CN110403904A - Carbetocin injection and its application - Google Patents
Carbetocin injection and its application Download PDFInfo
- Publication number
- CN110403904A CN110403904A CN201910679252.4A CN201910679252A CN110403904A CN 110403904 A CN110403904 A CN 110403904A CN 201910679252 A CN201910679252 A CN 201910679252A CN 110403904 A CN110403904 A CN 110403904A
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- Prior art keywords
- carbetocin
- injection
- uterus
- atonia
- oxytocin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to carbetocin injection and its applications, belong to Amino acid synthesis technical field, disclose a kind of injection comprising the carbetocin of Increased Plasma Half-life and pharmaceutically acceptable auxiliary material.Product of the present invention Increased Plasma Half-life, stability are promoted, and can be used to treat or prevent uterus atonia, and/or for treating or preventing the excessive bleeding after vaginal delivery.
Description
Technical field
The invention belongs to amino acid technical fields, and in particular to carbetocin injection and its application.
Background technique
Carbetocin is developed by Canadian Hui Ling pharmaceutical Co. Ltd, is a kind of artificial synthesized to have agonist
The long-acting oxytocins nonapeptide analog of property.
Chinese: carbetocin
Chinese pinyin name: kabeisuogongsu
English name: Carbetocin
No. CAS: 37025-55-1
Amino acid sequence:
Molecular formula: C45H69N11O12S
Molecular weight: 988.16
Chemical name: deammoniation -2- oxygen-methyl-tyrosine -1- κ oxytocin
Carbetocin is used under selective Epidural cavity or lumbar anesthesia after caesarean operation, and prevention uterine contractions fatigue and postpartum
Bleeding, rapid-action, long action time, clinical application are safe and effective.Currently, external listing has France and Canada.Wherein
Canadian brightness is insulted pharmacy (Ferring Inc.) and was listed at first in 2007, and in Discussion on Chinese Listed, dosage form is injection within 2009
Agent, trade name: glad, the English trade name: Duratocin of skilful spy；In addition, the Polypeptide Laboraries of France
France company lists bulk pharmaceutical chemicals in approval in 2011.The domestic head of Chengdu Sheng Nuo Biology Pharmacy Co., Ltd is imitative, has and independently knows
" the carbetocin injection " and bulk pharmaceutical chemicals for knowing property right were listed in acquisition state approval in 2016.Writing brush space medicine company was in 2016
The writing brush for researching and developing listing is precious®Carbetocin, meanwhile, the writing brush of writing brush space medicine company is precious®Carbetocin has also passed through U.S. FDA and European Union
Certification.
Uterotonic reason derives from the release of endogenous oxytocin and prostaglandin.Free intracellular calcium is flesh
The activator of meat excitation-contraction coupling, oxytocins can discharge and calcium ion is promoted to flow into myocyte, and prostaglandin is
Calcium ionophore forms complex with calcium ion, calcium ion is carried along into the cell.Into the calcium ion and flesh in myocyte
Filamentous actin, myosinogen, which combine, to be caused uterine contraction and repairs, and plays hemostasis by compression to the blood vessel on the wall of palace.Meanwhile by
Keep blood vessel full of twists and turns in muscle reparation, blood flow retardance is conducive to thrombosis, and blood sinus is closed.But uterus muscle fibers contract
Can also it loosen afterwards, thus basic hemostatic mechanism is blood clotting.Gestational period blood is in hypercoagulative state, in endogenous prostate
Blood platelet is largely assembled under the action of element, the intra platelet free calcium vaso-active substance of aggregation, reinforces vessel retraction, while causing to glue
Property deformation, formed thrombus, lead to a large amount of releases of coagulation factor, the sludged blood of further occurrence Coagulation test, formation can have
The blood vessel of effect blocking separation of placenta face exposure achievees the purpose that nature stops blooding.
Oxytocin is the substance that body generates, and is gone out quickly by oxytocinase and liver, kidney, intestines that placenta generates in vivo
It is living and remove, Half-life in vivo only 3-4min, the intracorporal effect of oxytocin closely disappearance at the end of third stage of labor.Oxytocin is only capable of
It stimulates upper uterine segment to shrink, increases drug dose after acceptor site saturation and do not play contraction, and the oxytocin of large dosage
It can lead to water intoxication.
Carbetocin is the improvement carried out on the basis of oxytocin, is to obtain after oxytocin structural modification: (1)
Deaminizing, 1 Cys of the bytyry instead of oxytocin；(2) remove disulfide bond, 4 of bytyry with 6 Cys of oxytocin
Sulfydryl formed thioether bond；(3) hydroxymethylation of Tyr.Above-mentioned modification can make carbetocin mitigate enzyme and curing
The degradation of object is closed, stability is improved.Although the two molecular structure has differences, in conjunction with the parent of membrane receptor in mesometrium
As power, due to the modification of structure, so that the metabolic stability of carbetocin is eager to excel than oxytocin, human muscle injects card
After shellfish oxytocin, 2min or so, uterus has one clearly to shrink, duration 40-60min.
The clinic and pharmacological property of carbetocin are similar with naturally-produced oxytocins, the oxytocins with uterine smooth muscle
Receptor combines, and causes the Rythmic contractions characteristic in uterus, on the basis of original contraction, increases its frequency and increases uterus tension.In
Under non pregnant state, the ocytocin receptor content in uterus is very low, during gestation increases, and peak is reached when childbirth.Therefore, card shellfish contracting
Palace element does not act on the uterus of non pregnant state, but uterus to gestation and the just uterus that produces have and effective shrink work
With.In view of the unicity of carbetocin product, and there are certain amount patients to need the auxiliary of long period for the prior art
Help uterine contraction and hemostasis, it is therefore desirable to develop the product of diversification, the demand of Lai Shiying clinical patients.
Summary of the invention
In order to overcome the drawbacks of the prior art, the present invention provides new carbetocin class, it further developed card shellfish
Oxytocin injection and its application.
The present invention is achieved by the following technical solution.
A kind of injection comprising the carbetocin of Increased Plasma Half-life and pharmaceutically acceptable auxiliary material.
Further, the amino acid sequence of the carbetocin is as follows:
Further, the composition of the injection are as follows: carbetocin 100 μ g, sodium chloride 9mg, glacial acetic acid adjust pH value to 4.0
± 0.2, water for injection adds to 1ml.
Further, the injection is used to treat or prevent uterus atonia, and/or for treating or preventing
Excessive bleeding after vaginal delivery.
Preferably, the uterus atonia include: after baby's vaginal delivery, baby pass through caesarean section give a birth
Uterus atonia afterwards.
Compared with prior art, the present invention has the advantages that following but be not restricted to that the following aspects:
Carbetocin of the present invention is improved on the basis of existing product, by the way that N-terminal Gly is replaced with [D-Arg],
Then acetylation is carried out, to reduce the hydrolysis of protease, increases half-life period, improves stability, it is intended to the card with existing listing
Shellfish oxytocin forms complementation；Metabolic half life is the promotion of the carbetocin of existing listing in serum, and bioactivity is deposited
In certain difference, but simultaneously less.
Modifying for chemical structure substantially increases the proteolytic degradation ability of peptide medicament, hence it is evident that extends half-life period, mentions
High bioavilability, but there are still certain limitation and deficiency, such as to easily lead to drug living for the conjugation of macromolecule polyalcohol
Property decrease to some degree；Deeper into research it is still underway.The present invention is in the preliminary stage of drug research and development, needs pair
Subsequent formulation development, pharmacological toxicology, pharmacokinetics and clinical application are further systematically studied.
Specific embodiment
In order to make those skilled in the art better understand the technical solutions in the application, having below in conjunction with the application
The technical solution of the application is clearly and completely described in body embodiment, it is clear that described embodiment is only this Shen
Please a part of the embodiment, instead of all the embodiments.Based on the embodiment in the application, those of ordinary skill in the art are not having
Every other embodiment obtained under the premise of creative work is made, should fall within the scope of the present invention.
Embodiment 1
Carbetocin of the present invention, amino acid sequence are as follows:
The Gly of N-terminal is replaced into [D-Arg]-NH-, then carries out acetylation；It contracts referring to the synthesis card shellfish of prior art routine
The method of palace element synthesizes amino acid sequence of the invention, then carries out acetylation and is prepared.
Potency is 8.26IU/mg(Chinese Pharmacopoeia 2010 version two, is surveyed using rat uterus smooth muscle bioassary method
Determine the biological value of oxytocin), and ingeniously special glad (commercial product) decreases, but difference is little.
Above-mentioned carbetocin is prepared into injection, specific as follows:
The pharmaceutical formulation is injection；Composition be 100 μ g of carbetocin, sodium chloride 9mg, glacial acetic acid adjust pH value to
4.0 ± 0.2, water for injection adds to 1ml.
Dosage form: injection；
Specification: 100 μ g/ml/ branch；
Inner packing: middle borosilicate ampoule.
The artificial synthesized carbetocin sterile solution of this strain, every 1ml should be 0.090- containing carbetocin
0.110mg；2-8 DEG C of preservation, cannot freeze, validity period 2 years.
Embodiment 2
Acute toxicity test
It is 1mg/kg that 20 rats are injected intravenously dosage daily, and related dead or clinic is existing with treatment for no discovery after 28d
As hematology, clinical biochemical and urinalysis are also without occurring and treatment-related variation.
Embodiment 3
Stability test
Experiment process is referring to " KRAJNICAKOVA M. etc., Spofa in early puerperium, 36 (10)
707-618,1991"；Half-life period in goat is 34.6min, extends 10min or more than commercially available carbetocin；
Half-life period in pig is 126.4min, extends 20min or more than commercially available carbetocin.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (5)
1. a kind of injection comprising the carbetocin of Increased Plasma Half-life and pharmaceutically acceptable auxiliary material.
2. injection according to claim 1, which is characterized in that the amino acid sequence of the carbetocin is as follows:
。
3. injection according to claim 2, which is characterized in that the composition of the injection are as follows: 100 μ of carbetocin
G, sodium chloride 9mg, glacial acetic acid adjust pH value to 4.0 ± 0.2, and water for injection adds to 1ml.
4. injection according to any one of claim 1 to 3 is used to treat or prevent uterus atonia, and/or
For treating or preventing the excessive bleeding after vaginal delivery.
5. injection according to claim 4, the uterus atonia includes: after baby's vaginal delivery, baby
Pass through the puerperal uterus atonia of caesarean section.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910679252.4A CN110403904A (en) | 2019-07-26 | 2019-07-26 | Carbetocin injection and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910679252.4A CN110403904A (en) | 2019-07-26 | 2019-07-26 | Carbetocin injection and its application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110403904A true CN110403904A (en) | 2019-11-05 |
Family
ID=68363364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910679252.4A Pending CN110403904A (en) | 2019-07-26 | 2019-07-26 | Carbetocin injection and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110403904A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801995A (en) * | 2007-07-23 | 2010-08-11 | Amp医疗有限两合公司 | antibiotic peptides |
| US20100247482A1 (en) * | 2004-09-21 | 2010-09-30 | Nastech Pharmaceutical Company Inc. | Tight junction modulator peptides for enhanced mucosal delivery of therapeutic compounds |
| CN102228678A (en) * | 2011-06-22 | 2011-11-02 | 深圳翰宇药业股份有限公司 | Carbetocin pharmaceutical composition and preparation method thereof |
| CN103124554A (en) * | 2010-09-30 | 2013-05-29 | 辉凌公司 | Pharmaceutical composition |
| CN104056249A (en) * | 2014-07-08 | 2014-09-24 | 西藏易明西雅生物医药科技有限公司 | Pharmaceutical composition containing active ingredient carbetocin and preparation of pharmaceutical composition |
| US20180000888A1 (en) * | 2015-01-30 | 2018-01-04 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| CN108699120A (en) * | 2015-11-16 | 2018-10-23 | Ubi蛋白公司 | Method for extending protein half life |
-
2019
- 2019-07-26 CN CN201910679252.4A patent/CN110403904A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100247482A1 (en) * | 2004-09-21 | 2010-09-30 | Nastech Pharmaceutical Company Inc. | Tight junction modulator peptides for enhanced mucosal delivery of therapeutic compounds |
| CN101801995A (en) * | 2007-07-23 | 2010-08-11 | Amp医疗有限两合公司 | antibiotic peptides |
| CN103124554A (en) * | 2010-09-30 | 2013-05-29 | 辉凌公司 | Pharmaceutical composition |
| CN102228678A (en) * | 2011-06-22 | 2011-11-02 | 深圳翰宇药业股份有限公司 | Carbetocin pharmaceutical composition and preparation method thereof |
| CN104056249A (en) * | 2014-07-08 | 2014-09-24 | 西藏易明西雅生物医药科技有限公司 | Pharmaceutical composition containing active ingredient carbetocin and preparation of pharmaceutical composition |
| US20180000888A1 (en) * | 2015-01-30 | 2018-01-04 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| CN108699120A (en) * | 2015-11-16 | 2018-10-23 | Ubi蛋白公司 | Method for extending protein half life |
Non-Patent Citations (3)
| Title |
|---|
| 方亮: "《药剂学》", 31 March 2016, 中国医药科技出版社 * |
| 辉凌制药（中国）有限公司: "《卡贝缩宫素注射液》", 15 April 2009, HTTP://ZY.YAOZH.COM/INSTRUCT/SMS20181205HB/1360.PDF，第1 * |
| 郭奇珍等: "《仿生化学》", 31 July 1990, 化学工业出版社 * |
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Application publication date: 20191105 |
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