CN101062406A - Reeombinnt human granulocyte colony stimulating factor microemulsion - Google Patents
Reeombinnt human granulocyte colony stimulating factor microemulsion Download PDFInfo
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- CN101062406A CN101062406A CNA2007100146446A CN200710014644A CN101062406A CN 101062406 A CN101062406 A CN 101062406A CN A2007100146446 A CNA2007100146446 A CN A2007100146446A CN 200710014644 A CN200710014644 A CN 200710014644A CN 101062406 A CN101062406 A CN 101062406A
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- stimulating factor
- colony stimulating
- granulocyte colony
- human granulocyte
- reeombinnt
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Abstract
The invention discloses a retooling human granulocyte colony stimulating factor microemulsion to medicinal technique, which comprises the following steps: allocating mass ratio of retooling human granulocyte colony stimulating factor, surface activator, cosurfactant, oil phase and water phase at 1 : (1-5) : (0. 5-3) : (1-3) : (500-2000); adding the retooling human granulocyte colony stimulating factor into oil phase; stirring evenly; dispersing in water phase; getting the product. This product is fit for treat neutrophilic granulocytopenia, which can keep bioavailability with the same effect in injection give medicine.
Description
Affiliated technical field:
The invention belongs to medical technology, particularly a kind of Reeombinnt human granulocyte colony stimulating factor microemulsion.
Background technology:
Recombinant human granulocyte colony stimulating factor is the Filgrastim (rhG-CSF) who is produced by the DNA recombinant technique, identical with the aminoacid sequence and the sugar chain of natural granulocyte colony-stimulating factor, the N end of different is recombinant human granulocyte colony stimulating factor chain contains methionine.This product can combine with target membrane receptor and work.Granulocyte colony-stimulating factor is that grain is one of major cytokine of hemopoietic in the adjusting bone marrow, mainly stimulates granulocyte series hemopoietic, also can make pluripotential hemopoietic stem cell enter cell cycle; Promote propagation, differentiation and the maturation of medullary system hemopoietic progenitor cell, regulate the propagation and the differentiation and maturation of neutrophil series cell; And order about neutrophilic granulocyte and release to blood flow, periphery neutrophilic granulocyte quantity being increased, and improve its function, activate the phagocytic capacity is at antibody-dependant cell cytotoxic activity of tumor cell etc.
Recombinant human granulocyte colony stimulating factor is applicable to the neutrophilic granulocytopenia that reasons such as cancer chemotherapy cause.The cancer patient uses the bone marrow depression chemotherapeutics, particularly after intensive, the bone marrow property deprived chemotherapy, the injection recombinant human granulocyte colony stimulating factor helps to prevent the generation of neutrophilic granulocytopenia, alleviate the degree that neutrophilic granulocyte reduces, shorten the persistent period of agranulocytosis, quicken the recovery of granulocyte number, promoting leucocytes quantity, thus the danger that concurrent infection generates heat reduced.Recombinant human granulocyte colony stimulating factor is very obvious to curative effects such as chronic granulocyte deficiency disease patient such as myelodysplastic syndrome, cyclic neutropenia agranulocytosis and aplastic anemia.
In addition, the recovery of neutrophilic granulocyte after recombinant human granulocyte colony stimulating factor all right (1) the promotion bone marrow transplantation.(2) neutrophilic granulocytopenia of myelodysplastic syndrome is followed in treatment.(3) property granulocytopenia among the hypoplastic anemia is followed in treatment.(4) congenital, the idopathic neutropenia of treatment.
In the prior art, recombinant human granulocyte colony stimulating factor is mainly by subcutaneous injection or intravenous mode administration, this is very inconvenient for the patient who needs medication, and drug administration by injection is needed the patient of long-term prescription to bring a lot of miseries simultaneously, makes the compliance of clinical application reduce.Though oral administration can effectively address the above problem, recombinant human granulocyte colony stimulating factor suffers very serious destruction in gastric juice, that is to say, recombinant human granulocyte colony stimulating factor is oral invalid.Owing to be subjected to the restriction of medicine stability and physicochemical property characteristics, also there is not the appropriate formulation form to be convenient to clinical use for recombinant human granulocyte colony stimulating factor, also can't effectively solve the problem of recombinant human granulocyte colony stimulating factor administering mode now.
Microemulsion formulation can improve a lot of bioavailability of medicament to a great extent, but this dosage form has very high requirement to the physicochemical property of medicine and stability, and preparation technology is also quite complicated, and a lot of difficulties is arranged in the industrialization of pharmaceuticals industry.
Summary of the invention:
The invention provides a kind of Reeombinnt human granulocyte colony stimulating factor microemulsion, it can pass through the nasal spray delivery.After both can having avoided oral administration by the mode of nasal-cavity administration, the destruction of recombinant human granulocyte colony stimulating factor in gastric juice, improved bioavailability greatly, avoided inconvenience that subcutaneous or intravenous injection brings to the patient and painful again, because preparing recombinant human granulocyte colony stimulating factor, the present invention becomes microemulsion formulation simultaneously, make the nasal spray route of administration can ignore to the zest damage of nasal mucosa, bioavailability experiment by macaque, be surprised to find the present invention and accomplished to compare, on bioavailability, do not have significant difference with the drug administration by injection approach.
Weight of the present invention is formed and is comprised:
Recombinant human granulocyte colony stimulating factor----------1 part
Surfactant------------------------1-5 part
Cosurfactant----------------------0.5-3 part
Oil phase------------------------------1-3 part
Water------------------------------500-2000 part
Described surfactant is meant one or more in polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene castor oil, sodium lauryl sulphate, sodium stearyl sulfate, sodium hexadecyl sulfate, lecithin, glyceryl monostearate, sucrose fatty acid ester, fatty acid esters of sorbitan, polyoxyethylene sorbitan fatty acid ester or the poloxamer.
Described cosurfactant is meant one or more in dehydrated alcohol, Macrogol 200, propylene glycol or the glycerol.
Described oil phase is meant one or more in glyceryl linoleate, diethylene glycol monoethyl ether, Semen Maydis oil, soybean oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, Oleum Gossypii semen, Oleum sesami or the olive oil.
Described water is meant one or more in water, fruit juice, normal saline or the glucose solution.
Preparation technology of the present invention adds in the oil phase of recipe quantity for taking by weighing the recipe quantity recombinant human granulocyte colony stimulating factor, stirs and makes dissolving, adds surfactant, the cosurfactant of recipe quantity again, stirs, and promptly gets microemulsion after aqueous phase disperses.
Reeombinnt human granulocyte colony stimulating factor microemulsion of the present invention is compared with the recombinant human granulocyte colony stimulating factor injection, because this dosage form is prepared into the administration of aerosol via intranasal application, make medicine to absorb rapidly and enter human circulation, both kept high bioavailability, " first pass effect " of avoiding oral administration to take place avoided subcutaneous again or inconvenience that intravenous injection brings and painful.Therefore, develop this product and will obtain social benefit and economic benefit widely.
The specific embodiment:
Now by the furthermore bright the present invention of following example, but the scope of the present patent application is not restricted to following examples.
Embodiment:
Seven kinds of concrete prescriptions are as follows: (determining the supplementary product kind and the quantity of microemulsion formulation)
Prescription A:
Recombinant human granulocyte colony stimulating factor 1.0g
Dehydrated alcohol 1.0g
Propylene glycol 0.5g
Polyoxyethylene hydrogenated Oleum Ricini 4.0g
Glyceryl linoleate 2.5g
Water 1000ml
Make the 1000ml microemulsion
Preparation technology: take by weighing 1.0g rhG-CSF, join in the glyceryl linoleate of 2.5g, stir and make dissolving, add polyoxyethylene hydrogenated Oleum Ricini 4.0g, dehydrated alcohol 1.0g again, propylene glycol 0.5g stirs, and promptly gets microemulsion after disperseing in 1000ml water.
Prescription B:
Recombinant human granulocyte colony stimulating factor 1.0g
Dehydrated alcohol 1.0g
Macrogol 200 0.5g
Fatty acid esters of sorbitan 2.0g
Olive oil 2.5g
Water 1000ml
Make the 1000ml microemulsion
Preparation technology is with prescription A.
Prescription C:
Recombinant human granulocyte colony stimulating factor 1.0g
Dehydrated alcohol 1.0g
Propylene glycol 1.0g
Lecithin 3.0g
Semen Maydis oil 2.5g
Fruit juice 1000ml
Make the 1000ml microemulsion
Preparation technology is with prescription A.
Prescription D:
Recombinant human granulocyte colony stimulating factor 1.0g
Macrogol 200 1.0g
Propylene glycol 1.0g
Poloxamer 3.0g
Diethylene glycol monoethyl ether 3.0g
Water 1000ml
Make the 1000ml microemulsion
Preparation technology is with prescription A.
Prescription E:
Recombinant human granulocyte colony stimulating factor 1.0g
Dehydrated alcohol 2.0g
Polyoxyethylene hydrogenated Oleum Ricini 4.0g
Glyceryl linoleate 2.5g
Water 1000ml
Make the 1000ml microemulsion
Preparation technology is with prescription A.
Prescription F:
Recombinant human granulocyte colony stimulating factor 1.0g
Macrogol 200 1.0g
Propylene glycol 1.0g
Polyoxyethylene hydrogenated Oleum Ricini 4.0g
Glyceryl linoleate 2.5g
Water 500ml
Make the 500ml microemulsion
Preparation technology is with prescription A.
Prescription G:
Recombinant human granulocyte colony stimulating factor 1.0g
Dehydrated alcohol 1.0g
Propylene glycol 0.5g
Polyoxyethylene hydrogenated Oleum Ricini 3.0g
Diethylene glycol monoethyl ether 3.0g
Water 1000ml
Make the 1000ml microemulsion
Preparation technology is with prescription A.
Application example:
Animal drug disposition dynamic metabolism experimental technique of the present invention is as follows: get 6 healthy adult macaques, be divided into 2 groups at random, 3 every group.Test for the first time, first group in femoribus internus subcutaneous injection recombinant human granulocyte colony stimulating factor, and dosage is 150 μ g/kg, administration volume 0.15ml/kg; The second treated animal nasal spray administration Reeombinnt human granulocyte colony stimulating factor microemulsion (according to write out a prescription A preparation of embodiment), dosage is 150 μ g/kg.Carry out the test second time all around after cleaning, the intersection administration, i.e. first group of nasal spray administration, second group of subcutaneous injection administration, dosage and administration volume are the same.Animal subject after administration 1,2,4,6,8,10,12,15,24,36,48 and 72h from forelimb ulnar vein blood sampling, blood in the centrifugal 10min of 4000rpm, is isolated serum ,-20 ℃ of preservations after room temperature is placed 30min.
Serum drug level with different time after 6 healthy macaques intersection subcutaneous injections of ELISA method mensuration and the nasal spray administration, experimental data is carried out date processing with the 3P97 medicine for calculation procedure, through goodness of fit relatively, model is eliminated in the data symbols unification chamber of being measured, and the moving parameter of the medicine that obtains is: the average out to peak time Tmax of subcutaneous injection recombinant human granulocyte colony stimulating factor and nasal spray Reeombinnt human granulocyte colony stimulating factor microemulsion is respectively 11.1 ± 1.9h and 10.3 ± 1.7h; Average peak concentration C max is respectively 2510 ± 673ng/ml and 2430 ± 512ng/ml; The average half-life t that removes
1/2keBe respectively 24.5 ± 3.2h and 24.1 ± 2.9h; Average clearance rate CL is respectively 3.6 ± 0.8ml/kg/h and 2.9 ± 0.8ml/kg/h; Average area under the drug-time curve AUC
(0-72h)Be respectively 74926 ± 19852h.ng/ml and 69084 ± 25630h.ng/ml; Average residence time MRT is respectively 31.0 ± 2.7h and 30.9 ± 2.5h.Calculate according to 0-72h, the nasal spray Reeombinnt human granulocyte colony stimulating factor microemulsion is 92.20 ± 25.61% to the relative bioavailability of subcutaneous injection recombinant human granulocyte colony stimulating factor.Through the sided t check, the result shows, the nasal spray Reeombinnt human granulocyte colony stimulating factor microemulsion shows the pharmacokinetics behavior basically identical of two kinds of administrations to there was no significant difference between the main pharmacokinetic parameters (especially bioavailability) of subcutaneous injection recombinant human granulocyte colony stimulating factor.Average blood drug level-time graph is seen Figure of description.
Claims (5)
1. Reeombinnt human granulocyte colony stimulating factor microemulsion is characterized in that its weight is formed to comprise:
Recombinant human granulocyte colony stimulating factor-----------1 part
Surfactant-------------------------1-5 part
Cosurfactant-----------------------0.5-3 part
Oil phase-------------------------------1-3 part
Water-------------------------------500-2000 part
Described surfactant is one or more in polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene castor oil, sodium lauryl sulphate, sodium stearyl sulfate, sodium hexadecyl sulfate, lecithin, glyceryl monostearate, sucrose fatty acid ester, fatty acid esters of sorbitan, polyoxyethylene sorbitan fatty acid ester or the poloxamer.
Described cosurfactant is meant one or more in dehydrated alcohol, Macrogol 200, propylene glycol or the glycerol.
Described oil phase is meant one or more in glyceryl linoleate, diethylene glycol monoethyl ether, Semen Maydis oil, soybean oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, Oleum Gossypii semen, Oleum sesami or the olive oil.
Described water is meant one or more in water, fruit juice, normal saline or the glucose solution.
2. Reeombinnt human granulocyte colony stimulating factor microemulsion according to claim 1 is characterized in that its weight composition comprises:
Recombinant human granulocyte colony stimulating factor-----------1 part
Polyoxyethylene hydrogenated Oleum Ricini-----------------1-5 part
Dehydrated alcohol---------------------------0.5-2 part
Propylene glycol-----------------------------0-1 part
Glyceryl linoleate-----------------------1-3 part
Water---------------------------------500-2000 part.
3. Reeombinnt human granulocyte colony stimulating factor microemulsion according to claim 1 is characterized in that its weight composition comprises:
Recombinant human granulocyte colony stimulating factor-----------1 part
Fatty acid esters of sorbitan-----------------1-3 part
Dehydrated alcohol---------------------------0.5-2 part
Macrogol 200------------------------0-1 part
Olive oil-----------------------------1-3 part
Water---------------------------------500-2000 part.
4. Reeombinnt human granulocyte colony stimulating factor microemulsion according to claim 1 is characterized in that its weight composition comprises:
Recombinant human granulocyte colony stimulating factor-----------1 part
Lecithin-----------------------------1-5 part
Dehydrated alcohol---------------------------0.5-2 part
Propylene glycol-----------------------------0-1 part
Semen Maydis oil-----------------------------1-3 part
Fruit juice-------------------------------500-2000 part.
5. Reeombinnt human granulocyte colony stimulating factor microemulsion according to claim 1 is characterized in that its weight composition comprises:
Recombinant human granulocyte colony stimulating factor-----------1 part
Poloxamer---------------------------5 parts
Macrogol 200------------------------0.5-2 part
Propylene glycol-----------------------------0-1 part
Diethylene glycol monoethyl ether---------------------1-3 part
Water---------------------------------500-2000 part.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100146446A CN101062406A (en) | 2007-05-17 | 2007-05-17 | Reeombinnt human granulocyte colony stimulating factor microemulsion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100146446A CN101062406A (en) | 2007-05-17 | 2007-05-17 | Reeombinnt human granulocyte colony stimulating factor microemulsion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101062406A true CN101062406A (en) | 2007-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007100146446A Pending CN101062406A (en) | 2007-05-17 | 2007-05-17 | Reeombinnt human granulocyte colony stimulating factor microemulsion |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055314A (en) * | 2015-09-28 | 2015-11-18 | 杭州安德科技有限公司 | Abiraterone oral spray and use and preparation methods thereof |
| CN113491682A (en) * | 2020-04-01 | 2021-10-12 | 宁海德宝立新材料有限公司 | Gallstone dissolving agent |
-
2007
- 2007-05-17 CN CNA2007100146446A patent/CN101062406A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055314A (en) * | 2015-09-28 | 2015-11-18 | 杭州安德科技有限公司 | Abiraterone oral spray and use and preparation methods thereof |
| CN113491682A (en) * | 2020-04-01 | 2021-10-12 | 宁海德宝立新材料有限公司 | Gallstone dissolving agent |
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