CN107596349A - A kind of erythropoietin preparation formula of stabilization - Google Patents
A kind of erythropoietin preparation formula of stabilization Download PDFInfo
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- CN107596349A CN107596349A CN201711013832.7A CN201711013832A CN107596349A CN 107596349 A CN107596349 A CN 107596349A CN 201711013832 A CN201711013832 A CN 201711013832A CN 107596349 A CN107596349 A CN 107596349A
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- epo
- preparation formula
- erythropoietin
- erythropoietin preparation
- stabilization according
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Abstract
The invention provides a kind of erythropoietin(EPO) of stabilization (EPO) pharmaceutical formulation, it includes：Erythropoietin(EPO), hyaluronidase, buffer, stabilizer and nonionic surfactant.EPO pharmaceutical formulations prepared by the present invention are used to subcutaneously or intramuscularly inject, and formulation is liquid drugs injection or freeze drying powder injection.The EPO of the present invention can be used for treatment disease such as anaemia, the cancer patient anaemia caused by chemicotherapy, operation consent autotransfusion, neonatal anemia caused by renal failure；It can also be used for beauty etc..
Description
Technical field
The present invention relates to field of biological pharmacy, more particularly to a kind of pharmaceutical formulation of erythropoietin(EPO) (EPO), it can generation
For traditional intravenously administrable approach, it is administered by the way of subcutaneously or intramuscularly injecting to patient.
Background technology
Erythropoietin(EPO) (Erythopoietin, EPO) is since in June, 1989 lists, and the indication that it is treated is not
Disconnected increase, in most cases, EPO are injected through intravenous (IV), but are come for uremic patient caused by kidney failure
Say, they need side to work, while receiving treatment, intravenous injection needs to complete in the case where medical personnel instruct, and takes longer.By changing
Become method of administration, such as hypodermic injection or intramuscular injection, can greatly facilitate patient or medical personnel to use, shorten administration time, it is special
Not for dialysis needs the patient of maintenance dose, themselves use is trained, great convenience is brought to patient.
To so far, the EPO specifications of Chinese market sale have 2000IU/mL/ bottles, 3000IU/mL/ bottles, 4000IU/
The plurality of specifications such as mL/ bottles, 5000IU/mL/ bottles, 6000IU/mL/ bottles, 10000IU/mL/ bottles, there is liquid drugs injection and freeze drying powder injection
Two kinds of formulations.In formula using human serum albumin as protective agent based on, Shenyang three lives etc., which also invents, is free of human serum albumin conduct
Protectant pharmaceutical formulation (patent CN1247257C).EPO manufacturer and external producer of these commercially available EPO from China,
Such as the Epogen of Amgen companies, (actual with Epogen is same production to subsidiary of Johnson ＆ Johnson Ortho Biotech Procrit products
Product) and Japanese Kyowa Hakko Kirin (Japan consonance kylin company) ESPO etc..In addition, Chinese market also has Amgen public
The long-acting EPO Aranesp of production are taken charge of, Aranesp is that Amgen companies are " high in one kind of the acquisition FDA approval listings of in September, 2001
The long-acting rhEPO-- alpha productions of glycosylation ", long-acting principle are by amino acid sequence of the human forcing erythrogenin through part modification
And attached sugar chain newly, it is allowed in the molecule thereof plus thus that longer serum half-life is presented and the generation of lasting promoting erythrocyte is lived
Property；And Mircera (polyethylene glycol Epoetin Beta) is another long-acting rhEPO- that Roche companies list in November, 2007
β, it is in the nature the Epoetin Beta of Pegylation, and substantially prolongs medicine by polyethyleneglycol modified Epoetin Beta makees
Use the time.Above-mentioned EPO is both needed to patient's intravenously administrable, and it contains active component EPO (2000-10000IU/mL), buffering in being formulated
Agent, protective agent etc..
But erythropoietin(EPO) is to so far, and in the market does not have a kind of formulation to be used to subcutaneously or intramuscularly inject, the present invention
Purpose be that EPO to be solved is used to be subcutaneously injected or the new formulation of intramuscular injection, be easy to medical personnel and patient to use.
The content of the invention
It is an object of the invention to provide a kind of unit containing high activity for being available for subcutaneously or intramuscularly the injecting EPO of stabilization system
Agent prescription.
In order to achieve the above object, technical scheme provided by the invention is as follows：A kind of erythropoietin(EPO) EPO systems of stabilization
Agent prescription, it includes：Erythropoietin(EPO), the hyaluronidase of pH7.0 ± 0.5, buffer, stabilizer and non-ionic surface are lived
Property agent.
Preferably, the erythropoietin(EPO) is the recombinant protein through bacterium, yeast or animal cell expression；Or from animal
The native protein extracted in tissue；Or these albumen are coupled formed EPO conjugates with some micromolecular compounds, they are equal
With the biological activity for promoting RBC acceptor garland rate.
Preferably, described hyaluronidase is the soluble protein that cell is expressed or extracted from animal tissue's (body fluid),
Further, described hyaluronidase is rPH20.
Preferably, one kind in human serum albumin, sucrose, trehalose dihydrate compound, mannose of the stabilizer or
Several mixtures.
Preferably, the buffer delays selected from citrate buffer solution, phosphate buffer, acetate buffer or histidine
Fliud flushing or other can be used for human injection buffer solution, buffer concentration 1-100mM.
Preferably, nonionic surfactant is selected from polysorbate 20, polyoxyethylene sorbitan monoleate or polyethylene-polypropylene polymerization
Thing.
Preferably, RBC acceptor garland rate cellulose content is 20ug/mL-50mg/mL, preferably 20ug/mL-10mg/mL, further preferably
Ground 100ug/mL-5mg/mL, more preferably 500ug/mL-3mg/mL.Select to use for convenience of medical personnel and patient, such as
100ug/ml/ bottles (branch), 200ug/ml/ bottles (branch), 300ug/ml/ bottles (branch), 4 00ug/ml/ bottles (branch), 500ug/ml/ bottles
(branch) etc., can also 1mg/ml/ bottles (branch), 2mg/ml/ bottles (branch), 3mg/ml/ bottles (branch), 4mg/ml/ bottles (branch), 5mg/ml/
Bottle (branch) or 10mg/ml/ bottles (branch) etc., EPO specific activity is about 100000IU/mg, then is converted into international unit, corresponds to
10000IU/ml/ bottles (branch), 20000IU/ml/ bottles (branch), 30000IU/ml/ bottles (branch), 40000IU/ml/ bottles (branch),
50000IU/ml/ bottles (branch).Can also be 100000IU/ml/ bottles (branch), 200000IU/ml/ bottles (branch), 300000IU/ml/
Bottle (branch), 400000IU/ml/ bottles (branch), 500000IU/ml/ bottles (branch) or 1000000IU/ml/ bottles (branch).
Preferably, hyaluronidase content is 100IU-20000IU/mL, preferably 300IU/mL to 2000IU/mL, more
Preferably 500-1500IU/mL.
Preferably, non-ionic surfactant concentration is 0.01 to 0.1% (w/v), preferably 0.01-0.08%, more excellent
Selection of land is 0.02-0.04%.
Preferably, stabilizer concentration is 5-200mM scopes, preferably 5-150mM, more preferably 10-100mM.
In some embodiments, the formulation stable for the EPO subcutaneously or intramuscularly injected has：
EPO active components containing 300ug-1000ug/mL, 10-100mM citrate buffer agents (pH5-8), 150-
300IU/mL hyaluronidase, 0.5mg/mL-5mg/mL human albumin, 0.01-0.05% nonionic surfactant.
It is that safely effectively, the content of addition has larger scope, such as 150-1500IU/mL that hyaluronidase, which has been recognized that,
With；
EPO active components containing 300ug-1000ug/mL, 10-100mM citrate buffer agents (pH5-8), 150-
300IU/mL hyaluronidase, 5-100mM trehalose dihydrate compound or sucrose, 0.01-0.05% non-ionic surface are lived
Agent；
EPO active components containing 1.2mg-2mg/mL, 10-100mM citrate buffers (pH5-8) or phosphate delay
Fliud flushing (pH5-8), 150-1000IU/mL hyaluronidases, 5-200mM sucrose or trehalose dihydrate compound as stabilizer,
0.02-0.2% nonionic surfactant；
EPO active components containing 3mg-5mg/mL, 10-100mM citrate buffers (pH5-8) or phosphate-buffered
Liquid (pH5-8), 150-1500IU/mL hyaluronidases, 5-200mM sucrose or trehalose dihydrate compound are as stabilizer, 0.02-
0.2% nonionic surfactant；
EPO active components containing 5mg-10mg/mL, 10-100mM citrate buffers (pH5-8) or phosphate delay
Fliud flushing (pH5-8), 150-2000IU/mL hyaluronidases, 5-200mM sucrose or trehalose dihydrate compound as stabilizer,
0.02-0.2% nonionic surfactant；
In particular cases to facilitate medical worker to use EPO, higher EPO concentration, such as 10-50mg/ can be taken
MLEPO, 10-100mM citrate buffer (pH5-8) or phosphate buffer (pH5-8), 150-15000IU/mL hyalomitomes
Sour enzyme, 5-200mM sucrose or trehalose dihydrate compound are as stabilizer, 0.02-0.2% nonionic surfactant.
The present invention stabilization erythropoietin preparation formula, for subcutaneously or intramuscularly injecting, its formulation be liquid or
Freeze-dried formulation.It is autologous for treating anaemia, the cancer patient anaemia caused by chemicotherapy, operation consent caused by renal failure
The diseases such as blood transfusion, neonatal anemia；It can also be used for beauty etc..
The volume subcutaneously or intramuscularly injected is generally less than 2ml, and this is due to that caused back-pressure causes skin after large volume is injected
Undertissue's oedema, it is therefore desirable to improve the protein concentration of unit volume or solve this contradiction using the method for multi-point injection.
High molecular weight protein medicine muscle or hypodermic injection, it is commonplace in antibody, as the anti-HER2 monoclonal antibody of high concentration (is used
In the tumours such as treatment breast cancer, patent CN1025789A)；The Avastin of high concentration (is used to treat the tumours such as lung cancer, patent
CN201410093781)；Adalimumab (treatment autoimmune disease) of high concentration etc., when these monoclonal antibodies are used to be subcutaneously injected
It is both needed to improve the protein concentration of unit volume, reduces the active drug deficiency caused by degraded is low with absorption efficiency.By using
A small amount of soluble hyaluronidase, the hyaluronic acid degraded in hypodermis, improve liquid barrier capabilities in tissue, increase
The permeability of tissue, be advantageous to the absorption of medicine.
The concentration of addition hyaluronidase depends on the content of active component EPO in the formula that provides in the present invention.This hair
Bright technical scheme can effectively facilitate EPO absorption, therefore, hyaluronidase to provide the hyaluronidase of sufficient amount
Minimum usage amount is typically not less than 100IU/mL.More particularly, the effective dose of hyaluronidase arrives in 150IU/ml
20000IU/ml, if we assume that the specific activity of hyaluronidase is 100000IU/mg, then the hyaluronidase added it is dense
Degree is about 0.015mg/ml to 0.2mg/mL.According in general general knowledge, hyaluronidase and EPO proportioning are 1:1000 or 1:
2000 or 1:3000 or 1:4000 or 1:5000 or more at high proportion etc..
It is right the invention provides the form that a kind of high concentration erythropoietin(EPO) and a small amount of soluble transparent matter acid enzyme combine
In those skilled in the art, it is readily understood that high concentration EPO preparations and hyaluronidase be used alone also can reach it is identical
Effect.Such as before or after high concentration EPO is injected, hyaluronidase is injected in close adjacent regions, also can reach identical effect
Fruit.
The present invention adds nonionic surfactant in the formulation, and this is required for the EPO containing high concentration
, because most of albumen easily form aggressiveness in higher concentrations, aggressiveness can cause the immunogenicity of human cytokines, cause to control
The failure for the treatment of.Assemble to reduce the albumen caused by high concentration, also need to add some a small amount of non-ionic surfaces work in formula
Property agent, prevent or reduce albumen aggregation, make preparation within a certain period of time, such as 2 years or be stable for more time.
Word：Erythropoietin(EPO) (Erythopoietin, EPO), refer to suppression marrow CFU-E apoptosis, thorn
Sharp reticulocyte discharges into blood circulation and stimulates intracellular protein to synthesize；Be internal erythrocyte proliferation, differentiation and
Maintain peripheral circulation erythrocyte number normally most important hemopoieticgrowth factor.EPO can be the restructuring of animal cell expression
Albumen, or the albumen extracted from animal tissue or body fluid, typically contain 160-170 amino acid sequence, typically recombinate
RHuEPO amino acid sequence is 165 amino acid, and natural EPO then has 166 amino acid, in its protein structure, typically contains
There are 3 N-type and 1 O-type sugar chain structure, but technical staff can also be transformed its amino acid sequence, increase 1-3 N-
Type glycosylation site, to increase the half-life period of EPO in vivo, the frequency of intravenous injection is reduced, or adopt and otherwise prolong
The half-life period of long EPO in vivo, be such as coupled with PEG (polyethylene glycol) compound of different molecular weight, as PEG4000,
PEG of PEG6000, PEG8000, even more macromolecular etc. forms PEG-EPO conjugates, and these various forms of EPO can be answered
Subcutaneously or intramuscularly injected with new Formulation Implementation provided by the invention.
Hyaluronidase is that have the active material of hyaluronic acid degradation.Equally, hyaluronidase can be that animal is thin
The recombinant protein of cellular expression, or the albumen extracted from tissue or body fluid, its feature contain 400-480 amino acid sequence
Row, molecular weight about 50k-70kDalton, have the activity of hyaluronic acid degradation, the typical hyaluronidase that recombinates is
rHP20.Contain 6 N-type glycosylation sites and 1 O-type glycosylation site in its amino acid sequence of described hyaluronidase.
EPO pharmaceutical formulations prepared by the present invention are used to subcutaneously or intramuscularly inject, and formulation is liquid drugs injection or freeze drying powder injection.This
The EPO pharmaceutical formulations of invention are used to treat anaemia (hemodialysis), cancer patient caused by renal failure caused by chemicotherapy
The diseases such as anaemia, operation consent autotransfusion, neonatal anemia；It can also be used for beauty etc..
Embodiment
Such scheme is described further below in conjunction with specific embodiment.It should be understood that these embodiments are to be used to illustrate
The present invention and be not limited to limit the scope of the present invention.The implementation condition used in embodiment can be done according to the condition of researcher into
One successive step, unreceipted implementation condition are usually the condition in normal experiment.
Introduce and summarize
The present invention by way of example rather than provides the mode of limitation to illustrate.It should be noted that in present disclosure
Described " one " or " one kind " embodiment is not necessarily referring to same embodiment, and refers at least a kind of.
Various aspects of the invention are described below.However, as will be readily apparent to one of skill in the art, can
Implement the present invention according to the only some or all of aspects of the present invention.For purposes of illustration, provide herein specific numbering, material and
Configuration, enables one to thoroughly understand the present invention.However, be evident that for those of skill in the art,
The present invention can be implemented without concrete details.In other examples, not make the present invention is obscure many institutes have been omitted or simplified
Known feature.
Various operations are described successively as multiple discrete steps, and with most helpful in the side for understanding the present invention
Formula illustrates；However, in-order description should not be construed as to imply that these operations are necessarily dependent on order.
Reactant according to type species is illustrated to various embodiments.To show for those of skill in the art and
It is clear to, any number of different types of reactant can be used to implement for the present invention, and be more than those for the purpose of illustration
And the reactant provided herein.In addition, also it is evident that, the invention is not limited in any specific mixing is shown
Example.
Specific embodiment
Example 1：
A kind of erythropoietin preparation formula of stabilization is made up of following component：500ug/mL EPO, 10mM citric acids
Buffer solution, pH7.0,2.5mg/mL human albumins, 150IU/mL hyaluronidases, 0.01% polysorbate 20.
Embodiment 2
A kind of erythropoietin preparation formula of stabilization is made up of following component：1.5mg/mLEPO, 10mM citric acid delay
Fliud flushing, pH7.0,100mM trehalose dihydrate compounds, 500IU/mL hyaluronidases, 0.04% polysorbate 20.
Embodiment 3
A kind of erythropoietin preparation formula of stabilization is made up of following component：5mg/mL EPO, 10mM phosphate delays
Fliud flushing, pH6.8,150mM trehalose dihydrate compounds, 1000IU/mL hyaluronidases, 0.04% polysorbate 20.
Embodiment 4.
A kind of erythropoietin preparation formula of stabilization is made up of following component：10mg/mL EPO, 10mM phosphate delays
Fliud flushing, pH6.8,200mM trehalose dihydrate compounds, 1500IU/mL hyaluronidases, 0.04% polysorbate 20.
Specific embodiment described above is only the preferred embodiment of the present invention, it is noted that for the art
For those of ordinary skill, under the premise without departing from the principles of the invention, some improvement or replacement can also be made, these improvement
Or replace and should also be as being considered as protection scope of the present invention.
Claims (10)
1. the erythropoietin preparation formula of a kind of stabilization, it is characterised in that it includes：
(1) erythropoietin(EPO),
(2) hyaluronidase,
(3) buffer of pH7.0 ± 0.5,
(4) stabilizer,
(5) nonionic surfactant.
2. the erythropoietin preparation formula of stabilization according to claim 1, it is characterised in that described red blood cell life
Cheng Su is the recombinant protein through bacterium, yeast or animal cell expression；Or the native protein extracted from animal tissue；Or these
Albumen is coupled formed EPO conjugates with some micromolecular compounds.
3. the erythropoietin preparation formula of stabilization according to claim 1, it is characterised in that the stabilizer is selected from
One or more of mixtures in human serum albumin, sucrose, trehalose dihydrate compound, mannose.
4. the erythropoietin preparation formula of stabilization according to claim 1, it is characterised in that the buffer is selected from
Citrate buffer solution, phosphate buffer, acetate buffer or histidine buffering liquid, buffer concentration 1-100mM.
5. the erythropoietin preparation formula of stabilization according to claim 1, it is characterised in that the non-ionic surface
Activating agent is selected from polysorbate 20, polyoxyethylene sorbitan monoleate or polyethylene-polypropylene polymer.
6. the erythropoietin preparation formula of the stabilization according to claim any one of 1-5, it is characterised in that red blood cell
Generation cellulose content is 20ug/mL-50mg/mL.
7. the erythropoietin preparation formula of the stabilization according to claim any one of 1-5, it is characterised in that described
Bright matter acid enzyme content is 100-20000IU/mL.
8. the erythropoietin preparation formula of the stabilization according to claim any one of 1-5, it is characterised in that described steady
It is 5-200mM to determine agent concentration.
9. the erythropoietin preparation formula of the stabilization according to claim any one of 1-5, it is characterised in that described non-
Ionic surface active agent content is in the range of 0.01 to 0.1% (w/v).
10. the erythropoietin preparation formula of stabilization according to claim 1, it is characterised in that its formulation is liquid
Or freeze-dried formulation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111558046A (en) * | 2020-05-27 | 2020-08-21 | 华润昂德生物药业有限公司 | Application of trehalose in preparation of recombinant human erythropoietin liquid preparation, preparation method and application |
| WO2022033480A1 (en) * | 2020-08-11 | 2022-02-17 | 隆延生物科技（上海）有限公司 | Liquid preparation and application thereof |
| CN114636818A (en) * | 2022-05-19 | 2022-06-17 | 天津德祥生物技术有限公司 | Coating liquid, erythrocyte membrane coating liquid containing coating liquid and application of erythrocyte membrane coating liquid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063809A1 (en) * | 2003-12-22 | 2005-07-14 | Dubai Genetics Fz-Llc | Nature-identical erythropoietin |
| CN104399075A (en) * | 2009-09-11 | 2015-03-11 | 霍夫曼-拉罗奇有限公司 | Highly concentrated pharmaceutical formulations |
| CN106729627A (en) * | 2016-12-14 | 2017-05-31 | 深圳未名新鹏生物医药有限公司 | A kind of recombinant human erythropoietin preparation |
-
2017
- 2017-10-26 CN CN201711013832.7A patent/CN107596349A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005063809A1 (en) * | 2003-12-22 | 2005-07-14 | Dubai Genetics Fz-Llc | Nature-identical erythropoietin |
| CN104399075A (en) * | 2009-09-11 | 2015-03-11 | 霍夫曼-拉罗奇有限公司 | Highly concentrated pharmaceutical formulations |
| CN106729627A (en) * | 2016-12-14 | 2017-05-31 | 深圳未名新鹏生物医药有限公司 | A kind of recombinant human erythropoietin preparation |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111558046A (en) * | 2020-05-27 | 2020-08-21 | 华润昂德生物药业有限公司 | Application of trehalose in preparation of recombinant human erythropoietin liquid preparation, preparation method and application |
| WO2022033480A1 (en) * | 2020-08-11 | 2022-02-17 | 隆延生物科技（上海）有限公司 | Liquid preparation and application thereof |
| CN114636818A (en) * | 2022-05-19 | 2022-06-17 | 天津德祥生物技术有限公司 | Coating liquid, erythrocyte membrane coating liquid containing coating liquid and application of erythrocyte membrane coating liquid |
| CN114636818B (en) * | 2022-05-19 | 2022-07-29 | 天津德祥生物技术有限公司 | Coating liquid, erythrocyte membrane coating liquid containing coating liquid and application of erythrocyte membrane coating liquid |
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