CN103127520B - The bond of polyethylene glycol and Tamsulosin and pharmaceutical composition thereof - Google Patents
The bond of polyethylene glycol and Tamsulosin and pharmaceutical composition thereof Download PDFInfo
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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Abstract
A kind of as polyethylene glycol-Tamsulosin bond of general formula (II) and the pharmaceutical composition that comprises this bond. In described bond, P, P ' are H or polyethylene glycol; And P, P ' are H when different. In Tamsulosin structure, contain sulfoamido, introduce low molecular poly by alkylated reaction, reduce the hydrophobicity of Tamsulosin, increase its hydrophily, reduce its blood-brain barrier transmitance, thereby reduce its toxicity.
Description
Technical field
The present invention relates to hydrophilic polymer-Tamsulosin bond, the low polyethylene glycol of especially little molecule and TamsulosinBond and pharmaceutical composition thereof.
Background technology
Benign prostate hyperplasia (BPH) is the optimum adenomatous hyperplasia of prostatic urethra peripheral region cell. During BPH isThe common disease of elderly men, frequently-occurring disease, clinical statistics shows, during 40-79 year, the incidence of disease of benign prostate hyperplasiaBe about 50%, 80 years old above male sex's incidence of disease up to 80%. The sensitiveness ratio of human body prostate to α receptor stimulating agentBladder is high, causes that sympathetic activation stimulates the AUR that can cause hypertrophy of the prostate patient, and the retardance of α acceptorAgent can selectively relax prostata tissue and smooth muscle of bladder and not affect the contraction of detrusor urinae of bladder, blocks thereby alleviate,Make to urinate unimpeded. It is applicable to improve the improvement of the symptoms such as frequent micturition that hyperplasia of prostate causes, urgent urination, dysuria, makes remnantsHypourocrinia.
At present, the method that clinical treatment benign prostate hyperplasia mainly adopts has vigilant wait, operative treatment and medicine to controlTreat etc. If for the drug main alpha-blocking agent of BPH, this class medicine is flat by expansion bladder outlet and prostateSliding flesh carrys out relief of symptoms. The representative medicine of this class medicine is Tamsulosin. Tamsulosin structural formula following (I).
Tamsulosin is long-acting α 1 acceptor inhibitor of third generation super-selective, can suppress specifically the contraction of prostate smooth musculature cells,Alleviate rapidly BPH clinical symptoms, good effect, less adverse effect. Sales volume rapid growth after Tamsulosin listing, isAt present domestic and international best selling variety. Although Tamsulosin good effect, the neural psychiatric system bad reaction such as have dizziness, walk haltingly.The main cause that bad reaction produces: α 1 adrenergic receptor spreads all over whole body, can send out after α 1 adrenergic receptor retardanceMore raw physiological change, relate generally to cardiovascular (CVS) and central nervous system (CNS), cause negative effect, as α 1ARAVasodilative effect can cause nasal obstruction, palpitaition, postural hypotension or faintness, the elderly can thereby fall down and causes injury or femoral neck boneHow folding, occur in the time going urine night, can cause death. α 1 adrenocepter inhibitor also can see through blood-brain barrier and enterEnter CNS, selective activation five hydroxytryptamine 1A acceptor, thereby the sympathetic tension force of reduction maincenter, decline peripheral vascular resistance,Blood pressure drop, it can cause giddy, the side effect such as dizzy, drowsiness, weak, tired to the direct effect of CNS. CauseThis, particularly need to provide a kind of hypotoxic Tamsulosin, lowers its toxic and side effect to cental system.
Polyethylene glycol (PEG) modification technique is the Novel medicine feeding technology developing rapidly in recent years, is mainly used inDrug administration by injection system. It is a kind of technology that will polyethylene glycol be linked to drug molecule or surface after activation. Medicine small molecule warpCross polyethyleneglycol modified after, mainly have the following advantages: 1, increase medicine water-soluble; 2, reduce toxicity; 3, extendMedicine circulating half-life, reduces medication number of times, improves patient dependence, improves the quality of living, and reduces medical expense; 4,Reduce enzyme degradation, improve bioavilability; 5, reduce blood-brain barrier transmitance, reduce maincenter side effect. With poly-second twoAfter alcohol link, there is change in the pharmacokinetics of medicine, and then change pharmacodynamics. Particularly polyethylene glycol can make blood medicine denseDegree maintains or approaches the time lengthening of aimed concn, keeps the drug effect of medicine to be brought into play fully. At present, in international marketThe representative of upper polyethyleneglycol modified drug products has: MICERA. At present, polyethyleneglycol modified small-molecule drug is not also ratified listing in international market, butIt is clinical to be that several products entered for two, three phases, and representative has NKTE-102 and the NKTR-118 of Nektar.
This experimental group is devoted to research (ZL03801109.3, the ZL20041 of pegylation small-molecule drug always0029615.3，ZL200480005763.X，ZL200810093688.7，ZL02107842.4，ZL02108778.4)。Be mainly to adopt polyethylene glycol to link with small-molecule drug, the product obtaining is having good improvement aspect solubilising attenuation.
This patent adopts Pegylation technology to carry out structure of modification to Tamsulosin, utilizes low-molecular-weight polyethylene glycol and smoothSuo Luoxin links, and increases the water-soluble of Tamsulosin itself, thereby lowers the toxic and side effect of Tamsulosin to cental system,Make it can be developed to injection or be applicable to oral preparation.
Summary of the invention
It is a kind of as polyethylene glycol-Tamsulosin bond of general formula (II) that one aspect of the present invention provides:
Wherein:
P, P ' are H or polyethylene glycol, and P, P ' are H when different.
In some embodiments of the present invention, P, P ' are as shown in the formula the single-ended polyethylene glycol of straight chain or the H that represent:
Wherein, n is the integer of 0-20.
In some embodiments of the present invention, P, P ' they are straight chain both-end polyethylene glycol, as shown in the formula expression:
Wherein, n is the integer of 0-20.
In some embodiments of the present invention, described polyethylene glycol-Tamsulosin bond is the poly-second of general formula (III)Glycol-Tamsulosin bond:
Wherein, n is the integer of 0-20.
In some embodiments of the present invention, described polyethylene glycol-Tamsulosin bond is the poly-second of general formula (IV)Glycol-Tamsulosin bond:
Wherein: n is the integer of 0-20.
In some embodiments of the present invention, n is the integer of 2-15.
In some embodiments of the present invention, n is the integer of 3-10.
In some embodiments of the present invention, described polyethylene glycol-Tamsulosin bond is selected from and has following structureOne of compound:
And
Polyethylene glycol-Tamsulosin bond of the general formula (V) that another aspect of the present invention provides,
Wherein: n is the integer of 0-20.
In some embodiments of the present invention, n is the integer of 0-15.
In some embodiments of the present invention, described polyethylene glycol-Tamsulosin bond is the change with following structureCompound:
Another aspect of the present invention is to provide and comprises described bond and pharmaceutically acceptable carrier or excipientPharmaceutical composition.
In some embodiments of the present invention, described pharmaceutical composition is tablet, suppository, pill, soft glutoid glueThe formulation of wafer, powder, solution, supensoid agent or aerosol.
Another aspect of the present invention is to provide the application of described bond in the medicine of preparing anti-prostatic hyperplasia.
Advantage of the present invention is can provide protection to Tamsulosin by the modification of hydrophilic polymer, improves drug absorption, prolongsLong action time, heightens the effect of a treatment, and reduces blood-brain barrier transmitance and avoids toxic and side effect.
Detailed description of the invention
In Tamsulosin structure, contain sulfoamido, can pass through alkylated reaction, introduce low molecular poly, reachThe hydrophobicity that reduces Tamsulosin, increases its hydrophily, reduces its blood-brain barrier transmitance, thereby reduces the object of its toxicity.
Bond of the present invention is prepared as follows: the low polyethylene glycol of hydrophily is carried out to modification, introduce halogen or first sulphurAcyl group, to the easily leaving group such as benzene mesyl, then under alkali condition, be combined with Tamsulosin. By introducing oligomeric second twoAlcohol, improves blood-brain barrier and sees through, thereby reduces its bad reaction and toxicity to cental system.
For low polyethylene glycol, adopt ethylene glycol polymerized unit to be represented, the general number that contains ethylene glycol unit that adoptsRepresent, ethylene glycol number of unit scope is 0-20, is preferably 3-10.
Polyethylene glycol of the present invention also comprises derivative and the analog of polyethylene glycol, also can be replaced by following hydrophilic polymerChange, described hydrophilic polymer selects free polyethylene glycol, polyglutamic acid, poly-aspartic-acid, polypropylene glycol, polyethyleneThe group that alcohol, polypropylene morpholine, Ju oxazoline and their copolymer form.
Bond of the present invention can pure compound form or suitable pharmaceutical compositions carry out administration, can adopt any canThe administering mode of accepting or carry out for the similar reagent of purposes. Therefore, the administering mode of employing can be selected by mouth, noseIn, non-enteron aisle, part, transdermal or rectal, its form is solid, semisolid or liquid preparation form administration, for example,Tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, supensoid agent or aerosol etc., preferably adopt suitableBe used for the presented in unit dosage form of the simple administration of exact dose. Composition can comprise conventional pharmaceutical carrier or excipient and conduct and liveThe bond of the present invention of property composition (one or more), in addition, also can comprise other medicament, carrier, assistant agent etc.
Conventionally,, according to required administering mode, pharmaceutically acceptable composition will comprise this of approximately 1 to approximately 99 % by weightThe suitable pharmaceutical excipient of bright bond and 99 to 1 % by weight. Preferred composition comprises approximately 5 to 75 % by weightBond of the present invention, all the other are suitable pharmaceutical excipient.
Can adopt the pharmaceutical composition of liquid form administration for example can pass through the means such as dissolving, dispersion by bond of the present invention(approximately 0.5 to approximately 20%) and the selective medicinal adjuvant existing dissolve, are scattered in carrier, and the example of carrier is water, saltWater, dextrose hydrate, glycerine, ethanol etc., thus solution or supensoid agent formed.
If necessary, pharmaceutical composition of the present invention also can comprise a small amount of auxiliary substance, as wetting agent or emulsifying agent,PH buffer, antioxidant etc., for example: citric acid, Arlacel-20, Emulphor FM, fourthBase hydroxy-methylbenzene etc.
Following examples are used for illustrating the present invention, but are not used for limiting the present invention.
Embodiment
Tamsulosin hydrochloride used in embodiment is provided by Shanghai Scientia Pharmaceutical Technology Co., Ltd., tert-butyl group bromination ammoniumFrom Xinfeng, Shouguang, chemical industry Co., Ltd buys, and paratoluensulfonyl chloride is buied from Shandong hundred million Yilong Industry Co., Ltd., sodium hydrideSlave ladder is uncommon likes that (Shanghai) changes into industrial development Co., Ltd and buys, mPEG (n=4)-OH, HO-PEG (n=6)-OH,MPEG (n=5)-OH buys from Jiaxing Bo Mei Bioisystech Co., Ltd.
Embodiment 1
The preparation of methoxyl group TEG and Tamsulosin bond (TSLX41)
In 250mL there-necked flask, add 9.07g paratoluensulfonyl chloride, 32mL pyridine, is cooled to 0 DEG C. By 8.26gMPEG (n=4)-OH and 16mL pyridine mix, and are added drop-wise in there-necked flask, within two hours, drip off, and control temperature is 0-10 DEG C.Continue stirring reaction two hours at this temperature. TLC monitoring reacts completely. In reactant liquor, add 130mL cold water and 48mLConcentrated hydrochloric acid, slowly stirs half an hour, and reactant liquor is transferred in 500mL separatory funnel, adds ethyl acetate extracting twice(200mL+100mL). Organic layer merges, and washes to neutrality anhydrous sodium sulfate drying two hours with water. Rotary Evaporators steamsGo out solvent. Obtain viscous liquid 11.34g altogether, be directly used in next step reaction.
Upper step intermediate is dissolved in 100mL acetonitrile, adds 25.66g tert-butyl group bromination ammonium, 50 DEG C are reacted 15 hours.Revolve to steam and remove acetonitrile, add 300mL water, be extracted with ethyl acetate three times (200mL*4), anhydrous sodium sulfate drying two is littleTime. Revolve and steam except desolventizing. Silicagel column separates and obtains 8.67g product, and yield is 80.66%.
By Tamsulosin hydrochloride 356mg, potash 664mg joins in the 100mL there-necked flask that fills 20mL acetonitrile,Stirring at room temperature 2 hours. The 10mL acetonitrile solution that is dissolved with 217mgmPEG (n=4) Br is joined in above-mentioned reaction bulb,Back flow reaction is spent the night. TLC monitoring reacts completely. Post separates and obtains colourless liquid 218mg, and yield is 14.3%. m/z[MH]+599.4。1H-NMR(DMSO-d6)：0.92-0.94(d，J＝6.2Hz，3H)，1.28(t，J＝6.9Hz，3H)，2.70-2.80(m，1H)，2.86-2.90(m，5H)，3.23(s，3H)，3.37(m，6H)，3.41(m，4H)，3.49(m，6H)，3.86(s，3H)，3.97(m，4H)，6.86(m，4H)，7.04(t，J＝5.7Hz，1H)，7.12(d，J＝8.5Hz，1H)，7.42(dd，J＝2.2Hz，J＝8.5Hz，1H)，7.54(d，J＝2.2Hz，1H)。
Embodiment 2
The preparation of bi-methoxy five ethylene glycol and Tamsulosin bond (TSLX52)
By Tamsulosin hydrochloride 356mg, potash 664mg joins in the 100mL there-necked flask that fills 20mL acetonitrile,Stirring at room temperature 2 hours. The 10mL acetonitrile solution that is dissolved with 759mgmPEG (n=5) Br is joined in above-mentioned reaction bulb,Back flow reaction is spent the night. TLC monitoring reacts completely. Post separates and obtains colourless liquid 258mg, and yield is 36.8%. m/z[MH]+877.8。1H-NMR(CDCl3)：1.10(d，J＝6.2Hz，3H)，1.39-1.44(t，J＝6.9Hz，3H)，2.60(m，1H)，2.90(m，1H)，3.05-3.13(m，4H)，3.37(s，6H)，3.45-3.55(m，20H)，3.60-3.65(m，20H)，3.90(s，3H)，4.07(m，2H)，4.17(t，J＝5.2Hz，2H)，6.90(m，5H)，7.37(dd，J＝8.5Hz，J＝2.2Hz，1H)，7.74(d，J＝2.2Hz，1H)。
Embodiment 3
The preparation of both-end six ethylene glycol and Tamsulosin bond (TSLXP62)
In 500mL there-necked flask, add 22.9g paratoluensulfonyl chloride, 80mL pyridine, is cooled to 0 DEG C. By 14.1gHO-PEG (n=6)-OH and 40mL pyridine mix, and are added drop-wise in there-necked flask, within two hours, drip off, and control temperature is 0-10 DEG C.Continue stirring reaction two hours at this temperature. TLC monitoring reacts completely. To add in reactant liquor 300mL cold water and120mL concentrated hydrochloric acid, slowly stirs half an hour, and reactant liquor is transferred in 1000mL separatory funnel, adds ethyl acetate extractionGet twice (300mL+200mL). Organic layer merges, and washes to neutrality anhydrous sodium sulfate drying two hours with water. Rotation is steamedSend out instrument and steam solvent. Obtain viscous liquid 28.7g altogether, be directly used in next step reaction.
Upper step intermediate is dissolved in 300mL acetonitrile, adds 28.7g tert-butyl group bromination ammonium, 50 DEG C are reacted 15 hours. RevolveAcetonitrile is removed in steaming, adds 750mL water, is extracted with ethyl acetate three times (400mL*4) anhydrous sodium sulfate drying two hours.Revolve and steam except desolventizing. Silicagel column separates and obtains 14.29g product, and yield is 70.4%.
Tamsulosin hydrochloride 890mg is dissolved in to 5mlN, in dinethylformamide solution, adds 160mgNaH, chamberTemperature stirs 1 hour. Add 406mgBr-PEG (n=6)-Br, room temperature reaction 20h. TLC monitoring reacts completely. Post separatesObtain colourless liquid 122mg, yield is 11.5%. M/z[MH]+1063.4。1H-NMR(DMSO-d6)：1.10(d，J＝6.2Hz，6H)，1.39-1.44(t，J＝6.9Hz，6H)，2.60(m，2H)，2.90(m，2H)，3.05-3.13(m，6H)，3.45-3.55(m，12H)，3.60-3.65(m，16H)，3.90(s，6H)，4.07(m，4H)，4.17(t，J＝5.2Hz，4H)，6.90(m，10H)，7.37(dd，J＝8.5Hz，J＝2.2Hz，2H)，7.74(d，J＝2.2Hz，2H)。
Embodiment 4
The antagonism of the bond that the different ethylene glycol of Tamsulosin is modified to α 1A acceptor
Tested material:
Methoxyl group TEG and Tamsulosin bond (TSLX41), bi-methoxy five ethylene glycol and Tamsulosin bond(TSLX52), both-end six ethylene glycol and three samples of Tamsulosin bond (TSLXP62) are as tested material.
Positive control:
Tamsulosin hydrochloride (TSLX), is to be provided by Shanghai Scientia Pharmaceutical Technology Co., Ltd., faces the used time and cushions with calciumLiquid is mixed with desired concn.
Experimental principle:
By having set up the clone of corotation α 1A-AR and G α 16, after being activated, acceptor can cause G α 16 albumenActivation, and then activate phospholipase C (PLC) and produce IP3 and DAG, IP3 can with endoplasmic reticulum in cell and mitochondria onIP3 receptors bind, thus the release of cellular calcium caused. Therefore, the variation of mensuration cellular calcium can be used as and detects α 1A-ARThe method of the state of activation. Fluo-4/AM is that a kind of calcium fluorescence probe indicator is used for measuring calcium ion, as nonpolar liposolubleThe compound of property, enters after cell under the effect of cell lipolytic enzyme, and AM group dissociates, and disengages Fluo-4; Due to Fluo-4Be polar molecule, be difficult for by bimolecular lipid membrane, it can make Fluo-4 be retained in for a long time in cell. Finally can pass throughThe fluorescence intensity that measurement is excited reflects the level that gα protein is activated. If the compound of screening can antagonism α 1A-ARAcceptor, can make calcium current reaction greatly reduce.
Experimental procedure:
By the HEK293 cell kind of stably express α 1A-AR/G α 16 in 96 orifice plates, overnight incubation.
2. suck the training liquid in kind of the hole that has cell, add freshly prepared dyestuff 40 μ l/ holes, in 37 DEG C of incubators, constant temperature is incubatedEducate 40 minutes.
With calcium buffer solution by drug dilution to be measured and mix.
4. dyestuff is exhausted and discarded, wash after one time with freshly prepared calcium buffer solution, change 50 μ l and be dissolved with medicine to be measuredCalcium buffer solution.
5. detect with FlexStationII instrument, within the 15th second, start automatically to add 25 μ l to be dissolved with α 1A-AR by instrument knownThe calcium buffer solution of activator, finally reads 525nm place fluorescent value.
6. data processing:
％response＝(D-B)/(S-B)*100％；
Wherein D is drug-induced calcium current peak value to be measured, and B is the calcium current peak value that blank calcium buffer solution causes, S is knownThe calcium current peak value that activator Phenylephrine (PE) causes.
Experimental result
By data processing software, initial data is processed to the IC that calculates three compounds50, result is as following table 1.
The IC of the bond that the different ethylene glycol of table 1 Tamsulosin is modified50
| Tested medicine | IC50(nM) | 95% fiducial limit (nM) |
| TSLX | 0.3193 | 0.1526 to 0.6681 |
| TSLXP41 | 1.017 | 0.4012 to 2.580 |
| TSLXP52 | 0.9965 | 0.4856 to 2.045 |
| TSLXP62 | 8.327 | 4.881 to 14.21 |
Claims (4)
1. polyethylene glycol-Tamsulosin bond, described bond is the compound with following structure:
2. comprise the pharmaceutical composition of bond as claimed in claim 1 and pharmaceutically acceptable carrier or excipient.
3. pharmaceutical composition as claimed in claim 2, wherein, described pharmaceutical composition be tablet, suppository, pill,The formulation of soft hard-gelatin capsules, powder, solution, supensoid agent or aerosol.
4. the application of bond as claimed in claim 1 in the medicine of preparing anti-prostatic hyperplasia.
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| CN201110393196.1A CN103127520B (en) | 2011-12-01 | 2011-12-01 | The bond of polyethylene glycol and Tamsulosin and pharmaceutical composition thereof |
| PCT/CN2012/001595 WO2013078769A1 (en) | 2011-12-01 | 2012-11-28 | Conjugate of polyethylene glycol and tamsulosin and pharmaceutical composition thereof |
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| CN201110393196.1A CN103127520B (en) | 2011-12-01 | 2011-12-01 | The bond of polyethylene glycol and Tamsulosin and pharmaceutical composition thereof |
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2012
- 2012-11-28 WO PCT/CN2012/001595 patent/WO2013078769A1/en active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| "PEG 修饰青霉素酰化酶及其在两水相生物转化体系中的分配";何汉平等;《华东理工大学学报》;20010228;第27卷(第1期);第109-112页 * |
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| Publication number | Publication date |
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| CN103127520A (en) | 2013-06-05 |
| WO2013078769A1 (en) | 2013-06-06 |
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