical composition and biological medicine uses thereof are disclosed. The composition comprises venlafaxine hydrochloride and a natural product compound (I) having a novel structure and separated from dry roots of licorice. When being used separately, the venlafaxine hydrochloride and the compound (I) both have a function of promoting fracture healing. When the venlafaxine hydrochloride and the compound (I) are used together, the function of promoting fracture healing is more obvious, and the venlafaxine hydrochloride and the compound (I) are synergistic. The composition can be developed into a medicine promoting facture healing. Compared with the prior art, the composition and the uses have significant substantive distinguishing features and significant improvements.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of VENLAFAXINE HCL, be specifically related to the medicine of VENLAFAXINE HCL
Compositions and the application in biological medicine thereof.
Background technology
VENLAFAXINE HCL is the reuptake suppression of three kinds of biogenic amines (5-hydroxy tryptamine, norepinephrine and dopamine)
Agent, wherein the strongest to serotonin reuptake transporter inhibitory action, the strongest to norepinephrine reuptake inhibitory action.Literary composition traction therapy
Pungent to muscarine, nicotine, histamine and adrenoceptor without effect, to monoamine oxidase, MAO unrestraint effect.
VENLAFAXINE HCL mainly by blocking the reuptake of NE and 5-HT simultaneously, raises NE and 5-HT concentration and plays double
Weight antidepressant effect, the reuptake to dopamine (DA), the slightest inhibitory action.To M cholinoceptor, adrenal gland
Element α 1, α 2, beta receptor, histamine H1-receptor is almost without affinity.Its active metabolite 0-ODV also can suppress
The reuptake of 5-HT and NE, specific activity original shape medicine is low.There are some researches show, during this product low dose, mainly suppress taking the photograph again of 5-HT
Taking, time heavy dose of, the reuptake to 5-HT and NE all has inhibitory action.This medicine is weaker than choosing to the inhibitory action of 5-HT reuptake
Selecting property 5-HT reuptake inhibitor (SSRI)；The inhibitory action of NE reuptake is also weaker than some tricyclic antidepressant (TCA)
Or selective N E reuptake depressant.But this product single or multiple is administered and all can reduce by isoproterenol stimulation in rats strobile
The cAMP concentration that body produces, causes the rapid downward regulation of epinephrine beta receptor, and TCA then needs long term administration just to have this effect.
Now think that the venlafaxine rapid downward regulation effect to epinephrine beta receptor is rapid-action relevant with it.
Up to now, there is not yet the dependency report of VENLAFAXINE HCL and pharmaceutical composition thereof and union of fracture.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of VENLAFAXINE HCL, this pharmaceutical composition draws containing hydrochloric acid literary composition
The natural product of the pungent and a kind of novel structure of method, VENLAFAXINE HCL and this natural product can work in coordination with promotion union of fracture.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of VENLAFAXINE HCL, including VENLAFAXINE HCL, compound as claimed in claim 1 (I)
Pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry rhizome of Radix Glycyrrhizae is pulverized by (a), uses
85～95% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
N-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract macroporous resin remove impurity, first with 10 column volumes of 8% ethanol elution, then with 12 posts of 70% ethanol elution
Volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol elution in (c) step (b)
Concentrate purification on normal-phase silica gel separates, successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1 and 5:1
Obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1,5:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 2:1；Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects 8～14 column volume eluting
Liquid, eluent is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is AB-8 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in preparation promotes the medicine of union of fracture.
The application in preparation promotes the medicine of union of fracture of the pharmaceutical composition of above-mentioned VENLAFAXINE HCL.
Advantages of the present invention: in the pharmaceutical composition of the VENLAFAXINE HCL that the present invention provides containing VENLAFAXINE HCL and a kind of from
When the natural product of the novel structure of isolated in the dry rhizome of Radix Glycyrrhizae, VENLAFAXINE HCL and this natural product independent role,
There is promotion union of fracture effect；During the two synergy, promote that the effect of union of fracture improves further, rush can be developed into
Enter the medicine of union of fracture.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng.
Separation method: the dry rhizome (2kg) of Radix Glycyrrhizae is pulverized by (a), extracts (20L × 3 time) with 90% alcohol heat reflux,
United extraction liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and
Water saturated n-butyl alcohol (4L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butanol extraction
Thing；B n-butyl alcohol extract AB-8 type macroporous resin remove impurity in () step (a), first with 10 cylinders of 8% ethanol elution
Long-pending, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；
In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 40:1 (8 column volumes),
The methylene chloride-methanol gradient elution of 20:1 (8 column volumes), 10:1 (8 column volumes) and 5:1 (10 column volumes) obtains
To 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1 (8 posts by volume ratio successively
Volume), the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) and 2:1 (5 column volumes) obtain 3 components；
E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is the first of 75% by concentration expressed in percentage by volume
Alcohol-water solution isocratic elution, collects 8～14 column volume eluents, eluent be concentrated under reduced pressure to give compound (I) (275mg,
HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 219.1346, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C14H18O2, degree of unsaturation is 6.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-4 (6.32, d,
J=9.6Hz), H-5 (6.21, dd, J=9.6,3.1Hz), H-6 (2.39, m), H-7 (3.73, m), H-8a (1.78,
M), H-8b (1.55, dd, J=12.2,8.1Hz), H-10a (2.53, d, J=15.8Hz), H-10b (2.31, d,
J=15.8Hz), H-11 (10.13, s), H-13 (0.84, d, J=7.3Hz), H-14 (1.04, s), H-15 (1.17,
s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 199.8 (C, 1-C), 141.2 (C, 2-C)
184.8 (C, 3-C), 132.3 (CH, 4-C), 154.7 (CH, 5-C), 31.1 (CH, 6-C), 52.7 (CH,
7-C), 45.3 (CH2, 8-C), 37.7 (C, 9-C), 51.2 (CH2, 10-C), 186.9 (CH, 11-C), 19.2
(CH3, 13-C), 28.3 (CH3, 14-C), 29.1 (CH3, 15-C).Infrared spectrum shows that this compound contains carbonyl
(1735cm-1), aldehyde radical 1628cm-1)。13C-NMR, DEPT and hsqc spectrum show 14 carbon signals, including
Three methyl, two methylene, five methines (aldehyde radical and two alkene carbon), and four quaternary carbon (two alkene
Carbon and a carbonyl carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is twin nuclei.1H-NMR composes knot
Close hsqc spectrum and show three methyl proton signal δH0.84 (3H, d, J=7.3Hz), 1.04 (3H, s), 1.17 (3H,
S), two groups of methene proton signal δH1.78 (1H, m) with 1.55 (1H, dd, J=12.2,8.1Hz), 2.53 (1H,
D, J=15.8Hz) and 2.31 (1H, d, J=15.8Hz), a pair olefinic proton signals δH6.32 (1H, d, J=9.6Hz)
With 6.21 (1H, dd, J=9.6,3.1Hz), an aldehyde radical proton signal δH10.13 (1H, s), two methine protons
Signal δH2.39 (1H, m) with 3.73 (1H, m).1H-1There is H-4/H-5/H-6/H-7/H in H COSY spectrum2-8 are correlated with
Signal, shows H-4 Yu C-2 and C-3, H-5 and C-4, C-6 and C-7, H-6 and C-1 and C-4 in HMBC spectrum simultaneously,
H-7 and C-5, H2-10 with C-1, C-7, C-8 and C-14, H-11 Yu C-1, C-2 and C-3, H3-13 and C-5 and C-7,
H3-14 with C-8, C-9 and C-10, H3-15 with C-9 and C-10 coherent signal, by the relevant information in above-mentioned H NMR spectroscopy
The connected mode of this compound can be built, and above-mentioned spectral data shows the notremulane that this compound is 12 carbon disappearances
Type sesquiterpene.In HMBC spectrum, the dependency of H-11 and H-4 and C-3 shows that C-3 is ketone carbonyl.In notremulane type times
In hemiterpene, H-6 Yu H-7 position is generally beta comfiguration, H3-14 usual places of configuration are β positions, H3-15 are configured as α position.At this chemical combination
H-6/H-7 and H-7/H embodied in the NOE test of thing3-14 coherent signals meet the configuration relationship of tremulane type sesquiterpene.
Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine this
Compound is as follows, and spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animal
Livid purple blue healthy rabbits 50, weight 2.0～2.5kg, male and female dual-purpose.Rabbit standard particle forage feed.By Lanzhou
Institute of biological products provides.
1.2 reagent and sample
VENLAFAXINE HCL is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
XIANLING GUBAO JIAONANG: be made up of medicines such as Herba Epimedii, Radix Dipsaci, Fructus Psoraleaes.Guizhou celestial being miraculous cure industry Co., Ltd produces.Sulfur
Formotal, Anesthesia medicine, Shanghai Xinya Pharmaceutical Industry Co. Ltd. produces.The solution of 2% is become to supply abdominal cavity with normal saline during use
Injection.Penicillin sodium, Harbin Pharmaceutical General Factory produces.
Prepared by 1.3 rabbit packets and model
After above-mentioned 50 rabbit adaptabilities are raised 3d, lumbar injection 2% penthiobarbital 40mg/kg anaesthetizes.Take radius stage casing to indulge
Row otch, appears radius stage casing, with the round emery wheel of dental burr, radius is sawn into Cranial defect standard transverse fracture wide for 3mm.Do not do
Fixing, postoperative intramuscular injection every day penicillin sodium 4 × 104U/kg, is used in conjunction 3d, is randomly divided into 5 groups after animal model, is respectively blank
Matched group, positive controls (XIANLING GUBAO JIAONANG, 280mg kg-1) and VENLAFAXINE HCL group (20mg kg-1), chemical combination
Thing (I) group (20mg kg-1), VENLAFAXINE HCL and compound (I) compositions group [10mg kg-1VENLAFAXINE HCL
+10mg·kg-1Compound (I)].Drug suspension administration by gavage is administered, and postoperative 1st day starts gavage.Positive controls fills
Taking XIANLING GUBAO 0.28g/kg, all with 10ml/kg distilled water diluting, blank group gavages 10ml/kg normal saline.Each rabbit fills
1 time/d of stomach, continuously to putting to death the date.
1.4 collections of specimens and process
Within after gavage the 3rd week, detect serum alkaline phosphatase (ALPase) in the blood sampling of ear central artery.In gavage the 14th day sky
Aeroembolism inserting method puts to death first rabbit, is often also divided into 2 subgroups, each subgroup 5 by randomized in group.In elbow joint detachment
Forearm, puts same can and takes the photograph X-ray film, the most completely separates radius, rejects soft tissue and the periosteum of attachment, uses normal saline
Gauze piece parcel radius specimen, puts-20 DEG C of refrigerator cold-storages standby.Opposite side radius specimen is sawed at each 1cm of fractures upper and lower
Disconnected, 4% formaldehyde is fixed standby.Within 31st day, the same method puts to death second batch rabbit, collect specimen.
1.5 serum levels of ALP ase measure
Use colorimetric method for determining serum alkaline phosphatase [S-ALP (IU/L)].
1.6 callus Biomechanics test
Radius specimen 2h before test is taken out, naturally thaws, put universal material experimental machine, make three-point bending test, test oar
Bone callus mechanical strength.Span 50mm, loading velocity 10mm/min, using maximum load as the mark of radius healing.
Regard fracture face as oval, with vernier caliper measurement fractures maximum gauge (d1) and minimum diameter (d2), draw maximum half
Footpath (a) and least radius (b), obtain the cross-sectional area of ellipse, calculate maximum stress.Computing formula is as follows:
Cross-sectional area: F=π ab (unit: mm2)；Maximum stress=maximum load/cross-sectional area (unit: N mm-2)
1.7 statistical method
X-ray film appraisal result is pressed mark and is compiled order, rank test between SPSS19.0 software group.Remaining each data is all with x ± s table
Showing, carrying out variance analysis with SPSS19.0 software, LSD method carries out significance test.
2, experimental result
2.1 pairs of Rabbits with Fracture model serum levels of ALP ase testing results.
Comparing with blank group, positive controls serum levels of ALP ase content raises (P < 0.05)；Compared with blank group,
VENLAFAXINE HCL and compound (I) compositions group serum levels of ALP ase content significantly raise (P < 0.01)；VENLAFAXINE HCL
(P < 0.05) is raised with compound (I) group serum levels of ALP ase content.The results are shown in Table 1.
2.2 pairs of Rabbits with Fracture model bone biomechanical test results
When 14 days, comparing with blank group, positive controls maximum stress raises (P < 0.05), and maximum load significantly raises
(P<0.01)；Compare with blank group, VENLAFAXINE HCL and compound (I) compositions group maximum stress and maximum load
Lotus significantly raised (P < 0.01)；VENLAFAXINE HCL group, compound (I) group maximum stress and maximum load raise (P < 0.05)；
When 31 days, compare with blank group, VENLAFAXINE HCL and compound (I) compositions group and positive controls maximum stress
Significantly raised with maximum load (P < 0.01)；VENLAFAXINE HCL group, compound (I) group maximum stress and maximum load liter
High (P < 0.05).The results are shown in Table 2 and table 3.
The table 1 impact on Rabbits with Fracture model blood ALPase
| Group | ALPase(IU/L) |
| Blank group | 118.170±7.960 |
| Positive controls | 141.000±9.279 |
| VENLAFAXINE HCL group | 130.5460±8.458 |
| Compound (I) group | 129.240±8.662 |
| VENLAFAXINE HCL and compound (I) compositions group | 163.670±9.224 |
The table 2 impact (14 days) on Rabbits with Fracture model bone biomechanical
The table 3 impact (31 days) on Rabbits with Fracture model bone biomechanical
The above results shows, when VENLAFAXINE HCL, compound (I) independent role, has the effect promoting union of fracture；
When VENLAFAXINE HCL and compound (I) synergy, promoting that the effect of union of fracture becomes apparent from, there is collaborative work in the two
With, the medicine of promotion union of fracture can be developed into.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a VENLAFAXINE HCL, it is characterised in that: include VENLAFAXINE HCL, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of VENLAFAXINE HCL the most according to claim 2, it is characterised in that: pharmaceutically acceptable
Carrier include diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant,
Absorption carrier or lubricant.
The pharmaceutical composition of VENLAFAXINE HCL the most according to claim 2, it is characterised in that: described dosage form include tablet,
Capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution
Agent, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry rhizome of Radix Glycyrrhizae is pulverized, with 85～95% alcohol heat reflux extraction, united extraction liquid, is concentrated into without alcohol taste, uses stone successively
Oil ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol
Extract；N-butyl alcohol extract macroporous resin remove impurity in (b) step (a), first with 10 column volumes of 8% ethanol elution,
Again with 12 column volumes of 70% ethanol elution, collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；(c)
In step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, and is 40:1,20:1,10:1 and 5:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 8:1,5:1 and 2:1；In (e) step (d)
The reverse phase silica gel that component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%,
Collecting 8～14 column volume eluents, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) 90% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is AB-8
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in preparation promotes the medicine of union of fracture of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described VENLAFAXINE HCL of claim 2～4 is in preparation promotes the medicine of union of fracture
Application.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1843393A (en) * | 2006-02-17 | 2006-10-11 | 阿尔贝拉医药(中国)有限公司 | Use of pharmaceutical composition containing aceglutamide and safflower |
| CN101095933A (en) * | 2007-07-05 | 2008-01-02 | 中国人民解放军第四一一医院 | Chinese traditional medicine compound recipe for healing bones and treating wound |
| CN102417509A (en) * | 2011-12-28 | 2012-04-18 | 大连美罗中药厂有限公司 | Application of three compounds extracted from starfish to promotion of bone fracture healing, and preparation method for three compounds |
| CN105753830A (en) * | 2016-04-28 | 2016-07-13 | 薛丽云 | Estazolam medicine composition and application thereof in biological medicine |
| CN105820143A (en) * | 2016-04-23 | 2016-08-03 | 吴珺 | Medicine composition of cholinophylline and application thereof to biological medicines |
-
2016
- 2016-04-18 CN CN201610240959.1A patent/CN105906497A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1843393A (en) * | 2006-02-17 | 2006-10-11 | 阿尔贝拉医药(中国)有限公司 | Use of pharmaceutical composition containing aceglutamide and safflower |
| CN101095933A (en) * | 2007-07-05 | 2008-01-02 | 中国人民解放军第四一一医院 | Chinese traditional medicine compound recipe for healing bones and treating wound |
| CN102417509A (en) * | 2011-12-28 | 2012-04-18 | 大连美罗中药厂有限公司 | Application of three compounds extracted from starfish to promotion of bone fracture healing, and preparation method for three compounds |
| CN105820143A (en) * | 2016-04-23 | 2016-08-03 | 吴珺 | Medicine composition of cholinophylline and application thereof to biological medicines |
| CN105753830A (en) * | 2016-04-28 | 2016-07-13 | 薛丽云 | Estazolam medicine composition and application thereof in biological medicine |
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Application publication date: 20160831 |