CN103127520A - Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same - Google Patents
Combination of polyethylene glycol and tamsulosin and pharmaceutical compound comprising same Download PDFInfo
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- CN103127520A CN103127520A CN2011103931961A CN201110393196A CN103127520A CN 103127520 A CN103127520 A CN 103127520A CN 2011103931961 A CN2011103931961 A CN 2011103931961A CN 201110393196 A CN201110393196 A CN 201110393196A CN 103127520 A CN103127520 A CN 103127520A
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/54—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
Abstract
The invention provides a combination of polyethylene glycol and tamsulosin and a pharmaceutical compound comprising the combination which is as shown in a general formula (II). In the combination, a P and a P' are H or polyethylene glycol, and the P and the P' cannot be the H at the same time. The tamsulosin structurally contains a sulfamide group, the low-molecular-weight polyethylene glycol is introduced through an alkylation reaction, and therefore hydrophobicity of the tamsulosin is lowered, hydrophilism of the tamsulosin is increased, and the blood-brain barrier permeability of the tamsulosin is lowered. Therefore, the toxicity of the tamsulosin is lowered.
Description
Technical field
The present invention relates to conjugate and the pharmaceutical composition thereof of the low Polyethylene Glycol of hydrophilic polymer-Tamsulosin conjugate, especially micromolecule and Tamsulosin.
Background technology
Benign prostate hyperplasia (BPH) is the optimum adenomatous hyperplasia of prostatic urethra peripheral region cell.BPH is commonly encountered diseases, the frequently-occurring disease of middle-aging male, and clinical statistics shows, during 40-79 year, the sickness rate of benign prostate hyperplasia is about male's sickness rate more than 50%, 80 years old up to 80%.The human body prostate is higher than bladder to the sensitivity of α receptor stimulating agent, cause that the sympathetic activation stimulation can cause prostate hyperplasia patient's acute urinary retention, and can the selectivity lax prostata tissue of α receptor blocking agent and smooth muscle of bladder and do not affect the contraction of detrusor of bladder, thereby alleviate and to block, make urinate unimpeded.It is applicable to improve the improvement of the symptoms such as frequent micturition that prostatic hyperplasia causes, urgent micturition, dysuria, and residual urine volume is reduced.
At present, the method that mainly adopts of clinical treatment benign prostate hyperplasia has vigilant wait, operative treatment and Drug therapy etc.If for the drug main alpha-blocking agent of BPH, this class medicine is to come relief of symptoms by expansion bladder outlet and prostate smooth musculature cells.The medicine that represents 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, alleviates rapidly the BPH clinical symptoms, good effect, less adverse effect.Sales volume rapid growth after the Tamsulosin listing is at present domestic and international best selling variety.Although the Tamsulosin good effect, the neural psychiatric system untoward reaction such as dizziness is arranged, walk haltingly.The main cause that untoward reaction produces: α 1 adrenoreceptor spreads all over whole body, after α 1 adrenoreceptor retardance, some physiological changies can occur, relate generally to cardiovascular (CVS) and central nervous system (CNS), cause negative effect, vasodilative effect as α 1ARA can cause nasal obstruction, cardiopalmus, postural hypotension or faintness, the old people can thereby fall down and causes injury or fracture of femoral neck, how to occur when going urine night, can cause death.α 1 adrenoceptor inhibitor also can see through blood brain barrier and enter CNS, selective activation five hydroxytryptamine 1A receptor, thereby the sympathetic tension force of reduction maincenter, peripheral vascular resistance is descended, Blood pressure drop, it can cause giddy, the side effect such as dizzy, drowsiness, weak, tired to the direct effect of CNS.Therefore, particularly need to provide a kind of hypotoxic Tamsulosin, lower it to the toxic and side effects of cental system.
Polyethylene Glycol (PEG) modification technique is a Novel medicine feeding technology that develops rapidly in recent years, is mainly used in the drug 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 mainly has the following advantages through after polyethyleneglycol modified: the water solublity that 1, increases medicine; 2, reduce toxicity; 3, prolong drug circulating half-life reduces the medication number of times, improves patient dependence, improves the quality of living, and reduces medical expense; 4, reduce enzyme degradation, improve bioavailability; 5, reduce the blood brain barrier transmitance, reduce the maincenter side effect.After linking with Polyethylene Glycol, change has occured in the pharmacokinetics of medicine, and then changes pharmacodynamics.Particularly Polyethylene Glycol can make blood drug level keep or near the time lengthening of aimed concn, keep the drug effect of medicine to be brought into play fully.At present, the representative of polyethyleneglycol modified drug products has in the international market:
MICERA.At present, polyethyleneglycol modified small-molecule drug is also not approval listing in the international market, and clinical but several products entered for two, three phases, representative has NKTE-102 and the NKTR-118 of Nektar.
This experimental group is devoted to the research (ZL03801109.3, ZL 200410029615.3, ZL 200480005763.X, ZL 200810093688.7, ZL 02107842.4, ZL 02108778.4) of pegylation small-molecule drug always.Be mainly to adopt Polyethylene Glycol to link with small-molecule drug, the product that obtains is having good improvement aspect the solubilising attenuation.
This patent adopts the Pegylation technology to carry out structure of modification to Tamsulosin, utilize low-molecular-weight Polyethylene Glycol and Tamsulosin to link, increase the water solublity of Tamsulosin itself, thereby lower Tamsulosin to the toxic and side effects of cental system, make it can be developed to injection or be fit to oral preparation.
Summary of the invention
One aspect of the present invention provides a kind of Polyethylene Glycol as general formula (II)-Tamsulosin conjugate:
Wherein:
P, P ' are H or Polyethylene Glycol, and P, P ' are not H simultaneously.
In some embodiments of the present invention, P, P ' are the single-ended Polyethylene Glycol of straight chain or the H as shown in the formula expression:
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 conjugate is the Polyethylene Glycol-Tamsulosin conjugate of general formula (III):
Wherein, n is the integer of 0-20.
In some embodiments of the present invention, described Polyethylene Glycol-Tamsulosin conjugate is the Polyethylene Glycol-Tamsulosin conjugate of general formula (IV):
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 conjugate is selected from one of compound that has following structure:
The Polyethylene Glycol of the logical formula V that another aspect of the present invention provides-Tamsulosin conjugate,
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 conjugate is the compound with following structure:
Another aspect of the present invention is to provide the pharmaceutical composition that comprises described conjugate and pharmaceutically acceptable carrier or excipient.
In some embodiments of the present invention, described pharmaceutical composition is the dosage form of tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol.
Another aspect of the present invention is to provide the application of described conjugate in the medicine of preparation anti-prostatic hyperplasia.
Advantage of the present invention is that the modification by hydrophilic polymer can provide protection to Tamsulosin, improves drug absorption, extends action time, heightens the effect of a treatment, and reduces the blood brain barrier transmitance and avoids toxic and side effects.
The specific embodiment
Contain sulfoamido in the Tamsulosin structure, can pass through alkylated reaction, introduce low molecular poly, reach the hydrophobicity that reduces Tamsulosin, increase its hydrophilic, reduce its blood brain barrier transmitance, thereby reduce the purpose of its toxicity.
Conjugate of the present invention prepares as follows: the low Polyethylene Glycol of hydrophilic is carried out modification, introduce halogen or mesyl, to the easy leaving group such as benzene mesyl, then be combined with Tamsulosin under alkali condition.By introducing low Polyethylene Glycol, improve blood brain barrier and see through, thereby reduce it to untoward reaction and the toxicity of cental system.
For low Polyethylene Glycol, adopt the ethylene glycol polymerized unit to be represented, the general number that contains the ethylene glycol unit that adopts represents, ethylene glycol unit number range is 0-20, is preferably 3-10.
Polyethylene Glycol of the present invention also comprises derivant and the analog of Polyethylene Glycol, also can be replaced by following hydrophilic polymer the group that described hydrophilic polymer selects free Polyethylene Glycol, polyglutamic acid, poly-aspartic-acid, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine, poly-oxazoline and their copolymer to form.
Conjugate of the present invention can the pure compound form or suitable pharmaceutical compositions carry out administration, the reagent that can adopt any acceptable administering mode or be used for similar purposes carries out.Therefore, the administering mode that adopts can be selected by mouth, intranasal, non-intestinal, 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, suspensoid or aerosol etc., the preferred presented in unit dosage form that adopts the simple administration that is applicable to exact dose.Compositions can comprise conventional pharmaceutical carrier or excipient and as the conjugate of the present invention of active component (one or more), in addition, also can comprise other medicament, carrier, adjuvant etc.
Usually, according to required administering mode, pharmaceutically acceptable compositions will comprise approximately 1 to the approximately conjugate of the present invention of 99 % by weight and the suitable pharmaceutical excipient of 99 to 1 % by weight.Preferred composition comprises the approximately conjugate of the present invention of 5 to 75 % by weight, and all the other are suitable pharmaceutical excipient.
The pharmaceutical composition that can adopt the liquid form administration such as the medicinal adjuvant dissolving that can conjugate of the present invention (approximately 0.5 to approximately 20%) and selectivity be existed by means such as dissolving, dispersions, be scattered in carrier, the example of carrier is water, saline, dextrose hydrate, glycerol, ethanol etc., thereby forms solution or suspensoid.
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 agent, antioxidant etc., such as: citric acid, Arlacel-20, Emulphor FM, Yoshinox BHT etc.
Following examples are used for illustrating the present invention, but are not used for limiting the present invention.
Embodiment
In embodiment, tamsulosin hydrochloride used is investigated things is to attain knowledge Pharmaceutical Technology Co., Ltd by Shanghai provides, tert-butyl group bromination ammonium is buied from Xinfeng, Shouguang chemical industry Co., Ltd, paratoluensulfonyl chloride from Shandong hundred million Yilong Industry Co., Ltd. buy, the sodium hydride slave ladder is uncommon likes that (Shanghai) changes into the industrial development company limited and buys, and 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 conjugate (TSLX41)
Add the 9.07g paratoluensulfonyl chloride in the 250mL there-necked flask, the 32mL pyridine is cooled to 0 ℃.With 8.26gmPEG (n=4)-OH and 16mL pyridine mixing, be added drop-wise in there-necked flask, dripped off in two hours, controlling temperature is 0-10 ℃.Continuation stirring reaction two hours at this temperature.The TLC monitoring reaction is complete.Add 130mL cold water and 48mL concentrated hydrochloric acid in reactant liquor, slowly stir half an hour, reactant liquor is transferred in the 500mL separatory funnel, add ethyl acetate extraction twice (200mL+100mL).Organic layer merges, and washes to neutrality anhydrous sodium sulfate drying two hours with water.Rotary Evaporators steams solvent.Obtain viscous liquid 11.34g altogether, be directly used in next step reaction.
Intermediate of upper step is dissolved in the 100mL acetonitrile, adds 25.66g tert-butyl group bromination ammonium, 50 ℃ were reacted 15 hours.Revolve to steam and remove acetonitrile, add 300mL water, with ethyl acetate extraction three times (200mL*4), anhydrous sodium sulfate drying two hours.Revolve the steaming desolventizing.The silicagel column separation obtains the 8.67g product, and yield is 80.66%.
With Tamsulosin hydrochlorate 356mg, potassium carbonate 664mg joins in the 100mL there-necked flask that fills the 20mL acetonitrile, stirring at room 2 hours.The 10mL acetonitrile solution that will be dissolved with 217mg mPEG (n=4) Br joins in above-mentioned reaction bulb, and back flow reaction is spent the night.The TLC monitoring reaction is complete.The post separation 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 conjugate (TSLX52)
With Tamsulosin hydrochlorate 356mg, potassium carbonate 664mg joins in the 100mL there-necked flask that fills the 20mL acetonitrile, stirring at room 2 hours.The 10mL acetonitrile solution that will be dissolved with 759mg mPEG (n=5) Br joins in above-mentioned reaction bulb, and back flow reaction is spent the night.The TLC monitoring reaction is complete.The post separation obtains colourless liquid 258mg, and yield is 36.8%.m/z[MH]
+877.8。
1H-NMR(CDCl
3)：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 conjugate (TSLXP62)
Add the 22.9g paratoluensulfonyl chloride in the 500mL there-necked flask, the 80mL pyridine is cooled to 0 ℃.With 14.1gHO-PEG (n=6)-OH and 40mL pyridine mixing, be added drop-wise in there-necked flask, dripped off in two hours, controlling temperature is 0-10 ℃.Continuation stirring reaction two hours at this temperature.The TLC monitoring reaction is complete.Add 300mL cold water and 120mL concentrated hydrochloric acid in reactant liquor, slowly stir half an hour, reactant liquor is transferred in the 1000mL separatory funnel, add ethyl acetate extraction twice (300mL+200mL).Organic layer merges, and washes to neutrality anhydrous sodium sulfate drying two hours with water.Rotary Evaporators steams solvent.Obtain viscous liquid 28.7g altogether, be directly used in next step reaction.
Intermediate of upper step is dissolved in the 300mL acetonitrile, adds 28.7g tert-butyl group bromination ammonium, 50 ℃ were reacted 15 hours.Revolve to steam and remove acetonitrile, add 750mL water, with ethyl acetate extraction three times (400mL*4), anhydrous sodium sulfate drying two hours.Revolve the steaming desolventizing.The silicagel column separation obtains the 14.29g product, and yield is 70.4%.
Tamsulosin hydrochlorate 890mg is dissolved in 5ml DMF solution, adds 160mg NaH, stirring at room 1 hour.Add 406mg Br-PEG (n=6)-Br, room temperature reaction 20h.The TLC monitoring reaction is complete.The post separation obtains colourless liquid 122mg, and 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 conjugate that the different ethylene glycol of Tamsulosin are modified to α 1A receptor
Tested material:
Methoxyl group TEG and Tamsulosin conjugate (TSLX41), bi-methoxy five ethylene glycol and Tamsulosin conjugate (TSLX52), both-end six ethylene glycol and three samples of Tamsulosin conjugate (TSLXP62) are as tested material.
Positive control:
Tamsulosin hydrochloride (TSLX) is to investigate things is to attain knowledge Pharmaceutical Technology Co., Ltd by Shanghai to provide, and faces the used time to be mixed with desired concn with the calcium buffer.
Experimental principle:
By having set up the cell line of corotation α 1A-AR and G α 16, can cause the activation of G α 16 albumen after making receptor be activated, and then activate phospholipase C (PLC) and produce IP3 and DAG, IP3 can with endoplasmic reticulum in cell and mitochondrion on the IP3 receptors bind, thereby cause the release of cellular calcium.Therefore, the variation of mensuration cellular calcium can be used as the method that detects the α 1A-AR state of activation.Fluo-4/AM is that a kind of calcium fluorescent probe indicator is used for measuring calcium ion, as nonpolar fat-soluble compound, enters after cell under the effect of cell lipolytic enzyme, and the AM group dissociates, and disengages Fluo-4; Because Fluo-4 is polar molecule, be difficult for by bimolecular lipid membrane, it can make Fluo-4 be retained in cell for a long time.Finally can reflect by the fluorescence intensity that measurement is excited the level that gα protein is activated.If the compound of screening can antagonism α 1A-AR receptor, the calcium current reaction is reduced greatly.
Experimental procedure:
With 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 the hole that cell kind is arranged, add freshly prepared dyestuff 40 μ l/ holes, 37 ℃ of interior constant-temperature incubations of incubators 40 minutes.
3. use the calcium buffer with drug dilution to be measured and mixing.
4. the dyestuff exhaustion is discarded, after washing one time with freshly prepared calcium buffer, change the calcium buffer that 50 μ l are dissolved with medicine to be measured.
5. detect with FlexStation II instrument, beginning in the 15th second adds 25 μ l to be dissolved with the calcium buffer of the known agonist of α 1A-AR by instrument automatically, finally reads 525nm place fluorescent value.
6. date processing:
％response＝(D-B)/(S-B)*100％；
Wherein D is drug-induced calcium current peak value to be measured, the calcium current peak value that B causes for blank calcium buffer, and S is the calcium current peak value that known agonist Phenylephrine (PE) causes.
Experimental result
By data processing software, initial data is processed the IC that calculates three compounds
50, result such as following table 1.
The IC of the conjugate that the different ethylene glycol of table 1 Tamsulosin are modified
50
| Tested medicine | IC 50(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 (14)
1. the Polyethylene Glycol as general formula (II)-Tamsulosin conjugate:
Wherein:
P, P ' are H or Polyethylene Glycol, and P, P ' are not H simultaneously.
2. Polyethylene Glycol as claimed in claim 1-Tamsulosin conjugate, wherein, P, P ' they are the single-ended Polyethylene Glycol of straight chain or the H as shown in the formula expression:
Wherein, n is the integer of 0-20.
3. Polyethylene Glycol as claimed in claim 1-Tamsulosin conjugate, wherein, P, P ' they are straight chain both-end Polyethylene Glycol, as shown in the formula expression:
Wherein, n is the integer of 0-20.
4. Polyethylene Glycol as claimed in claim 2-Tamsulosin conjugate, wherein, described conjugate is the Polyethylene Glycol-Tamsulosin conjugate of general formula (III):
Wherein, n is the integer of 0-20.
5. Polyethylene Glycol as claimed in claim 3-Tamsulosin conjugate, wherein, described conjugate is the Polyethylene Glycol-Tamsulosin conjugate of general formula (IV):
Wherein, n is the integer of 0-20.
6. Polyethylene Glycol as described in one of claim 2 to 5-Tamsulosin conjugate, wherein, n is the integer of 2-15.
7. Polyethylene Glycol as claimed in claim 6-Tamsulosin conjugate, wherein n is the integer of 3-10.
8. Polyethylene Glycol as claimed in claim 4-Tamsulosin conjugate, wherein said conjugate is selected from one of compound that has following structure:
9. the Polyethylene Glycol of a kind as logical formula V-Tamsulosin conjugate:
Wherein, n is the integer of 0-20.
10. Polyethylene Glycol as claimed in claim 9-Tamsulosin conjugate, wherein n is the integer of 0-15.
11. Polyethylene Glycol as claimed in claim 9-Tamsulosin conjugate, wherein said conjugate are the compound with following structure:
12. comprise the pharmaceutical composition of conjugate as described in any one of claim 1 to 11 and pharmaceutically acceptable carrier or excipient.
13. pharmaceutical composition as claimed in claim 12, wherein, described pharmaceutical composition is the dosage form of tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol.
14. the application of conjugate as described in any one of claim 1 to 11 in the medicine of preparation anti-prostatic hyperplasia.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| CN103127520A true CN103127520A (en) | 2013-06-05 |
| CN103127520B CN103127520B (en) | 2016-05-04 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014190763A1 (en) * | 2013-05-31 | 2014-12-04 | 天津键凯科技有限公司 | Low molecular weight polyethylene glycol drug conjugates having improved drug biological activity |
| CN106310289A (en) * | 2015-06-24 | 2017-01-11 | 天津键凯科技有限公司 | Conjugate of polyethylene glycol and narcotic and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105144A1 (en) * | 2001-04-17 | 2003-06-05 | Ping Gao | Stabilized oral pharmaceutical composition |
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| 《华东理工大学学报》 20010228 何汉平等 "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" 第109-112页 1-14 第27卷, 第1期 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014190763A1 (en) * | 2013-05-31 | 2014-12-04 | 天津键凯科技有限公司 | Low molecular weight polyethylene glycol drug conjugates having improved drug biological activity |
| CN104208715A (en) * | 2013-05-31 | 2014-12-17 | 天津键凯科技有限公司 | Low molecular weight polyethylene glycol drug conjugate with improved drug bioactivity |
| CN104208715B (en) * | 2013-05-31 | 2016-12-28 | 天津键凯科技有限公司 | There is the medicine bioactive low molecular poly drug conjugates of raising |
| CN106310289A (en) * | 2015-06-24 | 2017-01-11 | 天津键凯科技有限公司 | Conjugate of polyethylene glycol and narcotic and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013078769A1 (en) | 2013-06-06 |
| CN103127520B (en) | 2016-05-04 |
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