CN101993433B - Olmesartan organic amine salt, preparation method and application thereof - Google Patents
Olmesartan organic amine salt, preparation method and application thereof Download PDFInfo
- Publication number
- CN101993433B CN101993433B CN 201010257447 CN201010257447A CN101993433B CN 101993433 B CN101993433 B CN 101993433B CN 201010257447 CN201010257447 CN 201010257447 CN 201010257447 A CN201010257447 A CN 201010257447A CN 101993433 B CN101993433 B CN 101993433B
- Authority
- CN
- China
- Prior art keywords
- olmesartan
- preparation
- organic amine
- amine salt
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000005480 Olmesartan Substances 0.000 title claims abstract description 29
- 229960005117 olmesartan Drugs 0.000 title claims abstract description 29
- -1 amine salt Chemical class 0.000 title claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 239000002220 antihypertensive agent Substances 0.000 claims abstract description 4
- 229940127088 antihypertensive drug Drugs 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical group NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical group C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 5
- 229960001231 choline Drugs 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003799 water insoluble solvent Substances 0.000 claims description 4
- 239000003021 water soluble solvent Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 150000002148 esters Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 230000001631 hypertensive effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 238000012360 testing method Methods 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 239000004381 Choline salt Substances 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000019417 choline salt Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an olmesartan organic amine salt, a preparation method and application thereof. Particularly, the invention relates to an olmesartan organic amine salt of formula (I) and a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of such compounds and application of olmesartan organic amine in the preparation of antihypertensive drugs.
Description
Technical field
The present invention relates to Olmesartan organic amine salt, preparation and preparation method thereof, and the pharmaceutical composition that contains this compound for the treatment of significant quantity, and for the preparation of the purposes in the antihypertensive drug.
Background technology
Olmesartan is selectivity Angiotensin II 1 receptor (AT1) antagonist, blocks the vasoconstriction effect of Angiotensin II by the combination of selective exclusion Angiotensin II and vascular smooth muscle AT1 acceptor, thereby reduces blood pressure.
Have carboxyl in the Olmesartan molecular structure, the interior absorption of its body is relatively poor, is unfavorable for being prepared to pharmaceutical dosage form.In order to improve its bioavailability, people are made into active ester by the method for chemically modified, i.e. olmesartan medoxomill, and its bioavailability is about 26%, and is also undesirable, modifies so that this drug molecular structure is complicated in addition, increased synthetic difficulty.
Summary of the invention
In order to overcome the low shortcoming of Olmesartan bioavailability, the present invention finds by research, and Olmesartan and organic amine salify can be improved its pharmacokinetic characteristic well, improves its bioavailability, is more suitable in conventional formulation technique.
The object of the present invention is to provide the Olmesartan organic amine salt, preparation shown in the formula (I), have lower array structure:
Wherein, B is organic amine, is selected from methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, thanomin, piperazine, dibenzyl-ethylenediamin, meglumine, tromethane, tetramethyl-quaternary ammonium, tetraethyl-quaternary ammonium or choline; Be preferably thanomin
Or choline
Another object of the present invention is to provide the method for preparing above-claimed cpd, the method comprises the following steps:
1) in alcohol organic solvent, adds respectively Olmesartan acid and organic amine B, make it salify under room temperature or the heating;
2) obtain the crystal of Olmesartan organic amine salt, preparation with single or mixed solvent crystallization, filtration, dry treatment process.
Wherein said single or mixed solvent comprises water-soluble solvent and water-insoluble solvent, and described water-soluble solvent is selected from lower alcohol, acetone or its mixture; Described water-insoluble solvent is selected from esters solvent, ether solvent, halogenated hydrocarbon solvent or its mixture; Described lower alcohol is selected from methyl alcohol, ethanol, propyl alcohol or Virahol.
Another object of the present invention is to provide a kind of hypertensive pharmaceutical composition that is used for the treatment of, wherein contain Olmesartan organic amine salt, preparation and pharmaceutically acceptable carrier as the treatment significant quantity of effective constituent.
Further, the purposes of pharmaceutical composition in the preparation antihypertensive drug that the invention provides Olmesartan organic amine salt, preparation and contain them.
In the process for preparation of pharmaceutical composition, importantly drug substance is a kind of form that is convenient to operation and processes.Not only from the preparation method's that obtains viable commercial angle, and contain the angle of the pharmaceutical preparation of this active compound from subsequently preparation, this all is very important.
In addition, in the process of pharmaceutical compositions, importantly after patient's administration, provide a kind of reliable, reproducible and constant drug plasma concentration curve.
The chemical stability of activeconstituents, solid-state stability and " storage time " are very important factor equally.This drug substance and the composition that comprises it should preferably can store the quite a while effectively, and the physics-chem characteristic of activeconstituents (for example its chemical constitution, density, water absorbability and solubleness) does not show significant variation.
In addition, providing as far as possible, the medicine of chemical pure form is very important equally.
Those skilled in the art are appreciated that, typically, if a kind of medicine can obtain with stable form at an easy rate, for example stable crystal formation can provide following advantage: be easy to process, be easy to prepare suitable pharmaceutical preparation and have reliable dissolving characteristic so.
The activeconstituents significant quantity is to be effective non-toxic, the scope of preferred 0.001～100mg/kg TBW, more preferably 0.001～50mg/kg.When treatment needed the patient of Olmesartan organic amine salt, preparation treatment, preferred oral or parenteral administration comprised part, rectum, through skin, injection or continue transfusion.Human oral administration dosage preferably includes 0.05～3500mg activeconstituents, most preferably 0.5～1000mg activeconstituents.Use is preferred than the oral administration form of low dosage.Yet, to patient safety at one's leisure, also can the administration of administered with high dose parenteral.Above-mentioned dosage relates to preferably the amount of the activeconstituents that represents with free acid.
Those skilled in the art should affirm, character and the degree for the treatment of disease looked at the best administration quantity of activeconstituents individual dose and interval, form of administration, approach and position, and the concrete patient for the treatment of and decide, and this preferred plan can be definite by common technology.Those skilled in the art also should be understood that the best course for the treatment of, and the dosage number of times that namely gives activeconstituents in the given time every day can use the test of really constant current modulation journey commonly used to determine through those skilled in the art.
Compound of the present invention can oral or parenteral administration, can be made into to comprise that tablet, pill, pulvis and granule are used for various route of administration.In these solid preparations, activeconstituents mixes mutually with a kind of inert diluent at least.According to routine operation, oral preparations also can comprise just inert diluent other materials in addition, such as lubricant, glidant and antioxidant.If make capsule, tablet and pill, comprise buffer reagent in the preparation.Tablet and pill also can be made into sustained release forms.
Although also can adopt the non-aqueous solution of emulsion, parenteral drug-delivery preparation of the present invention comprises aseptic aqueous solution.These formulations also can comprise adjuvant, such as sanitas, wetting agent, permeate agent, buffer reagent, emulsifying agent and dispersion agent.Its sterilization can be adopted bacterium to hold back filter (bacteria retainingfilter) and filter, and adds disinfectant in composition, the method sterilization of irradiation composition or heating combination.
Salt of the present invention is compared with Olmesartan, and major advantage is as follows:
(1) salt of the present invention is at the solvent of routine, obviously increases such as the solubleness in the water, in methyl alcohol and 0.1% hydrochloric acid, is applicable to conventional formulation.
(2) salt of the present invention has the characteristic of the stability of improvement.
(3) salt of the present invention has better bioavailability.
(4) salt of the present invention with high yield, high purity, fast, convenient and low cost is prepared, wherein ethanolamine salt, choline salt have superiority in operational path, directly crystallize out.
Embodiment
Embodiment one
The preparation of Olmesartan ethanolamine salt
Olmesartan acid (1.34g) is joined in the methyl alcohol (30ml), add thanomin (0.183g) under the room temperature, be warming up to backflow, the elimination insolubles, filtrate decompression concentrates desolventizing, and residuum adds acetone (20ml) and stirs 2h, filter, oven dry gets white solid 1.42 grams.
Embodiment two
The preparation of Olmesartan choline salt
Olmesartan acid (1.34g), 46% aqueous choline base solution (0.79g) are joined in the ethanol (40ml), stir be concentrated into behind the 1h dried, add Virahol stirring at room 1h after elimination not tolerant, filtrate is concentrated into dried, add acetone and stir 2h, filter, dry to get white solid 1.21 grams.
Test example one: bioavailability test
Take male beasle dog as subjects, body weight 7-9kg, divide three groups, every group 6, to olmesartan medoxomill, embodiment one compound, embodiment two compounds totally three compounds test respectively, dosage is 1mg/kg (all with acid calculate), compound all is made into suspension with 0.5%CMC-Na, the administration volume is 20ml/, fasting 12h before the test.
Result such as table 1.
Table 1
Conclusion (of pressure testing): compare with olmesartan medoxomill, in animal (beasle dog) body, the compounds of this invention has shown better absorption, i.e. higher relative bioavailability.
Test example two: solubleness testing experiment (seeing Table 2 and 3)
Conclusion (of pressure testing): compare with olmesartan medoxomill, the solubleness of compound provided by the invention in conventional solvent obviously raises.
Claims (8)
1. the Olmesartan organic amine salt, preparation shown in the formula (I):
Wherein, B is thanomin or choline.
2. Olmesartan organic amine salt, preparation according to claim 1, wherein B is the thanomin shown in the formula (II).
3. Olmesartan organic amine salt, preparation according to claim 1, wherein B is the choline shown in the formula (III).
4. method for preparing such as each described Olmesartan organic amine salt, preparation of claim 1-3, the method comprises the following steps:
1) in alcohol organic solvent, adds respectively Olmesartan acid and organic amine B, make it salify under room temperature or the heating;
2) obtain the crystal of Olmesartan organic amine salt, preparation with single or mixed solvent crystallization, filtration, dry treatment process.
5. method according to claim 4, wherein said single or mixed solvent is selected from water-soluble solvent and water-insoluble solvent.
6. method according to claim 5, wherein
Described water-soluble solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, acetone or its mixture; And
Described water-insoluble solvent is selected from esters solvent, ether solvent, halogenated hydrocarbon solvent or its mixture.
7. one kind is used for the treatment of hypertensive pharmaceutical composition, this pharmaceutical composition contain as the treatment significant quantity of effective constituent such as each described Olmesartan organic amine salt, preparation of claim 1-3 and pharmaceutically acceptable carrier.
8. the application in the preparation antihypertensive drug such as each described Olmesartan organic amine salt, preparation of claim 1-3 or pharmaceutical composition as claimed in claim 7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010257447 CN101993433B (en) | 2009-08-11 | 2010-08-11 | Olmesartan organic amine salt, preparation method and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910164838 | 2009-08-11 | ||
| CN200910164838.3 | 2009-08-11 | ||
| CN 201010257447 CN101993433B (en) | 2009-08-11 | 2010-08-11 | Olmesartan organic amine salt, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101993433A CN101993433A (en) | 2011-03-30 |
| CN101993433B true CN101993433B (en) | 2013-04-24 |
Family
ID=43784248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010257447 Expired - Fee Related CN101993433B (en) | 2009-08-11 | 2010-08-11 | Olmesartan organic amine salt, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101993433B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727356A (en) * | 2018-06-28 | 2018-11-02 | 江苏新瑞药业有限公司 | A kind of synthetic method of olmesartan medoxomil alkali metal salt |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5744612A (en) * | 1996-03-21 | 1998-04-28 | Toyo Kasei Kogyo Company Limited | Process for preparation of 5- substituted tetrazoles |
| CN1638764A (en) * | 2002-03-08 | 2005-07-13 | 三共株式会社 | Eye drops containing tetrazole derivative |
-
2010
- 2010-08-11 CN CN 201010257447 patent/CN101993433B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5744612A (en) * | 1996-03-21 | 1998-04-28 | Toyo Kasei Kogyo Company Limited | Process for preparation of 5- substituted tetrazoles |
| CN1638764A (en) * | 2002-03-08 | 2005-07-13 | 三共株式会社 | Eye drops containing tetrazole derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101993433A (en) | 2011-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2828177T3 (en) | Procedure for the treatment of tumor, pharmaceutical composition and medicine cabinet | |
| JP6876758B2 (en) | Dosage form composition comprising an inhibitor of Bruton's tyrosine kinase | |
| TWI384984B (en) | Orally adminstrable anticancer pharmaceutical composition | |
| ES2702541T3 (en) | Donepezil pamoate, method of preparation and its use | |
| ES2792149T3 (en) | Pharmaceutical Compositions Having Improved Storage Stability | |
| JP5406197B2 (en) | Co-solvent compositions and methods for improving delivery of dantrolene therapeutics | |
| JP2021178846A (en) | Formulations of bendamustine | |
| JP2012518008A (en) | Delayed release oral dosage composition containing amorphous CDDO-ME | |
| BRPI0716227A2 (en) | DRY COMPOUND FORMULATIONS AND USE | |
| US12016951B2 (en) | Edaravone pharmaceutical composition | |
| CN102548988B (en) | Azilsartan organic amine salts, preparation method and use thereof | |
| CN102603723B (en) | Azilsartan organic amine salts, and preparation method and application thereof | |
| JP6265999B2 (en) | Long-acting injection preparation containing optically active tolvaptan and method for producing the same | |
| US20200376004A1 (en) | Amorphous onapristone compositions and methods of making the same | |
| TW201705960A (en) | Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester | |
| CN109843868A (en) | The active inhibition of OLIG2 | |
| CN101961311A (en) | 5alpha-androstane (alkyl)-3beta,5,6beta-triol injection and preparation method thereof | |
| CN101993433B (en) | Olmesartan organic amine salt, preparation method and application thereof | |
| CN101921264A (en) | Candesartan organic amine salt and preparation method and application thereof | |
| CN101596189A (en) | The Pharmaceutical composition that contains imidazole-5-carboxylic acid derivatives | |
| CN107235960B (en) | Amide derivatives, preparation method and medical application thereof | |
| JP5872060B2 (en) | Methods and improved pharmaceutical compositions for enhancing transdermal delivery of PDE-5 inhibitors | |
| CN111346104B (en) | Morphine-6-glucuronide transdermal drug delivery pharmaceutical composition, preparation method and application thereof | |
| WO2014007239A1 (en) | Composition containing amphotericin b | |
| JPH09104627A (en) | Aqueous eye lotion containing apaphant as active component |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: JIANGSU HANSOH MEDICAL RESEARCH INSTITUTE CO., LTD. Effective date: 20140618 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140618 Address after: 222047 Lianyungang Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: JIANGSU HANSOH MEDICINE INSTITUTE Co.,Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160315 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222047 Lianyungang Development Zone, Jiangsu Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130424 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |