CN102302446B - 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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- CN102302446B CN102302446B CN 201110267989 CN201110267989A CN102302446B CN 102302446 B CN102302446 B CN 102302446B CN 201110267989 CN201110267989 CN 201110267989 CN 201110267989 A CN201110267989 A CN 201110267989A CN 102302446 B CN102302446 B CN 102302446B
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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 growth hormone injection that can directly use.
Background technology
Recombinant human somatropin (Recombinant human Growth Hormone, rhGH) produces for recombinant DNA technology, is made of its structure and the aminoacid sequence genetically engineered drug consistent with the spontaneous growth hormone 191 aminoacid.Utilize recombinant human somatropin that recombinant DNA technology produces through for many years clinical practice, proved its effectiveness and safety clinically.
This protide product of recombinant human somatropin adopts Freeze Drying Technique usually, namely utilize freezing solution under the low-temp low-pressure condition, directly distillation is removed moisture and is finished 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 activity recovery.But cryodesiccated process is very complicated, in first, second drying stage of pre-cooling and storage process, the structure of medicine may be affected by wherein physicochemical change and change, particularly two of protein and peptide drugs, tertiary structure easily is damaged, lose activity and affect drug effect, and course of dissolution again, protein might rupture and destroy activity.Use clinically rhGH treatment 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 thus being discontented with of patient.So, need a kind of suitable aqueous formulation to reduce the inconvenience that medication brings to patient and household thereof.
Summary of the invention
But main purpose of the present invention provides the recombinant human growth hormone 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 solution adopted in the present invention is: a kind of recombinant human growth hormone 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, PLURONICS F87 are 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml; The pH value of described 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 growth hormone injection that can directly use comprises the component of following concentration proportioning:
Recombinant human somatropin 0.67～10mg/ml, citrate 5～20mmol/L, PLURONICS F87 are 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml; The pH value of described injection is 5.5～7.0.PLURONICS F87 wherein is as a kind of surfactant, also demonstrates unique effect aspect cytoprotective, its with the Polysorbate of routine for example polysorbas20 or Tween 80 compare, PLURONICS F87 can not cause hemolytic reaction; Thereby citrate buffer agent is used for the pH value of adjusting injection guarantees that the recombinant human somatropin is unaffected; Glycine act as stabilizing agent, keep the ambient stable of liquid, and certain tension force; 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 every Index for examination is all up to specification.
Preferred described citrate is 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 described injection is 5.5～7.0, and the pH value of preferred described injection is 6.2.
Under above-mentioned preferred component and concentration conditions, this injection is after depositing 18 months under 2～8 ℃ of conditions, and good stability, indices all meet relevant regulations.
Described injection is 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 greatly saved production time and cost.
Injection of the present invention has in use omitted the again step of dissolving, has greatly made things convenient for the patient to inject voluntarily, and has reduced germ contamination equivalent risk in the injection process.
The concrete preparation process of injection of the present invention is: at first preparation contains the stabilizing agent mother solution of sodium citrate, PLURONICS F87, glycine, mannitol; Then measure recombinant human somatropin's stock solution of assay approval by recipe quantity, slowly add in the stabilizing agent mother solution.Adjust the aforesaid liquid pH value with dilute hydrochloric acid, diluted sodium hydroxide solution again, after-teeming is penetrated and is diluted with water to required concentration requirement, and mixing, 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, be distributed into pre-encapsulated injector.
Embodiment 1
Get sodium citrate 5mmol, PLURONICS F87 3000mg, glycine 500mg, mannitol 30000mg add water for injection 500ml in container, and behind the dissolving mixing, it is for 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, adjust aforesaid liquid pH to 5.5 with dilute hydrochloric acid, diluted sodium hydroxide solution, 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, be distributed into pre-encapsulated injector.
Embodiment 2
Get sodium citrate 20mmol, PLURONICS F87 5000mg, glycine 1500mg, mannitol 60000mg add water for injection 500ml in container, and behind the dissolving mixing, it is for 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, adjust aforesaid liquid pH to 7.0 with dilute hydrochloric acid, diluted sodium hydroxide solution, 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, be distributed into pre-encapsulated injector.
Embodiment 3
Get sodium citrate 10mmol, PLURONICS F87 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is for 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, adjust aforesaid liquid pH to 6.2 with dilute hydrochloric acid, diluted sodium hydroxide solution, 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, PLURONICS F87 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is for 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, adjust aforesaid liquid pH to 6.2 with dilute hydrochloric acid, diluted sodium hydroxide solution, 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, PLURONICS F87 4500mg, glycine 900mg, mannitol 45000mg add water for injection 500ml in container, and behind the dissolving mixing, it is for 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, adjust aforesaid liquid pH to 6.2 with dilute hydrochloric acid, diluted sodium hydroxide solution, 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 determine prescription of the present invention and preparation method stability, respectively prescription of the present invention is carried out study on the stability, respectively at 0 month, March, June, JIUYUE, December, sampling in 18 months, investigate its appearance character, pH, content, macromolecule protein, associated protein, the index such as aseptic.The result: prescription of the present invention is after depositing 18 months under 2～8 ℃ of conditions of actual storage requirement near medicine, and every Index for examination is all up to specification.Concrete outcome sees Table 2.
Table 1: the stability test result who stores under 4 ℃ of conditions of recombinant human growth hormone injection:
As seen from the above table, the indices of this injection all meets the investigation index.
Recombinant human growth hormone 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 growth hormone injection of the present invention is used for promoting 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 for the treatment of, or follow the doctor's advice.Recombinant human growth hormone 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 for the treatment of in general two weeks.Wherein 1IU is about 0.333mg/ml.
This product 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 without obviously accelerating impact, the clinical use safety of this medicine, non-evident effect on the stone age.
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 be according to the practical situation of conditions of patients and body in the clinical practice for the treatment of burn, the rational dosage of selecting properly.
Wound healing index situation before and after the table 4 experimenter medication
Claims (7)
1. recombinant human growth hormone injection that can directly use is characterized in that: be made of following component:
Recombinant human somatropin 0.67～10mg/ml, citrate 5～20mmol/L, PLURONICS F87 are 3～5mg/ml, glycine 0.5～1.5mg/ml, mannitol 30～60mg/ml and water for injection; The pH value of described injection is 5.5～7.0;
This injection preparation process is: first configuration contains the stabilizing agent mother solution of sodium citrate, PLURONICS F87, glycine, mannitol; Then will slowly add by recombinant human somatropin's stock solution that recipe quantity is measured in the stabilizing agent mother solution; Adjust the aforesaid liquid pH value with dilute hydrochloric acid, diluted sodium hydroxide solution again, after-teeming is penetrated and is diluted with water to required concentration requirement, and mixing; Dilute hydrochloric acid and diluted sodium hydroxide solution concentration are 0.1mmol/L, and the solution that contains the recombinant human somatropin that will prepare at last is with 0.22 μ m filter membrane aseptic filtration.
2. a kind of recombinant human growth hormone injection that can directly use according to claim 1, it is characterized in that: preferred described citrate is sodium citrate, its concentration is 5mmol/L.
3. a kind of recombinant human growth hormone 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 growth hormone 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 growth hormone 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 growth hormone injection that can directly use according to claim 1, it is characterized in that: the pH value of preferred described injection is 6.2.
7. the described a kind of recombinant human growth hormone injection that can directly use of any one according to claim 1～6 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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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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