CN105687131A - Injection solvent capable of improving stability of thrombus treatment drug and preparation method of solvent - Google Patents
Injection solvent capable of improving stability of thrombus treatment drug and preparation method of solvent Download PDFInfo
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- CN105687131A CN105687131A CN201610142493.1A CN201610142493A CN105687131A CN 105687131 A CN105687131 A CN 105687131A CN 201610142493 A CN201610142493 A CN 201610142493A CN 105687131 A CN105687131 A CN 105687131A
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- injection
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- tween
- dispersant
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention belongs to the technical field of medicines and particularly relates to an injection solvent capable of improving stability of a thrombus treatment drug and a preparation method of the solvent. The solvent is mainly prepared from a dispersant, sodium acetate and water for injection. The preparation is stable in quality, the process is simple, the problem that the activity is reduced after a dalteparin sodium injection is matched with a 0.9% sodium chloride injection and a 5% glucose injection is effectively solved, and the clinical use safety of the product is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of solvent for injection that can improve treatment thrombosis medicine stability and preparation method thereof。
Background technology
Dalteparin sodium injection is mainly used in acute deep venous thrombosis, acute renal is tended to end because of decline or chronic renal insufficiency person carry out hemodialysis with prevent blood circulation in vitro during blood filtration in occur blood coagulation, unstable coronary artery disease and prevention relevant with operation thrombotic treatment。
Dalteparin sodium is developed by Pharmacia (Pfizer) company, and 1985 with trade name Fragmin?First list in Germany。Dalteparin sodium is the sodium salt of a kind of Low molecular heparin, is the sodium salt of the CSSO3 fragment that the heparin extracted by intestinal mucosa obtains through nitrous acid degraded, and for polysaccharide mixture, mean molecule quantity is about 6000 dalton。
Its molecular structural formula is:
Its molecular weight distribution is:
Chinese Patent Application No. 201410420314.7 discloses the production technology of a kind of high stability dalteparin sodium injection, and the production technology of the present invention, including under omnidistance inflated with nitrogen: 1) dalteparin sodium crude drug is dissolved in water for injection, stirring makes medicinal liquid molten clearly；2) molten clear after medicinal liquid add the activated carbon of 0.08～0.15%w/w, stirring is not less than 25min, initial filter, regulates the pH of medicinal liquid between 5.0～7.5；3) filtration sterilization, fill, obtain dalteparin sodium injection。The production technology of the present invention, it is possible to effectively removing the lipid impurities in dalteparin sodium injection, the activity of product does not have significantly sacrificing。Using dalteparin sodium injection stability prepared by production technology of the present invention high, the injection of low activity concentration and high activity concentration, Acceleration study is after 3 months, and its activity, color all still conform to standard。
Mentioning in the dalteparin sodium injection operation instructions that U.S. FDA official website is announced, dalteparin sodium injection is compatible with isotonic 0.9% sodium chloride injection being placed in vial and plastic bottle or isotonic 5% glucose injection, and solution must use in 12 hours。Inventor also further confirms in test this discussion, dilute after the dalteparin sodium injection that current technology prepares and isotonic 0.9% sodium chloride injection or 5% glucose injection compatibility, along with its activity decrease of prolongation of standing time, cause that solution Clinical practice curative effect reduces。
Summary of the invention
For above deficiency, the invention provides a kind of solvent for injection that can improve treatment thrombosis medicine stability: be mainly made up of dispersant, sodium acetate and water for injection。
Solvent for injection provided by the invention: described dispersant is one or more in Polysorbate, polyoxyethylene fatty acid ester, Pluronic F68 and castor oil derivatives, select further in Polysorbate and polyoxyethylene fatty acid ester one or several, more preferably Polysorbate。
Solvent for injection provided by the invention: described dispersant Polysorbate is one or several in tween 20, Tween-40, Tween-60, tween 80, more preferably tween 20。
Solvent for injection provided by the invention: described dispersant tween 20 concentration is 10mg/ml ~ 16mg/ml, more preferably 14mg/ml。
Solvent for injection provided by the invention: described sodium acetate concentration is 5.0mg/ml ~ 6.0mg/ml, more preferably 5.5mg/ml。
Invention further provides above-mentioned solvent for injection preparation method, mainly comprise the steps that the dispersant weighing recipe quantity and sodium acetate are dissolved in appropriate water for injection, be uniformly mixed, it is settled to total amount, stirring and evenly mixing with water for injection, filters, fill, sterilizing, visual inspection gets product。
Above-mentioned solvent for injection of the present invention has the advantage that invention formulation steady quality, technique is simple, the problem occurring activity reduction after effectively solving dalteparin sodium injection and 0.9% sodium chloride injection, 5% glucose injection compatibility, improves the safety of product Clinical practice。
Detailed description of the invention
Embodiment 1:
Prescription
Preparation technology
The tween 20 and the 5.0g sodium acetate that weigh 10.0g are dissolved in appropriate water for injection, are uniformly mixed, and are settled to 1000ml, stirring and evenly mixing with water for injection, filter, and fill, sterilizing, visual inspection gets product。
Embodiment 2:
Prescription
Preparation technology
The sodium acetate of the tween 20 and 5.5g that weigh 14.0g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection gets product。
Embodiment 3:
Prescription
Preparation technology
The sodium acetate of the tween 20 and 6.0g that weigh 16.0g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection gets product。
Embodiment 4:
Prescription
Preparation technology
The sodium acetate of the tween 20 and 5.0g that weigh 14.0g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection gets product。
Embodiment 5:
Prescription
Preparation technology
The sodium acetate of the tween 20 and 6.0g that weigh 14.0g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection gets product。
Comparative example 1:
Prescription
Preparation technology
The tween 20 weighing 14.0g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection get product。
Comparative example 2:
Prescription
Preparation technology
The sodium acetate weighing 5.5g is dissolved in appropriate water for injection, is uniformly mixed, and is settled to 1000ml, stirring and evenly mixing with water for injection, filters, and fill, sterilizing, visual inspection get product。
The preparation of dalteparin sodium injection liquid samples
Sample 1:
Prescription
Preparation technology
The sodium chloride weighing recipe quantity is dissolved in appropriate water for injection, it is uniformly mixed, add the dalteparin sodium of recipe quantity, stirring and dissolving, regulates pH value with the sodium hydroxide solution of the hydrochloric acid solution of 0.1mol/L or 0.1mol/L, is settled to total amount with water for injection, stirring and evenly mixing, filtering, fill, visual inspection gets product。
Sample 2:
Prescription
Preparation technology
The sodium chloride and the benzyl alcohol that weigh recipe quantity are dissolved in appropriate water for injection, it is uniformly mixed, add the dalteparin sodium of recipe quantity, stirring and dissolving, regulates pH value with the sodium hydroxide solution of the hydrochloric acid solution of 0.1mol/L or 0.1mol/L, is settled to total amount with water for injection, stirring and evenly mixing, filtering, fill, visual inspection gets product。
Sample 3:
Prescription
Preparation technology
The dalteparin sodium weighing recipe quantity is dissolved in the water for injection of 30～40 DEG C, and stirring makes medicinal liquid molten clearly；Adding the activated carbon of 100 order 0.1w/w, stir 30min, 0.45 μm of filter membrane initial filter, the pH regulating medicinal liquid is 6.5；Being settled to total amount, stirring and evenly mixing with water for injection, filter, fill, visual inspection gets product。
Checking embodiment
Sample one, sample two, sample three are carried out compatibility with embodiment 1,0.9% sodium chloride injection and 5% glucose injection respectively, measures the situation of change of the indices such as its weight average molecular weight, molecular weight<3000 components, molecular weight>8000 components and anti-FXa activity respectively with 0,4,8,12 hours。Sample one, sample two, sample three respectively with embodiment 1,0.9% sodium chloride injection and 5% glucose injection compatibility in Table 1, Compatibility result is in Table 2。
Table 1 sample and embodiment 1,0.9% sodium chloride injection and 5% glucose injection compatibility situation
Table 2 sample investigates result with embodiment 1,0.9% sodium chloride injection and 5% glucose injection compatibility mechanism
In test, the present invention also by sample one, sample two, sample three respectively with comparative example 1, comparative example 2,0.9% sodium chloride injection and 5% glucose injection compatibility, but its compatibility situation be better than contrast compatibility 1 ~ 6, be inferior to embodiment 1 ~ 6。
By above experiment investigation result it can be seen that the solvent for injection of the embodiment of the present invention 1～5 gained can improve the indices stability such as sample weight average molecular weight, molecular weight<3000 components, molecular weight>8000 components and anti-FXa activity significantly。Sample one, sample two, sample three are respectively after embodiment 1,0.9% sodium chloride injection and 5% glucose injection dilute, its concentration reduces, sample disperses further in medicinal liquid, sample three through with after embodiment 1,0.9% sodium chloride injection and 5% glucose injection compatibility, compatibility three, compatibility six to be substantially better than contrast compatibility three, contrast compatibility six, further embody the superiority of solvent for injection of the present invention。
Claims (10)
1. the solvent for injection that can improve treatment thrombosis medicine stability: be mainly made up of dispersant, sodium acetate and water for injection。
2. solvent for injection according to claim 1, it is characterised in that described dispersant is one or more in Polysorbate, polyoxyethylene fatty acid ester, Pluronic F68 and castor oil derivatives。
3. the solvent for injection according to claim 1,2, it is characterised in that described dispersant is one or several in Polysorbate and polyoxyethylene fatty acid ester。
4. the solvent for injection according to claim 1 ~ 3, it is characterised in that described dispersant Polysorbate is one or several in tween 20, Tween-40, Tween-60, tween 80。
5. the solvent for injection according to claim 1 ~ 4, it is characterised in that described dispersant is tween 20。
6. the solvent for injection according to claim 1 ~ 5, it is characterised in that described dispersant tween 20 concentration is 10mg/ml ~ 16mg/ml。
7. the solvent for injection according to claim 1 ~ 6, it is characterised in that described dispersant tween 20 concentration is 14mg/ml。
8. solvent for injection according to claim 1, it is characterised in that described sodium acetate concentration is 5.0mg/ml ~ 6.0mg/ml。
9. the solvent for injection according to claim 1,8, it is characterised in that described sodium acetate concentration is 5.5mg/ml。
10. solvent for injection according to claim 1, it is characterized in that, the preparation method of described solvent for injection comprises the steps: to weigh the dispersant of recipe quantity and sodium acetate is dissolved in appropriate water for injection, it is uniformly mixed, it is settled to total amount, stirring and evenly mixing with water for injection, filters, fill, visual inspection gets product。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610142493.1A CN105687131A (en) | 2016-03-14 | 2016-03-14 | Injection solvent capable of improving stability of thrombus treatment drug and preparation method of solvent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610142493.1A CN105687131A (en) | 2016-03-14 | 2016-03-14 | Injection solvent capable of improving stability of thrombus treatment drug and preparation method of solvent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105687131A true CN105687131A (en) | 2016-06-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610142493.1A Pending CN105687131A (en) | 2016-03-14 | 2016-03-14 | Injection solvent capable of improving stability of thrombus treatment drug and preparation method of solvent |
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| Country | Link |
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| CN (1) | CN105687131A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1460484A (en) * | 2003-06-17 | 2003-12-10 | 王衍庆 | Bacillus prodigiosus polysaccharide for nose drops |
| WO2014193821A1 (en) * | 2013-05-28 | 2014-12-04 | Momenta Pharmaceuticals, Inc. | Pharmaceutical compositions comprising pyrophosphate |
| CN104188902A (en) * | 2014-08-25 | 2014-12-10 | 深圳市天道医药有限公司 | Process for producing high-stability dalteparin sodium injection |
-
2016
- 2016-03-14 CN CN201610142493.1A patent/CN105687131A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1460484A (en) * | 2003-06-17 | 2003-12-10 | 王衍庆 | Bacillus prodigiosus polysaccharide for nose drops |
| WO2014193821A1 (en) * | 2013-05-28 | 2014-12-04 | Momenta Pharmaceuticals, Inc. | Pharmaceutical compositions comprising pyrophosphate |
| CN104188902A (en) * | 2014-08-25 | 2014-12-10 | 深圳市天道医药有限公司 | Process for producing high-stability dalteparin sodium injection |
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Address after: Longshan road 033000 Shanxi city of Lvliang province Lishi District No. 633 Hualong District 1 building 2-102 Applicant after: Zhang Guangquan Address before: 250000 Ji'nan, China Hi tech Zone, Shandong Chong Hua Road, No. 11 Applicant before: Zhang Guangquan |
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Application publication date: 20160622 |
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