CN100367964C - Inclusion preparation of levosimendan and beta cyclodextrin - Google Patents
Inclusion preparation of levosimendan and beta cyclodextrin Download PDFInfo
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- CN100367964C CN100367964C CNB2004100376675A CN200410037667A CN100367964C CN 100367964 C CN100367964 C CN 100367964C CN B2004100376675 A CNB2004100376675 A CN B2004100376675A CN 200410037667 A CN200410037667 A CN 200410037667A CN 100367964 C CN100367964 C CN 100367964C
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- levosimendan
- injection
- beta cyclodextrin
- hydroxypropyl beta
- preparation
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Abstract
The present invention relates to medicine for resisting heart failure, namely an inclusion preparation of levosimendan-beta cyclodextrin or derivatives thereof. The preparation uses levosimendan which is calcium sensitive positive inotropic medicine as a main molecule, and beta cyclodextrin or derivatives thereof, such as hydroxypropyl beta cyclodextrin, as a guest molecule to prepare an inclusion.
Description
Technical field:
The present invention relates to a kind of anti-heart failure medicine-quick property of beta cyclodextrin inclusion preparation, particularly calcium inotropic agent levosimendan is that host molecule, hydroxypropyl beta cyclodextrin are the preparation of the inclusion of enclosed molecule.
Technical background:
Levosimendan, chemical name [(4-(1,4,5,6-tetrahydrochysene-4-methyl-6-oxo-3-pyridazinyl) phenyl) hydrazono-] Cyanoacetyl-Cyacetazid, its structural formula is as follows:
Levosimendan is a calcium enhanced sensitivity cardiac muscle positive inotropic medicament, is mainly used in the treatment of congestive heart failure.Its preparation method sees EP56556B1, WO97/35841, WO01/19334, WO98/01111, CN1470238A.
Levosimendan is the crystallization of yellow powder shape, is slightly soluble in water, and pKa is 6.26, and dissolubility is 0.4mg/ml in phosphate buffer (pH7.4), and dissolubility is respectively 0.03mg/ml and 0.02mg/ml in pH6 and pH2 water; Indissoluble and easily degraded in the water.The levosimendan preparation that has gone on the market is left Xi Meng-KollidonPF12 injection, and still, Chinese Pharmacopoeia 2000 editions does not record non-blood vessel adjuvant KollidonPF12, has report to think that it is bad that KollidonPF12 makes solubilising stabilizing agent effect.
Summary of the invention:
The present invention adopts beta cyclodextrin or derivatives thereof and levosimendan to form clathrate,, has obtained and has made the levosimendan good stability, the effect that dissolubility is strong as solvent for injection with ethanol.
The invention provides a kind of new levosimendan injection and preparation method thereof.
The present invention also provides the method that increases the levosimendan dissolubility.
Injection of the present invention contains the levosimendan of effective dose, the beta cyclodextrin or derivatives thereof, and injectable ethanol also can add excipient and PH regulator in case of necessity.
Use the cyclodextrin or derivatives thereof that levosimendan is carried out enclose, so that levosimendan is easily molten.As use beta-schardinger dextrin-or HP-.Preferably use HP-(Hydroxypropyl-beta-Cyclodextrin; Be called for short: HP-β-CD or HPB).HP-is safe, nontoxic, stable blood vessel and the medicinal adjuvant of non-blood vessel.
Injection of the present invention, levosimendan and beta-schardinger dextrin-or derivatives thereof form clathrate, and wherein the weight ratio of levosimendan and beta-schardinger dextrin-or derivatives thereof is 1: 1～1: 100.The weight ratio of preferred levosimendan and cyclodextrin or derivatives thereof is 1: 5～1: 30.Mol ratio can be 1: 10, is preferably 1: 5.Above-mentioned clathrate can be as the raw material of injection, powder pin or transfusion.Said injection can be " 1-20ml injection with small volume ", " freeze-dried powder ", " aseptic powder injection " or add in " glucose infusion liquid, sodium chloride transfusion, xylitol transfusion ", " vein emulsion ", " injection ", said " freeze-dried powder " is that levosimendan beta-schardinger dextrin-or derivatives thereof forms in the solution of clathrate and adds suitable excipient, as mannitol, lactose, dextran, sorbitol, sucrose, sodium chloride, xylitol etc., get by lyophilization.Said " aseptic powder injection " is to add suitable excipient in the solution of levosimendan beta-schardinger dextrin-or derivatives thereof formation clathrate, as PH regulator, mannitol, lactose, dextran, sorbitol, glucose, sucrose, sodium chloride, xylitol etc., the powder that obtains by " lyophilization " or " spray drying " carries out aseptic subpackaged getting.
The present invention also provides the preparation method of injection of the present invention, carries out the preparation of the injection of the present invention of enclose for above-mentioned use beta-schardinger dextrin-or derivatives thereof, may further comprise the steps:
A) the beta-schardinger dextrin-or derivatives thereof is placed ethanol, after the stirring and dissolving, add again the levosimendan stirring at room make molten, levosimendan beta-schardinger dextrin-or derivatives thereof inclusion complex in solution,
Can add PH regulator, mannitol, lactose, dextran, sorbitol, sucrose, glucose, sodium chloride, xylitol, injection ethanol when b) gained solution needs as excipient and make it dissolving,
C) solution that in case of necessity step b or step c is obtained is through vacuum drying or spray drying, levosimendan powder-beta-dextrin or derivatives thereof clathrate injection powder,
D) packing.
Injection of the present invention contains the 1-100mg levosimendan, preferably 1-10mg, more preferably 2-5mg in the per unit preparation.
Injection of the present invention, described solvent for injection are injection ethanol, preferably dehydrated alcohol.
Injection of the present invention adds the PH regulator in case of necessity, and described PH regulator is selected from acidic materials, and example hydrochloric acid, citric acid, acetic acid, phosphoric acid etc. are preferably citric acid.
The present invention with levosimendan make host molecule, the beta cyclodextrin or derivatives thereof is made enclosed molecule, the enclosed molecule hydroxypropyl beta cyclodextrin has been carried out following experiment to the solubilizing effect of host molecule levosimendan: concrete steps are: get levosimendan and hydroxypropyl beta cyclodextrin (HP β CD) in molar ratio and be dissolved in the injection dehydrated alcohol, make the PH regulator with citric acid/ammonium carbonate, the investigation hydroxypropyl beta cyclodextrin to the solubilizing effect of levosimendan, the results are shown in Figure 1 under different pH.As can be seen from the results, the dissolubility of levosimendan and pH value of solution, hydroxypropyl beta cyclodextrin amount are relevant.
The checking of Levosimendan hydroxypropyl beta cyclodextrin solubilizing effect:
Prepare its alcoholic solution by Levosimendan hydroxypropyl beta cyclodextrin certain mol proportion, put vacuum drying, get pale yellow powder down to doing; A certain amount of powder is added respectively in ethanol, the water, solution; Above-mentioned solution is put the freezing liquid of crossing of refrigerator, and its alcoholic solution does not have separates out, and its aqueous solution room temperature is placed to fusing, does not have precipitation and separates out.The result shows that hydroxypropyl beta cyclodextrin has carried out enclose to levosimendan.
Levosimendan hydroxypropyl beta cyclodextrin ethanol liquid, Levosimendan KollidonPF12 ethanol liquid, the Levosimendan hydroxypropyl beta cyclodextrin aqueous solution of preparation carries out stability relatively, the results are shown in Table 1:
Table 1 Levosimendan hydroxypropyl beta cyclodextrin ethanol liquid, Levosimendan KollidonPF12 ethanol liquid, Levosimendan hydroxypropyl beta cyclodextrin aqueous solution carry out stability relatively
| Room temperature standing time (my god) | Related substance (%) | ||
| Levosimendan HP β CD ethanol | Levosimendan KollidonPF12 ethanol | Levosimendan HP β CD aqueous solution | |
| 0 7 14 21 | 0.17 0.17 0.19 0.20 | 0.34 0.36 0.44 0.58 | 0.24 1.23 3.78 6.32 |
The mensuration of related substance is meant the mensuration of the impurity content in the levosimendan, and the result shows that Levosimendan hydroxypropyl beta cyclodextrin ethanol liquid stability of the present invention obviously improves in the table.
Carry out the compatibility test of pharmacological effect, toxicity, stability and preparation, injection safety of the present invention, stable, effective, simple to operate by the injection that Levosimendan hydroxypropyl beta cyclodextrin clathrate of the present invention is made.
Fig. 1 is: hydroxypropyl beta cyclodextrin (HP β CD) is to the solubilizing effect figure of levosimendan, and shade is the levosimendan dissolve area.
The specific embodiment:
Further specify the present invention by the following examples.
Embodiment 1
Levosimendan 2.5mg/ml, hydroxypropyl beta cyclodextrin 50mg/ml, injection ethanol 5ml dissolve injection solution.
Embodiment 2
Levosimendan 2.5mg/ml, hydroxypropyl beta cyclodextrin 50mg/ml, citric acid 2mg/ml, injection ethanol 5ml dissolve injection solution.
Embodiment 3
Levosimendan 2.5mg/ml, hydroxypropyl beta cyclodextrin 50mg/ml, injection ethanol 5ml dissolving, filtration, vacuum drying get Levosimendan hydroxypropyl beta cyclodextrin clathrate dry powder.
Embodiment 4
Levosimendan 2.5mg/ml, hydroxypropyl beta cyclodextrin 50mg/ml, injection ethanol 5ml dissolving, filtration, vacuum drying powder mix to such an extent that Levosimendan hydroxypropyl beta cyclodextrin-mannitol mixes powder with a certain amount of injection mannitol.
Embodiment 5
Levosimendan 2.5mg/ml, hydroxypropyl beta cyclodextrin 50mg/ml, injection ethanol 5ml dissolving, filtration, vacuum drying powder are dissolved in the finite concentration Osmitrol, get Levosimendan hydroxypropyl beta cyclodextrin-mannitol after filtration, the lyophilization and mix powder.
Claims (2)
1. injection, it is characterized in that, the clathrate that contains the levosimendan hydroxypropyl beta cyclodextrin, PH regulator and injection dehydrated alcohol, wherein the mol ratio of levosimendan and hydroxypropyl beta cyclodextrin is 1: 5, and described PH regulator is a citric acid, contains the 2.5mg/ml levosimendan in the described injection, the 50mg/ml hydroxypropyl beta cyclodextrin, injection dehydrated alcohol 5ml.
2. the preparation method of the injection of claim 1, it is characterized in that, hydroxypropyl beta cyclodextrin is placed ethanol, after the stirring and dissolving, add levosimendan, stirring at room gets the levosimendan hydroxypropyl beta cyclodextrin clathrate, reuse injection dehydrated alcohol is a solvent, makes injection by routine techniques.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100376675A CN100367964C (en) | 2004-04-29 | 2004-04-29 | Inclusion preparation of levosimendan and beta cyclodextrin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100376675A CN100367964C (en) | 2004-04-29 | 2004-04-29 | Inclusion preparation of levosimendan and beta cyclodextrin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1689573A CN1689573A (en) | 2005-11-02 |
| CN100367964C true CN100367964C (en) | 2008-02-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100376675A Expired - Fee Related CN100367964C (en) | 2004-04-29 | 2004-04-29 | Inclusion preparation of levosimendan and beta cyclodextrin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020041180A1 (en) * | 2018-08-21 | 2020-02-27 | Tenax Therapeutics, Inc. | Pharmaceutical compositions for subcutaneous administration of levosimendan |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101411708B (en) * | 2007-10-17 | 2010-12-22 | 齐鲁制药有限公司 | Stable Levosimendan pharmaceutical composition and preparation method thereof |
| ME03761B (en) | 2015-11-06 | 2021-01-20 | Carinopharm Gmbh | Improved formulations of levosimendan for intravenous administration as infusion or injection and of infusion concentrate |
| CN108261398A (en) * | 2016-12-30 | 2018-07-10 | 齐鲁制药有限公司 | A kind of injection pharmaceutical preparation containing Levosimendan and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1373665A (en) * | 1999-09-10 | 2002-10-09 | 欧里恩公司 | Pharmaceutical solutions for levosimendan |
| CN1470238A (en) * | 2003-06-18 | 2004-01-28 | 王景成 | Levosimendan formulation and its preparing method |
-
2004
- 2004-04-29 CN CNB2004100376675A patent/CN100367964C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1373665A (en) * | 1999-09-10 | 2002-10-09 | 欧里恩公司 | Pharmaceutical solutions for levosimendan |
| CN1470238A (en) * | 2003-06-18 | 2004-01-28 | 王景成 | Levosimendan formulation and its preparing method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020041180A1 (en) * | 2018-08-21 | 2020-02-27 | Tenax Therapeutics, Inc. | Pharmaceutical compositions for subcutaneous administration of levosimendan |
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| CN1689573A (en) | 2005-11-02 |
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Assignee: Jiangsu Yabang Shengyuan Medicine Co., Ltd. Assignor: Wang Siqing Contract fulfillment period: 2009.7.2 to 2014.7.2 Contract record no.: 2009320001620 Denomination of invention: Inclusion preparation of levosimendan and beta cyclodextrin Granted publication date: 20080213 License type: Exclusive license Record date: 20090828 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.7.2 TO 2014.7.2; CHANGE OF CONTRACT Name of requester: JIANGSU YABANG SHENGYUAN MEDICINE CO., LTD. Effective date: 20090828 |
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| CF01 | Termination of patent right due to non-payment of annual fee |