CN109091456A - A kind of heparin sodium injection and preparation method thereof - Google Patents
A kind of heparin sodium injection and preparation method thereof Download PDFInfo
- Publication number
- CN109091456A CN109091456A CN201811229678.1A CN201811229678A CN109091456A CN 109091456 A CN109091456 A CN 109091456A CN 201811229678 A CN201811229678 A CN 201811229678A CN 109091456 A CN109091456 A CN 109091456A
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- CN
- China
- Prior art keywords
- heparin sodium
- injection
- benzyl alcohol
- sodium injection
- sulfate
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- 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.)
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Classifications
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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
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a kind of heparin sodium injections and preparation method thereof, are made of heparin sodium, benzyl alcohol, water for injection, and the pH of the heparin sodium injection is 6.5-7.5.The present invention substitutes phenol using benzyl alcohol; when heparin sodium injection is acidic environment; sulfate hydrolysis will promote alcoholic extract hydroxyl group and sulfate and carboxyl that esterification occurs; and then make to hydrolyze reverse progress; protect sulfate simultaneously; the sulfate content being always ensured that in heparin molecule is in maintenance level, improves stability of the heparin sodium injection in acidic environment, guarantees that the anticoagulant active in 36 months validity periods is stablized.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of heparin sodium injection and preparation method thereof.
Background technique
Heparin finds from liver first and is gained the name, by gucosamine, L- idose aldehyde glycosides, N-Acetyl-D-glucosamine and the Portugal D-
The glutinous Alginic Sodium Diester that grape uronic acid alternately forms, average molecular weight 15KD are in highly acid, exist in lung, vascular wall, intestines
It is a kind of natural anticoagulative substance in animal body in the tissue such as mucous membrane.Heparin sodium can interfere many links of blood clotting process, in body
It is inside and outside to have blood coagulation resisting function.Its mechanism of action is more complicated, mainly by combining with antithrombin Ⅲ (AT- III), and enhances
The latter to the II of activation, Ⅸ, X, Ⅺ and Ⅻ coagulation factor inhibiting effect, consequence be related to preventing platelet aggregation and destroy,
It interferes the formation of factor Ⅹ, factor is prevented to become fibrin ferment, inhibit fibrin ferment, so that fibrinogen be interfered to become
Fibrin plays anticoagulation.
The osmotic pressure deficiency of heparin sodium injection, which will generate local blood coagulation, causes syringe needle to block, and osmotic pressure is excessively high to cause part
The adverse reactions such as irritation and bleeding, existing heparin sodium injection generally use sodium chloride as standard isotonic solution regulator, pH
Value is that 7.0 or so, CN103191054 discloses a kind of heparin sodium tube sealing injection and preparation method thereof, which uses Portugal
Grape sugar, sodium dihydrogen phosphate and disodium hydrogen phosphate are 6-7 as isotonic agent, adjusting pH value, and solution is made to reach 260-320mOsm/kg.
Existing heparin sodium injection usually adds phenol as preservative, and phenol is only capable of preventing or inhibiting microorganism growth numerous
It grows, also needs to carry out high-temperature sterilization after filling, high temperature will lead to pH decline, and within 36 months validity periods, pH also can gradually decline,
The heparin sodium injection slant acidity that initial pH is 7.0 or so is eventually led to, and it is closely related with blood coagulation resisting function in heparin sodium
Sulfate will hydrolyze under acidic environment, and anticoagulant active is caused to significantly reduce.Therefore, current it is a key issue that how to mention
Stability of the high heparin sodium injection in acidic environment has preferable anticoagulation living to guarantee it within 36 months validity periods
Property.
Summary of the invention
It is an object of the invention to: it is poor for above-mentioned existing heparin sodium injection facile hydrolysis, stability in acidic environment
The problem of, the present invention provides a kind of heparin sodium injection and preparation method thereof.
The technical solution adopted by the invention is as follows:
A kind of heparin sodium injection is made of heparin sodium, benzyl alcohol, water for injection, and the pH of the heparin sodium injection is
6.5-7.5。
Most of esterifications carry out extremely slow, it usually needs use acidic catalyst, acidic catalyst plays de- simultaneously
Water effect makes to react to the progress of the direction of esterification, this is because most organic acids belong to weak acid, and for acid stronger organic
Acid can not use acidic catalyst in esterification, only be dehydrated under room temperature.In heparin molecule of the present invention containing sulfate and
Carboxyl, be in highly acid, in acidic environment, sulfate hydrolysis consumption water, be equivalent to and play dehydration, promote sulfate and
The hydroxyl of carboxyl and benzyl alcohol carries out esterification, and esterification then consumes heparin molecule, so that hydrolysis inversely carries out,
Once then promoting esterification to carry out that is, sulfate hydrolyzes, is carried out so that hydrolysis is reverse, be always ensured that heparin molecule
In sulfate content be in maintenance level, also, sulfate esterification can also play a protective role to it.In addition, liver of the present invention
After plain sodium injection is injected in human body, benzyl alcohol is oxidized to benzoic acid, is then condensed with the glycine in liver, with hippuric acid
Form excretes, and can restore the sulfate of esterification, guarantees that sulfate normally plays anticoagulant active.
Existing heparin sodium injection is preservative usually using phenol, and the hydroxyl in phenol occurs esterification and is stranded very much
Difficulty, under the conditions of the present invention, phenol can not be esterified with sulfate and carboxyl, and phenol is in alkalinity in heparin sodium injection
When, it can be reacted with sodium hydroxide and generate sodium phenate, when high-temperature sterilization, sodium phenate decomposes to give off toxic gas, meanwhile, high temperature promotes
Sulfate hydrolysis, heparin sodium are higher than 60 DEG C, and the temperature of bioactivity decline, usual high-temperature sterilization is higher than 100 DEG C, anticoagulant active
It significantly reduces, and the present invention substitutes phenol using benzyl alcohol, on the one hand avoids giving off poisonous gas when high-temperature sterilization, another party
Face, while high temperature promotes sulfate hydrolysis, esterification can also be reinforced, and then inhibit hydrolysis, significantly reduce temperature change pair
The influence of sulfate hydrolysis, avoids high temperature from generating large effect to anticoagulant active.
Further, it is 1-2% that benzyl alcohol, which accounts for the mass percent of heparin sodium injection,.
Further, it is 2-4% that heparin sodium, which accounts for the mass percent of heparin sodium injection,.
Further, pH value is adjusted using sodium hydroxide solution.
A kind of preparation method of the heparin sodium injection as described in any one of claim 1-4, comprising the following steps:
(1) benzyl alcohol is added in water for injection, stirs evenly, forms benzyl alcohol aqueous solution；
(2) heparin sodium is added in benzyl alcohol aqueous solution, stirs evenly, and adjusting pH is 6.5-7.5；
(3) it is sterile filtered；
(4) encapsulating, packing to get.
Further, in step (3), the method for aseptic filtration are as follows: through 0.22 μm of membrane filtration of two-stage.
In conclusion by adopting the above-described technical solution, the beneficial effects of the present invention are:
1. the present invention substitutes phenol using benzyl alcohol, when heparin sodium injection is acidic environment, sulfate hydrolysis will promote
Esterification occurs for alcoholic extract hydroxyl group and sulfate and carboxyl, and then makes to hydrolyze reverse progress, while protect sulfate, begins
Guarantee that the sulfate content in heparin molecule is in maintenance level eventually, improves stabilization of the heparin sodium injection in acidic environment
Property, guarantee that the anticoagulant active in 36 months validity periods is stablized；
2. existing heparin sodium injection also will do it high-temperature sterilization after filling, high temperature can promote sulfate to hydrolyze, and logical
The temperature of normal high-temperature sterilization is higher than 100 DEG C, will lead to anticoagulant active significant decrease, and high temperature of the present invention promotes sulfate hydrolysis
Meanwhile esterification can also be reinforced, and then inhibit hydrolysis, significantly reduce the influence that temperature change hydrolyzes sulfate, avoid height
Temperature generates large effect to anticoagulant active；
3. preservative only has bacteriostasis in low concentration, concentration increases or extends action time, then has bactericidal effect, this
Invention benzyl alcohol can be higher than phenol (0.1-0.5wt%), have preferable bactericidal effect, can cancel filling as preservative, concentration
High-temperature sterilizing process after dress avoids high temperature to the adverse effect of product quality, enhances product stability, while shortening production week
Phase reduces production cost.
Specific embodiment
All features disclosed in this specification can be with any other than mutually exclusive feature and/or step
Mode combines.
Embodiment 1
A kind of preparation method of heparin sodium injection, comprising the following steps:
(1) benzyl alcohol that mass percent is 1% is added in water for injection, stirs evenly, forms benzyl alcohol aqueous solution；
(2) heparin sodium that mass percent is 2% is added in benzyl alcohol aqueous solution, stirs evenly, using sodium hydroxide
It is 6.5-7.5 that solution, which adjusts pH value,；
(3) it is sterile filtered through 0.22 μm of filter membrane of two-stage；
(4) encapsulating, packing to get.
Embodiment 2
A kind of preparation method of heparin sodium injection, comprising the following steps:
(1) benzyl alcohol that mass percent is 1.5% is added in water for injection, stirs evenly, it is water-soluble to form benzyl alcohol
Liquid；
(2) heparin sodium that mass percent is 3% is added in benzyl alcohol aqueous solution, stirs evenly, using sodium hydroxide
It is 6.5-7.5 that solution, which adjusts pH value,；
(3) it is sterile filtered through 0.22 μm of filter membrane of two-stage；
(4) encapsulating, packing to get.
Embodiment 3
A kind of preparation method of heparin sodium injection, comprising the following steps:
(1) benzyl alcohol that mass percent is 2% is added in water for injection, stirs evenly, forms benzyl alcohol aqueous solution；
(2) heparin sodium that mass percent is 4% is added in benzyl alcohol aqueous solution, stirs evenly, using sodium hydroxide
It is 6.5-7.5 that solution, which adjusts pH value,；
(3) it is sterile filtered through 0.22 μm of filter membrane of two-stage；
(4) encapsulating, packing to get.
Embodiment 4
According to the step of embodiment 1 and embodiment 3 and method be prepared into potency be 3500IU/ml heparin sodium injection,
The phenol that the benzyl alcohol replacement mass percent that mass percent is 1% is 0.5% by the step method according to embodiment 1, system
The standby heparin sodium injection for being 3500IU/ml at potency, as control group, and pH value is measured with acidometer (PHBJ-260), it adopts
With the potency after spectrophotometry measurement storage 0,3,6,9,12 month, 1 the results are shown in Table, it can be seen that embodiment 1-3 and right
It is gradually decreased according to the pH of group with the extension of storage time, the heparin sodium injection of control group is after storage 1 year, activity
It is decreased obviously, and the activity change of the heparin sodium injection of 1-3 of the embodiment of the present invention is little, excellent in stability.
The variation of 1 heparin sodium injection active constituent of table
Embodiment 5
Embodiment 2 and control group carry out high-temperature sterilization, sterilization process are as follows: 115 DEG C of sterilizing 15min, measurement sterilizing front and back
Potency variation, the results are shown in Table 2, it can be seen that activity is decreased obviously after control group sterilizing, is infused using heparin sodium prepared by the present invention
Activity then slightly decreases after penetrating liquid sterilizing.
The active constituent variation of the sterilizing of table 2 front and back
It is as described above the embodiment of the present invention.The present invention is not limited to the above-described embodiments, anyone should learn that
The structure change made under the inspiration of the present invention, the technical schemes that are same or similar to the present invention each fall within this
Within the protection scope of invention.
Claims (6)
1. a kind of heparin sodium injection, which is characterized in that be made of heparin sodium, benzyl alcohol, water for injection, the heparin sodium injection
The pH of liquid is 6.5-7.5.
2. a kind of heparin sodium injection according to claim 1, which is characterized in that the benzyl alcohol accounts for heparin sodium injection
Mass percent be 1-2%.
3. a kind of heparin sodium injection according to claim 1, which is characterized in that the heparin sodium accounts for heparin sodium injection
Mass percent be 2-4%.
4. a kind of heparin sodium injection according to claim 1, which is characterized in that adjust pH using sodium hydroxide solution
Value.
5. a kind of preparation method of the heparin sodium injection as described in any one of claim 1-4, which is characterized in that including with
Lower step:
(1) benzyl alcohol is added in water for injection, stirs evenly, forms benzyl alcohol aqueous solution；
(2) heparin sodium is added in benzyl alcohol aqueous solution, stirs evenly, and adjusting pH is 6.5-7.5；
(3) it is sterile filtered；
(4) encapsulating, packing to get.
6. a kind of preparation method of heparin sodium injection according to claim 5, which is characterized in that in the step (3),
The method of aseptic filtration are as follows: through 0.22 μm of membrane filtration of two-stage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811229678.1A CN109091456A (en) | 2018-10-22 | 2018-10-22 | A kind of heparin sodium injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811229678.1A CN109091456A (en) | 2018-10-22 | 2018-10-22 | A kind of heparin sodium injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109091456A true CN109091456A (en) | 2018-12-28 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811229678.1A Pending CN109091456A (en) | 2018-10-22 | 2018-10-22 | A kind of heparin sodium injection and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004010596A (en) * | 2002-06-11 | 2004-01-15 | Terumo Corp | Heparin sodium injection formulation |
| US20040087544A1 (en) * | 2001-04-17 | 2004-05-06 | Russo Elisa Mannochio De Souza | Pharmaceutical compositions of topic use, applied in treatment of skin and/or mucous injuries use of compositions in treatment of skin and/or mucous injuries and use of compounds in treatment of skin and/or mucous injuries |
| CN103961311A (en) * | 2014-05-26 | 2014-08-06 | 成都市海通药业有限公司 | Heparin sodium injection and preparation method thereof |
| CN104095808A (en) * | 2014-07-17 | 2014-10-15 | 上海第一生化药业有限公司 | Heparin sodium injection and preparation method thereof |
-
2018
- 2018-10-22 CN CN201811229678.1A patent/CN109091456A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040087544A1 (en) * | 2001-04-17 | 2004-05-06 | Russo Elisa Mannochio De Souza | Pharmaceutical compositions of topic use, applied in treatment of skin and/or mucous injuries use of compositions in treatment of skin and/or mucous injuries and use of compounds in treatment of skin and/or mucous injuries |
| JP2004010596A (en) * | 2002-06-11 | 2004-01-15 | Terumo Corp | Heparin sodium injection formulation |
| CN103961311A (en) * | 2014-05-26 | 2014-08-06 | 成都市海通药业有限公司 | Heparin sodium injection and preparation method thereof |
| CN104095808A (en) * | 2014-07-17 | 2014-10-15 | 上海第一生化药业有限公司 | Heparin sodium injection and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 张兆旺著: "《中药药剂学》", 31 July 2017, 中国中医药出版社 * |
| 徐浩主编: "《药用辅料质量管理规范与现代辅料新技术应用全书 2》", 28 February 2005, 天津电子出版社 * |
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Application publication date: 20181228 |
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