CN102302446A - Recombinant human growth hormone injection capable of being directly used - Google Patents
Recombinant human growth hormone injection capable of being directly used Download PDFInfo
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- CN102302446A CN102302446A CN 201110267989 CN201110267989A CN102302446A CN 102302446 A CN102302446 A CN 102302446A CN 201110267989 CN201110267989 CN 201110267989 CN 201110267989 A CN201110267989 A CN 201110267989A CN 102302446 A CN102302446 A CN 102302446A
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- injection
- recombinant human
- human somatropin
- growth hormone
- human growth
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Abstract
The invention mainly aims to provide recombinant human growth hormone injection capable of being directly used. For fulfilling the purposes, the invention adopts the technical scheme that: the recombinant human growth hormone injection capable of being directly used comprises the following components: 0.67 to 10 mg/ml of recombinant human growth hormone, 5 to 20 mmol/L of citrate, 3 to 5 mg/ml of poloxamer 188, 0.5 to 1.5 mg/ml of glycine, and 30 to 60 mg/ml of mannitol; the pH value of the injection is 5.5 to 7.0; and the injection is filled into a pre-filled syringe. The injection can substitute the traditional powder preparation, is more convenient and easier in clinical use, and can be injected by a patient.
Description
Technical field
The present invention relates to field of medicaments, specifically relate to a kind of recombinant human somatropin's injection that can directly use.
Background technology
(Recombinant human Growth Hormone rhGH) produces for recombinant DNA technology the recombinant human somatropin, is made up of its structure and the aminoacid sequence genetically engineered drug consistent with the spontaneous growth hormone 191 aminoacid.The recombinant human somatropin's warp clinical practice for many years that utilizes recombinant DNA technology to produce has proved its effectiveness and safety clinically.
This protide product of recombinant human somatropin adopts Freeze Drying Technique usually; Promptly utilize refrigerated solution under the low-temp low-pressure condition; Directly distillation is removed moisture and is accomplished drying from frozen state without liquid state; Make medicine keep original physicochemical property and physiologically active; Its distinctive loose and porous structure can make medicine be easy to again rehydration and recovers active.But cryodesiccated process is very complicated; In first, second drying stage of pre-cooling and storage process; The structure of medicine possibly influenced by wherein physicochemical change and change; Particularly two of protein and peptide drugs, tertiary structure is prone to be damaged; Lose activity and influence drug effect; And course of dissolution once more, protein might rupture and destroy activity.Use rhGH treatment clinically since the children growth of endogenous growth hormone due to lacking slowly; Because its treatment cycle is long, so how the patient oneself is in inject, but because powder pin course of dissolution is complicated; And unpredictable danger is arranged, thereby cause being discontented with of patient thus.So, need a kind of suitable aqueous formulation to reduce the inconvenience that medication brings for patient and household thereof.
Summary of the invention
But main purpose of the present invention provides recombinant human somatropin's injection that a kind of direct injection uses, and easy to use, suitable patient injects voluntarily.
In order to realize the foregoing invention purpose, the technical scheme that the present invention adopted is: a kind of recombinant human somatropin's injection that can directly use is characterized in that: the component that comprises following concentration proportioning:
Recombinant human somatropin 0.67～10mg/ml, citrate 5～20mmol/L, poloxamer 188 is 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml; The pH value of said injection is 5.5～7.0.
The alternative traditional powder injection formulation of injection of the present invention, its clinical use is convenient, easy.
The specific embodiment
A kind of recombinant human somatropin's injection that can directly use comprises the component of following concentration proportioning:
Recombinant human somatropin 0.67～10mg/ml, citrate 5～20mmol/L, poloxamer 188 is 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml; The pH value of said injection is 5.5～7.0.Poloxamer 188 wherein is as a kind of surfactant, aspect cytoprotective, also demonstrates unique effect, its with the Polysorbate of routine for example polysorbas20 or Tween 80 compare, poloxamer 188 can not cause hemolytic reaction; Thereby citrate buffer agent is used to regulate the pH value of injection guarantees that the recombinant human somatropin is unaffected; Glycine act as stabilizing agent, keep the ambient stable of liquid, and certain force of strain; Mannitol is in order to keep equating of its osmotic pressure of injection and plasma osmotic pressure.The clinical use of this injection is convenient, easy; This injection is after depositing 18 months under 2～8 ℃ of conditions, and each item inspection index is all up to specification.
Preferred described citrate is a sodium citrate, and its concentration is 5mmol/L.
Preferred poloxamer concentration is 4.5mg/ml.
Preferred glycine concentration is 0.9mg/ml.
Preferred mannitol concentration is 45mg/ml.
The pH value of said injection is 5.5～7.0, and the pH value of preferred said injection is 6.2.
Under above-mentioned preferred ingredients and concentration conditions, this injection after depositing 18 months under 2～8 ℃ of conditions, good stability, each item index all meets relevant regulations.
Described injection is a plurality of specifications, makes things convenient for selection of clinical to use.Particularly treat the children growth of endogenous growth hormone due to lacking slowly and severe burn treat two aspect indications; Clinical dosage is various; The patient can select suitable specification according to s own situation; Reduce drug waste, and avoided repeatedly using the dangerous and antiseptic risk of the germ contamination that brings.
Described injection adopts pre-encapsulated injector as inner container.Pre-encapsulated injector has accurately that dosage presets, and clinical use is convenient, easy, can obviously reduce nosocomial infection's probability, adopts suitable needle gauge and syringe, uses more flexibly, is suitable for the patient and injects voluntarily.
Injection of the present invention has omitted the lyophilizing program in process of production, has practiced thrift production time and cost greatly.
Injection of the present invention has in use omitted once more dissolved step, has greatly made things convenient for the patient to inject voluntarily, and has reduced germ contamination equivalent risk in the injection process.
Specifically preparation process of injection of the present invention is: at first preparation contains the stabilizing agent mother solution of sodium citrate, poloxamer 188, glycine, mannitol; Measure recombinant human somatropin's stock solution of assay approval then by recipe quantity, slowly add in the stabilizing agent mother solution.With dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH value, after-teeming is penetrated and is diluted with water to required concentration requirement, and mixing again, and dilute hydrochloric acid and diluted sodium hydroxide solution concentration are 0.1mmol/L; The solution that contains the recombinant human somatropin that will prepare at last with 0.22 μ m filter membrane aseptic filtration after, divide the pre-encapsulated injector of packing into.
Embodiment 1
Get sodium citrate 5mmol, poloxamer 188 3000mg, glycine 500mg, mannitol 30000mg add water for injection 500ml in container, and behind the dissolving mixing, it is subsequent use to get the stabilizing agent mother solution;
Measure recombinant human somatropin's stock solution of 670mg assay approval, slowly add in the stabilizing agent mother solution, with dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH to 5.5, after-teeming is penetrated water and is settled to 1000ml, mixing;
The solution that contains the recombinant human somatropin for preparing with 0.22 μ m filter membrane aseptic filtration after, divide the pre-encapsulated injector of packing into.
Embodiment 2
Get sodium citrate 20mmol, poloxamer 188 5000mg, glycine 1500mg, mannitol 60000mg add water for injection 500ml in container, and behind the dissolving mixing, it is subsequent use to get the stabilizing agent mother solution;
Measure recombinant human somatropin's stock solution of 3330mg assay approval, slowly add in the stabilizing agent mother solution, with dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH to 7.0, after-teeming is penetrated water and is settled to 1000ml, mixing;
The solution that contains the recombinant human somatropin for preparing with 0.22 μ m filter membrane aseptic filtration after, divide the pre-encapsulated injector of packing into.
Embodiment 3
Get sodium citrate 10mmol, poloxamer 188 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is subsequent use to get the stabilizing agent mother solution;
Measure recombinant human somatropin's stock solution of 5330mg assay approval, slowly add in the stabilizing agent mother solution, with dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH to 6.2, after-teeming is penetrated water and is settled to 1000ml, mixing;
The solution that contains the recombinant human somatropin for preparing with 0.22 μ m filter membrane aseptic filtration after, adopt the pre-encapsulated injector fill.
Embodiment 4
Get sodium citrate 10mmol, poloxamer 188 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is subsequent use to get the stabilizing agent mother solution;
Measure recombinant human somatropin's stock solution of 10000mg assay approval, slowly add in the stabilizing agent mother solution, with dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH to 6.2, after-teeming is penetrated water and is settled to 1000ml, mixing;
The solution that contains the recombinant human somatropin for preparing adopts the pre-encapsulated injector fill after with 0.22 μ m filter membrane aseptic filtration.
Embodiment 5
Get sodium citrate 20mmol, poloxamer 188 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is subsequent use to get the stabilizing agent mother solution;
Measure recombinant human somatropin's stock solution of 10000mg assay approval, slowly add in the stabilizing agent mother solution, with dilute hydrochloric acid, diluted sodium hydroxide solution adjustment aforesaid liquid pH to 6.2, after-teeming is penetrated water and is settled to 1000ml, mixing;
The solution that contains the recombinant human somatropin for preparing adopts the pre-encapsulated injector fill after with 0.22 μ m filter membrane aseptic filtration.
In order to confirm prescription of the present invention and method for preparing stability; Respectively prescription of the present invention is carried out study on the stability,, investigate its appearance character, pH, content, macromolecule protein, associated protein, index such as aseptic respectively at 0 month, March, June, JIUYUE, December, sampling in 18 months.The result: prescription of the present invention is after depositing 18 months under 2～8 ℃ of conditions of actual storage requirement near medicine, and each item inspection index is all up to specification.Concrete outcome is seen table 2.
Table 1: the stability test result who stores under 4 ℃ of conditions of recombinant human somatropin's injection:
Can know that by last table each item index of this injection all meets the investigation index.
Recombinant human somatropin's injection of the present invention is used for the slow and severe burn treatment of children growth due to the endogenous growth hormone shortage.Raw material is the recombinant human somatropin who utilizes technique for gene engineering to obtain.
Recombinant human somatropin's injection of the present invention is used to promote that the dosage of children growth varies with each individual, and recommended dose is 0.1～0.15IU/kg body weight/day, every day 1 time, and subcutaneous injection, be 3 months to 3 years the course of treatment, or follow the doctor's advice.Recombinant human somatropin's injection of the present invention, being used for severe burn treatment recommended dose is 0.2～0.4IU/kg body weight/day, every day 1 time, subcutaneous injection is about the course of treatment in general two weeks.Wherein 1IU is about 0.333mg/ml.
These article GHD (GHD) patient has carried out 6 months clinical treatment test.The result shows the effect that significantly short growth in stature is arranged, and ripe nothing of stone age is obviously quickened influence, and this medicine is clinical safe in utilization, non-evident effect.
The index situation of different time height, body weight before and after the table 3 experimenter medication
The clinical test results of syndrome treated with recombinant human growth hormone severe burn proves: rhGH can significantly improve the wound healing percentage rate, dwindles the wound surface area, shortens wound healing time, thereby shortens the length of patient stay, reduces hospitalization cost.
This clinical trial dosage adopts the variable dose design, the result of the test prompting, and rhGH should correctly select rational dosage according to the practical situation of conditions of patients and body in the clinical practice of treatment burn.
Wound healing index situation before and after the table 4 experimenter medication
Claims (7)
1. recombinant human somatropin's injection that can directly use is characterized in that: the component that comprises following concentration proportioning:
Recombinant human somatropin 0.67～10mg/ml, citrate 5～20mmol/L, the husky nurse 188 of poloxamer is 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml; The pH value of said injection is 5.5～7.0.
2. a kind of recombinant human somatropin's injection that can directly use according to claim 1, it is characterized in that: preferred described citrate is a sodium citrate, its concentration is 5mmol/L.
3. a kind of recombinant human somatropin's injection that can directly use according to claim 1 is characterized in that: preferred poloxamer concentration is 4.5mg/ml.
4. a kind of recombinant human somatropin's injection that can directly use according to claim 1 is characterized in that: preferred glycine concentration is 0.9mg/ml.
5. a kind of recombinant human somatropin's injection that can directly use according to claim 1 is characterized in that: preferred mannitol concentration is 45mg/ml.
6. a kind of recombinant human somatropin's injection that can directly use according to claim 1, it is characterized in that: the pH value of preferred said injection is 6.2.
7. according to any described a kind of recombinant human somatropin's injection that can directly use in the claim 1～6, it is characterized in that: described injection is to adopt pre-encapsulated injector as inner container.
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| CN 201110267989 CN102302446B (en) | 2011-09-08 | 2011-09-08 | Recombinant human growth hormone injection capable of being directly used |
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| CN 201110267989 CN102302446B (en) | 2011-09-08 | 2011-09-08 | Recombinant human growth hormone injection capable of being directly used |
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| CN102302446A true CN102302446A (en) | 2012-01-04 |
| CN102302446B CN102302446B (en) | 2013-04-17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115400076A (en) * | 2022-08-17 | 2022-11-29 | 安徽安科生物工程（集团）股份有限公司 | Formula of recombinant human growth hormone-Fc fusion protein injection preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090163419A1 (en) * | 1988-04-15 | 2009-06-25 | Genentech, Inc. | Human growth hormone aqueous formulation |
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- 2011-09-08 CN CN 201110267989 patent/CN102302446B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090163419A1 (en) * | 1988-04-15 | 2009-06-25 | Genentech, Inc. | Human growth hormone aqueous formulation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115400076A (en) * | 2022-08-17 | 2022-11-29 | 安徽安科生物工程（集团）股份有限公司 | Formula of recombinant human growth hormone-Fc fusion protein injection preparation |
| CN115400076B (en) * | 2022-08-17 | 2023-09-05 | 安徽安科生物工程（集团）股份有限公司 | Recombinant human growth hormone-Fc fusion protein injection formulation |
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| CN102302446B (en) | 2013-04-17 |
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Denomination of invention: Recombinant human growth hormone injection capable of being directly used Effective date of registration: 20161101 Granted publication date: 20130417 Pledgee: Huizhou Merchants Bank Hefei Mengcheng road subbranch Pledgor: Anhui Anke Biotechnology (Group) Co., Ltd. Registration number: 2016990000929 |
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Date of cancellation: 20210209 Granted publication date: 20130417 Pledgee: Huizhou Merchants Bank Hefei Mengcheng road subbranch Pledgor: ANHUI ANKE BIOTECHNOLOGY (Group) Co.,Ltd. Registration number: 2016990000929 |
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