CN1033738C - Stable pharmaceutical preparation containing granulocyte colony stimulating factor and process for producing same - Google Patents
Stable pharmaceutical preparation containing granulocyte colony stimulating factor and process for producing same Download PDFInfo
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- CN1033738C CN1033738C CN87104963A CN87104963A CN1033738C CN 1033738 C CN1033738 C CN 1033738C CN 87104963 A CN87104963 A CN 87104963A CN 87104963 A CN87104963 A CN 87104963A CN 1033738 C CN1033738 C CN 1033738C
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Abstract
A stable granulocyte colony stimulating factor-containing pharmaceutical preparation contains, in addition to granulocyte colony stimulating factor as an active agent, at least one substance selected from a pharmaceutically acceptable surfactant, saccharide, protein and high-molecular weight compound.
Description
The invention relates to a kind of preparation that contains granulocytosis colony stimulative factor.Special and a kind of stable pharmaceutical that contains granulocytosis colony stimulative factor of the present invention is relevant, this medicament can prevent active component (for example granulocytosis colony stimulative factor) because the absorption of dress product wall, or combination, polymerization and even oxidation and inactivation or lose.
Chemotherapy is the multiple a kind of method that catches of treatment, but finds recently, changes furuncle and can cause for example formation of fastbacteria of some serious clinical problem, variation of pathogen and the serious effect of paying.Therefore these problems for fear of relevant with chemotherapy comprise for example antibiotic, and the application of chemotherapeutics such as antibacterial is wanted to adopt a kind ofly can activate the material that the infectious bacteria host gives anti-ability, thereby aforementioned chemotherapy problem can all be solved.Give in the anti-ability host multiple, leukocyticly engulf bacterial action and it is believed that at the initial stage of bacterial infection influence is the strongest, it is contemplated that therefore differentiation comes to the ripening period and can strengthen host's anti-infection ability greatly by promoting the growth of neutrophilic leukocyte.(G-CSF) is a kind of ten minutes utility with above-mentioned effect to granulocytosis colony stimulative factor, and same assignee's past attempts of the present invention was submitted a relevant patent (Japanese patent application No23777/1985) of G-CSF as a kind of anti-infective of utilizing.
Therefore as mentioned above, current chemotherapy of carrying out exists multiple unavoidable problem, is adopting as possible to activate the medicine that host or infected patient give anti-ability.Indubitable, G-CSF itself has the ability that the activation host gives anti-effect, but also finds, if with its with can activate a kind of material that the host gives anti-ability and merge and be applied to clinically, G-CSF then has great curative effect.
G-CSF consumption is few, and G-CSF content is that the drug dose of 0.1-500 micrograms (being preferably 5-50 micrograms) is generally each adult 1-7 times weekly.For example ampoule or injector wall absorb by container but G-CSF is easy to.Therefore if medicine is injected with this aqueous solution form, just it can be adsorbed on its container for example on ampoule or the injector wall.So make G-CSF can not fully show the activity of medicine, the also feasible G-CSF that must add cushion owing to adsorb the loss result that may cause.
In addition, G-CSF instability is to environmental factors temperature for example, humidity.Oxygen and ultraviolet are extremely sensitive.Because the effect of these factors, physics or chemical change can take place in G-CSF, for example combination, polymerization and oxidation and loss of activity greatly.If with the ten minutes accurate way, very little take G-CSF, these phenomenons can cause being difficult to play fully therapeutical effect.
Therefore need development a kind of stable G-CSF medicament, it can fully prevent the active decline of its active component.Here it is provides the main target of the present invention of a kind of stable G-CSF medicament.
The inventor has carried out deep research in order to improve the stability that contains G-CSF medicament, and if find to add pharmaceutically useful surfactant, saccharide, protein or high-molecular weight compounds then can effectively reach this purpose.
Therefore, the invention is characterized in and contain G-CSF and be selected from least a material that to do in medicinal surfactant, saccharide, protein and the polymer substance.
Adopt for example Japanese patent application NO153273/1984, any method of 269455/1985,269456/1985,270833/1985,270839/1985 description can obtain containing the medicament of the present invention of C-CSF.A kind of cell strain (CNCM registration number I-315 or I-483) that for example can be by cultivate suffering from oral cancer patient oncocyte or in a kind of appropriate host cell (for example escherichia coli, C127 cell or Chinese hamster ovary cell) prepare G-CSF of people by recombinant DNA (adopting people G-solid acting on of CSF coding base to prepare) expression.
Any highly purified human G-CSF can add in the medicament of the present invention as G-CSF.G-the GSF of separation of human from the cultured cell supernatant of a kind of generation people G-CSF preferably, and obtain active polypeptide of a kind of people of having G-CSF or glycoprotein the host that can transform from the recombinant vector of a kind of people of containing G-CSF active polypeptide encoding gene.
Two routine best G-the CSF example is as follows: (1) has the molecular weight of the people G of following physicochemical properties-CSF:i): adopt dodecyl sodium sulfate-poly-propionic acid amide. gel electrophoresis determining molecular weight to be approximately 19,000 ± 1,000.Ii) isoelectric point, IP: in PI=5.5 ± 0.1, having one in the isoelectric point, IP of PI=5.8 ± 0.1 and PI=6.1 ± 0.1 3 at least is its isoelectric point, IP.Iii) uv absorption: obtained the maximum absorption is at 280nm, and the minimal absorption value is at 250nm.Iv) 21 residue amino acid sequences of N-terminal are:
H
2N-Soviet Union-dried meat-bright-Gan-dried meat-third-Si-Si-bright-dried meat-glutamine-Si-phenylpropyl alcohol-bright-bright-Lai-Guang-bright-Gan-glutamine-figured silk fabrics-(2) human G-CSF or have the active peptide species of people's granulocyte stimulating factor, this polypeptide are partly or entirely to express with following aminoacid sequence.Or a kind of a kind of glycoprotein of chatting a polypeptide and a sugar chain part to some extent that contains.(Met)
nThr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu ( Val Ser Glu ) mCys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro ( m01; And n is 0 or 11).
The detailed method for preparing this two class G-CSF is seen Japanese patent application No153273/1984,269455/1985, and 269456/1985/, 270838/1985 and 270839/1985 description, all these are all submitted by the assignee of the present invention.
Another method that can adopt is that the cell and the outgrowth malignant cell of a kind of oneself that produce G-CSF are merged, and cultivates the hybridoma that obtains then under the condition that is added with or is not added with cytokinin.
As requested, adopt any known method further purify and concentrate after the people G-CSF solution that contains that obtains can freezingly preserve, perhaps behind the freeze-drying and dehydrating, can preserve this solution.
In order to obtain containing the stable pharmaceutical of G-CSF, the process that can adopt the present invention to mention specially prepares all these people G-CSF.
Being used for the surfactant exemplary that the present invention contains G-CSF stable pharmaceutical is described below: the non-ionic surface active agent with 6-18HLB, for example sorbitan fatty acid esters is (as the sad monoesters of sorbitan, sorbitan lauric acid monoesters, with sorbitan Palmic acid monoesters), fatty acid glyceride (caprylic acid monoester for example, glycerol myristic acid monoester and glycerol hard fatty acids monoesters), polyglyceryl fatty acid ester (ten glycerol hard fatty acids monoesters for example, ten glycerol hard fatty acids dibasic acid esters, with ten glycerol linoleic acid monoesters), polyoxyethylene sorbitan fatty acid esters is (as polyoxyethylene sorbitan lauric acid monoesters, polyoxyethylene sorbitan oleic acid monoester, polyoxyethylene sorbitan hard fatty acids monoesters, the polyoxyethylene sorbitan cetylate, polyoxyethylene sorbitan oleic acid three esters and polyoxyethylene sorbitan, hard fatty acids three esters), Polyoxyethylene Sorbitol Fatty Acid Esters is (as polyoxyethylene sorbitol hard fatty acids four esters, with polyoxyethylene sorbitol oleic acid four esters), polyethylene fatty acid glyceride (as polyoxyethylene glycerol hard fatty acids monoesters), polyethylene glycol fatty acid ester (as polyethylene glycol hard fatty acids diester), polyoxyethylene alkyl ether (as polyoxyethylene laurel ether), polyoxyethylene polyoxy-propylene is (as polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether and polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkylphenyl group ether (as the polyoxyethylene nonyl ethers), polyoxyethylene castor oil, the hard Oleum Ricini of polyoxy ethyl (polyoxy ethyl castor oil hydrogenated), polyoxy ethanol Cera Flava derivant (as polyoxy ethyl sorbitol Cera Flava), Wool wax alcohols,ethoxylated derivant (as Wool wax alcohols,ethoxylated) and polyoxyethylene fatty acid amide (as polyethylene hard fatty acids amide); Non-ionic surface active agent for example has a C
10-C
18The alkyl sulfate of alkyl, (as sodium hexadecyl sulfate, sodium lauryl sulphate and oily sodium sulfate) polyoxyethylene alkyl ether sulfate salt, wherein oxygen ethylene average mol number is 2-4, and alkyl has 10-18 carbon atoms (as the polyoxyethylene sodium lauryl sulphate), the alkylthio succinate, wherein alkyl has 8-18 carbon atoms (as dodecyl esters of sulfosuccinic acids sodium); The neutral surface active agent, lecithin for example, glycerol phosphate, cephalin (as sphingomyelin), and sucrose fatty acid ester, wherein fatty acid has 12-18 carbon atoms.Certainly these tables and activating agent both can use separately also and can mix use.
The preferably per by weight 1 part of G of the dosage of surfactant of listing above-CSF 1-10000 part activating agent.
Being used for the present invention preparation contains and stablizes the saccharide that G-the CSF medicament is used and can select to do the medicinal monosaccharide that has, oligosaccharide and polysaccharide and phospholipid and nucleotide derivative.Exemplary is as follows; The sucrose alcohol of trivalent and Geng Gao, glycerol for example, erithritol, arabitol, xylitol, sorbitol and mannitol; Acid sugar is glucuronic acid for example, iduronic acid, neuraminic acid, galacturonic acid, gluconic acid, mannuronic acid, the glucose keto acid, galactose keto acid and gulose keto acid, hyaluronic acid and salt thereof, chondroitin sulfate and salt thereof, also has heparin, inulin, chitin and derivant thereof, dextrin, mean molecule quantity are 5000-150000 glucosan and alginic acid and salt thereof.No matter be single with or share, all these saccharides all are useful.
The saccharide consumption of listing above, 1 portion of G-CSF1-10000 portion sugar preferably by weight.
Be used for the protein exemplary that the present invention contains the G-CSF stable pharmaceutical and comprise the human serum albumin, human serum globulin, gelatin, gelatin (mean molecule quantity=7000-100 of acid treatment, 000), gelatin of alkali treatment (mean molecule quantity=7000-100,000) and collagen protein.Indubitable, these albumen both can be singly with also mixing usefulness.
Above listed protein consumption by weight every part of G-CSF can add 1-20,000 part.
Can be used for the macromolecular compound exemplary that the present invention contains G-CSF stable pharmaceutical and comprise for example hydroxypropyl cellulose of natural polymer, hydroxy methocel, sodium carboxymethyl cellulose and hydroxyethyl-cellulose; Synthetic polymer is polyethylene ethanedioic acid (molecular weight=300-6,000) for example, polyvinyl alcohol (molecular weight=20,000-100,000) and polyvinylpyrrolidone (molecular weight=20,000-100,000).Indubitable these macromolecular compounds both can be singly with also merging use.
The optimum dose of listing in top high-molecular weight compounds every part of G-CSF by weight adds 1-20,000 part.
Except above-mentioned surfactant, outside saccharide, protein or the macromolecular compound, can also be from aminoacid, sulfur-bearing Reducing agent and antioxidant apoplexy due to endogenous wind select at least-kind add in the medicament that the present invention contains G-CSF.The hydrogen base acid of illustrating comprises glycine, threonyl, tryptophan, lysine, hydroxylysine, histidine, arginine, cysteine, cystine and methionine.The sulfur-bearing Reducing agent of being mentioned comprises N-acetylcystein, N-acetyl homocysteine, thioctic acid, thiodiglycol, sulfur ethanolamine, thioglycerin, the sulfur sorbitol, sulfur glycol acid and salt thereof, thiosulfate, sulfur hydracid sodium, sodium pyrosulfite, sodium sulfite, thiolactic acid, dithiothreitol, DTT, glutathion, with a kind of sulfur Reducing agent that has sulfydryl of gentleness, for example a kind of C
1-C
7The sulfur alkanoic acid.The antioxidant of being mentioned comprises, arabo-ascorbic acid, two butylated hydroxytoluene, anethole htpb, ae-α-tocopheronic acid, tocopherol acetate, L-ascorbic acid and salt thereof, L-ascorbic acid Petiolus Trachycarpi salt, L-ascorbic acid stearate, three amyl group gallates, propyl group gallate and chelating agen are disodiumedetate (EDTA) for example, tetrasodium pyrophosphate and Polymeric sodium metaphosphate..
Above-mentioned aminoacid, sulfur-bearing Reducing agent and antioxidant or its mixture is 1-10,000 part of every part of G-CSF dosage by weight.
Stabilization formulations in order to contain G-CSF with suitable dose form preparation the present invention can add following one or more reagent: diluent, cosolvent, isotonic agent, excipient, PH regulator, emollient and buffer.
Stable G of the present invention-CSF medicament both can have been prepared for oral use, also can non-intestinal usefulness, for example inject in many ways.The ad hoc fashion of taking has determined different dosage.Representative dosage forms comprises: be applicable to oral for example tablet, pill, capsule, granule and suspension, solution, suspension and cold dry preparation are mainly used in intravenous injection, intramuscular injection etc. down injection and wait in injection, be suitable for through mucosa take as rectal suppository, nasal drop and vaginal suppository.
According to the present invention, from surfactant, saccharide, at least can select a kind of adding in the medicament that contains G-CSF in protein or the macromolecular compound class material, so, can prevent to be adsorbed on chamber wall or the syringe simultaneously, and can in the long duration, keep stable.About utilizing above-mentioned substance to stablize G-CSF and preventing that the detailed mechanism of adsorbing from understanding fully.When surfactant exists, topped as the proteic G of mercapto water-CSF surface by surfactant institute, form soluble substance, so, a spot of G-CSF of plate also can prevent to be adsorbed on chamber wall and the syringe.Saccharide or hydrophilic macromolecular compound form the hydration layer between G-CSF and container and injector wall, therefore can effectively prevent to adsorb G-CSF.Albumen then and G-CSF competitive Adsorption on container and injector wall, therefore can effectively suppress the absorption of G-CSF.
Except preventing G-CSF absorption, above-mentioned substance also can prevent the combination or the polymerization of G-CSF molecule.Have surfactant, when saccharide, protein or macromolecular compound, single G-CSF molecular dispersion is in these materials, and the intermolecular interaction of G-CSF reduces greatly so that cause its in conjunction with or the remarkable minimizing of polymerizing power.In addition, these materials can stop the autoxidation process of quickening under high temperature and humidity, or anti-the oxidation combination or the polymerization that cause.Add a seed amino acid, sulfur-bearing Reducing agent or a kind of antioxidant can further strengthen and prevent G-CSF autoxidation, combination or polymeric effect.
The problems referred to above are worth paying special attention to injection solution and suspension, but for example in the process of tablet formulation G-CSF these problems are being arranged also with other dosage form.Add surfactant for latter event, saccharide, protein or macromolecular compound are also effective.
Be selected from surfactant by adding, saccharide, a kind of material of protein and macromolecular compound class, G-CSF is highly stable, can keep active for a long time, and this will be confirmed in the infra example.In order to reach this purpose, in these materials the quantity of each particularly its lower limit be crucial, following scope is ideal: each part G-CSF adds 1-10,000 portion of sugar, 1-20,000 part of protein and 1-20,000 part of macromolecular compound by weight.
According to the present invention, surfactant, saccharide, protein and/or macromolecular compound use by specific concentrations, and its effect is not only to prevent that G-CSF is adsorbed on container and the injector wall, and is to strengthen containing the stability of G-CSF medicament.Thereby just may ensure that patient takes a small amount of and is the G-CSF of height exact dose.Because G-CSF is very expensive, use will cause production to contain G-CSF medicament price reduction like this.
In order further to illustrate the present invention, provide following example, but this does not mean that as a kind of restriction.In these examples, adopt following any method can determine the residual activity of G-CSF.A) bone marrow cells in mice soft agar assay
Mix horse serum (0.4ml), 0.1 ml sample, 0.1ml C3H/H
e(female) Os Mus myelocyte suspension (0.5-1 * 0.5 nucleus) and 0.4ml contain the 5A culture fluid of the modification MeCoy of 0.75% agar, side (35mm to the plastics plate of tissue culture
φ) solidify, in 37 ℃ at 5%CO
2Cultivated 5 days under/95% air and 100% humidity.Calculate the colony number (colony contains at least 50 cells) that forms and measure activity, form a colony and be decided to be an active unit.
MeCoy5A culture fluid according to the modification of the following step compound method (a) usefulness.The 5A culture solution (double concentration) of the MeCoy that revises
The 5A culture fluid (Gibco) of 12 gram MeCoy, 2.55 gram MEM aminoacid-vitamin medium (Nissui Seiyaku company) 2.18 gram sodium bicarbonate and 50,000 unit potassium penicillin G is dissolved in for twice in 500 ml distilled waters, then, by microporous filter membrane (0.22um) aseptic filtration solution.(b) RPHPLC (reversed-phase high-performance liquid chromatography):
Use anti-phase C
8Post (4.6mm * 300mm, 5um) and normal propyl alcohol/trifluoracetic acid mixed liquor as mobile phase, under the condition of following gradient elution, determine the residual activity of G-CSF (injection is equivalent to the amount of 1 microgram): time (second) solvent (A) solvent (B) gradient
Solvent (A): 30% normal propyl alcohol and 0.1% trifluoracetic acid solvent (B): 60% normal propyl alcohol and 0.1% trifluoracetic acid
The detection wavelength is 210nm, and the active percentage rate of residue G-CSF calculates by following formula:
×100
The G of Ce Dinging-CSF surplus has good dependency with the result who records with bone marrow cells in mice soft agar method (a) in this way.Example 1
A kind of stabilizing agent that table 1 is listed adds among 5 microgram G-CSF, (contains 100mM chloro sodium, PH7.4), makes every milliliter of medicament that contains 5 microgram G-CSF, cold then doing in the aseptic 20mM of the being dissolved in buffer of mixture.According to G-CSF activity change that the time presented, usefulness method (a) is measured, and the results are shown in Table 1.The residual activity of G-CSF that term " active (%) " representative is relevant with initial unit, with following formulate:
Cold driedly carry out with the following step:
G-CSF the solution that contains stability is put into sulfanilamide handled the disinfectant vial, at-40 ℃ or be lower than-40 ℃ freezing 4 hours, then carry out dry 48 hours of the first time, be heated to 0 ℃ from-40 ℃, pressure increases to 0.1 holder from 0.03 holder, carry out dry 12 hours of the second time then, temperature is heated to 20 ℃ from 0 ℃, pressure increases to 0.08 holder from 0.03 holder, then the disinfectant drying nitrogen is charged into bottle inside, make it reach an atmospheric pressure, bottle seals with aluminium lid with cold dried rubber closure beyond the Great Wall at last.Table 1
Stabilizing agent | Quantity (by weight) | Active (%) | |
Preserve after 6 months for 4 ℃ | Preserve after 1 month for 37 ℃ | ||
Xylitol mannitol glucuronic acid hyaluronic acid glucan (m.w.40; 000) the white polyethylene glycol (m.w.4 of gelatin collagen dawn of the acid-treated gelatin alkali treatment of white man's serum globulins of clear dawn of heparin chitosan alginic acid human serum; 000) hydroxypropyl cellulose sodium carboxymethylcellulose CMC polyvinyl alcohol (m.w.50; 000) polyvinylpyrrolidone (m.w.50,000) | 10,000 10,000 10,000 2,000 2,000 5,000 2,000 2,000 1,000 1,000 2,000 1,000 2,000 10,000 1,000 1,000 5,000 2,000 2,000 | 92 91 86 92 95 85 93 90 98 98 97 99 95 94 98 88 92 96 95 | 86 85 82 89 90 80 91 90 99 95 95 96 90 90 94 80 90 95 94 |
White mannitol cysteine of clear dawn of human serum | 2,000 2,000 100 | 100 | 97 |
Table 1 (continuing)
Example 2
Stabilizing agent | Quantity (by weight) | Active (%) | |
Preserve after 6 months for 4 ℃ | Preserve after 1 month for 37 ℃ | ||
White polyoxyethylene sorbitan monolaurate mannitol of clear dawn of human serum | 2,000 100 2,000 | 99 | 96 |
White hydroxypropyl cellulose glucosan of clear dawn of human serum (m.w.40,000) | 2,000 500 2,000 | 98 | 92 |
Polyoxyethylene sorbitan lauric acid Sorbitol | 100 2,000 | 98 | 96 |
The hard Oleum Ricini glucosan of polyoxyethylene (m.w.40,000) | 100 2,000 | 94 | 92 |
Do not add | - | 74 | 58 |
Add a kind of stabilizing agent of listing in table 2 to 10 micrograms G-CSF, to (contain 100mM sodium chloride in the aseptic 20mM of the being dissolved in phosphate buffer of mixture, PH7.4) preparation becomes every milliliter of medicament that contains 10 microgram G-CSF, in the vial that the aseptic sulfanilamide of packing into of preparation was handled, seal, be prepared into G-CSF solution.Adopt the same quadrat method of example 1 to measure in the solution, the results are shown in table 2 along with the activity change of time G-CSF.
Table 2
Stabilizing agent | Quantity (by weight) | Active (%) | ||
Preserve after 7 days for 4 ℃ | 4 ℃ preserve February after | Room temperature preservation is after January | ||
Mannitol hyaluronic acid glucan (m.w.40; 000) white polyethylene glycol (m.w.4 of glycerine neuraminic acid chitin dextrin human serum white man's serum globulins of clear dawn acid treatment gelatin alkali treatment gelatin collagen dawn; 000) hydroxypropyl cellulose sodium carboxymethylcellulose hydroxyethylcellulose polyvinyl alcohol (m.w.50; 000) polyvinylpyrrolidone (m.w.50,000) sorbitan monolaurate Tween 20 | 5,000 2,000 2,000 10,000 5,000 2,000 2,000 1,000 1,000 2,000 500 2,000 10,000 2,000 2,000 4,000 4,000 4,000 400 400 | 91 93 96 90 93 95 90 99 98 97 99 99 94 98 92 92 97 95 97 100 | 87 87 95 90 91 92 92 95 94 96 95 94 89 95 91 94 93 95 96 96 | 82 70 85 88 84 86 87 92 90 87 92 88 90 92 80 90 90 92 95 94 |
Table 2 (continuing)
Example 3
Stabilizing agent | Quantity (by weight) | Active (%) | ||
Preserve after 7 days for 4 ℃ | 4 ℃ preserve February after | Room temperature preservation is after January | ||
Polyoxyethylene sorbitan single-stearic hydrochlorate polyoxyethylene, the hard Oleum Ricini dodecyl sodium sulfate of polyoxypropylene glycol ether polyoxyethylene lecithin | 400 400 400 2,000 2,000 | 98 100 99 97 97 | 97 94 98 93 94 | 94 93 90 87 90 |
White mannitol cysteine of clear dawn of human serum | 2,000 2,000 100 | 100 | 99 | 97 |
White polyoxyethylene sorbitan monolaurate mannitol of clear dawn of human serum | 2,000 100 2,000 | 99 | 97 | 95 |
White hydroxypropyl cellulose glucosan of clear dawn of human serum (m.w.40,000) | 1,000 500 2,000 | 99 | 97 | 95 |
Polyoxyethylene sorbitan monopalmitate Sorbitol | 100 2,000 | 96 | 96 | 93 |
The hard Oleum Ricini glucosan of polyoxyethylene (m.w.40,000) | 100 2,000 | 95 | 92 | 92 |
Do not add | - | 72 | 61 | 47 |
Add a kind of stabilizing agent of listing in table 3 to 10 micrograms G-CSF, will (contain 100mM sodium chloride, PH7.4) be prepared into every milliliter of medicament that contains 10 microgram G-CSF in the aseptic 20mM of the being dissolved in phosphate buffer of mixture.1 ml of formulation is added in the silication vial that sulfanilamide handled, place 4 ℃.Every kind of stabilizing agent prevents that effect that G-CSF absorbs can be by in half an hour, after 2 hours and 4 hours in the mensuration solution G-CSF retentive activity estimate.Measure and adopt the method for (b) used reverse phase HPLC to carry out, the results are shown in table 3.
Table 3
Stabilizing agent | Quantity (by weight) | Retentive activity (%) | |||
Beginning | Half an hour | 2 hours | 24 hours | ||
Mannitol hyaluronic acid glucan (m.w.40; 000) white polyethylene glycol (m.w.4 of glycerine heparin glucuronic acid glucose ketone acid clear dawn of human serum white man's serum globulins alkali treatment gelatin acid treatment gelatin collagen dawn; 000) the plain sodium carboxymethylcellulose hydroxyethylcellulose of hydroxypropyl cellulose polyvinyl alcohol (m.w.50; 000) the hard castor mushroom of polyvinylpyrrolidone (m.w.50,000) suction D-sorbite list caprylate polyoxyethylene sorbitan monostearate polyoxyethylene oil | 5,000 2,000 2,000 10,000 2,000 5,000 5,000 1,000 1,000 500 2,000 2,000 10,000 2,000 2,000 4,000 4,000 4,000 400 400 400 | 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 | 93 97 98 94 92 96 92 100 98 99 99 100 100 100 98 96 99 98 100 100 99 | 90 92 95 91 90 90 88 101 100 98 97 98 100 100 96 93 100 98 100 98 101 | 91 92 96 90 90 91 90 99 98 99 97 99 99 99 95 92 98 96 98 100 99 |
Table 3 (continuing)
Stabilizing agent | Quantity (by weight) | Retentive activity (%) | |||
Beginning | Half an hour | 2 hours | 24 hours | ||
Dodecyl sodium sulfate lecithin | 2,000 2,000 | 100 100 | 100 99 | 99 100 | 97 98 |
White mannitol cysteine of clear dawn of human serum | 2,000 2,000 100 | 100 | 100 | 100 | 101 |
White polyoxyethylene sorbitan monolaurate mannitol of clear dawn of human serum | 2,000 100 2,000 | 100 | 100 | 98 | 99 |
White hydroxypropyl cellulose glucosan of clear dawn of human serum (m.w.40,000) | 1,000 500 2,000 | 100 | 101 | 99 | 100 |
Polyoxyethylene sorbitan monolaurate Sorbitol | 100 2,000 | 100 | 100 | 99 | 99 |
The hard Oleum Ricini glucosan of polyoxyethylene (m.w.40,000) | 100 2,000 | 100 | 100 | 98 | 97 |
Do not add | - | 100 | 91 | 72 | 73 |
Claims (1)
1. a production contains the method for the medicament of stable granulocytosis colony stimulative factor, this method comprises: under 1-30 ℃ temperature conditions with granulocytosis colony stimulative factor (G-CSF) be selected from dehydration pears sugar alcohol fatty acid ester, polyoxyethylene sorbitan fatty acid esters, cithrol, polyoxyethylene polyoxy-propylene, polyoxy ethylization hardened castor oil, alkyl sulfate, lecithin, glycerol, xylitol, Sorbitol, mannitol, glucuronic acid, neuraminic acid, ketogluconic acid, hyaluronic acid and its salt, heparin, chitin and derivant thereof, chitosan and derivant thereof, dextrin, mean molecule quantity is 5,000-150,000 glucosan, alginic acid and salt thereof, the human serum albumin, the human serum globulin, gelatin, mean molecule quantity is 7,000-100,000 the acid or the gelatin of alkali treatment, collagen protein, hydroxypropyl cellulose, hydroxy methocel, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, molecular weight is 300-6,000 Polyethylene Glycol, molecular weight is 20,000-100,000 polyvinyl alcohol, molecular weight is 20,000-100, at least a material of 000 polyvinylpyrrolidone mixes, then the mixture that produces is dissolved in a kind of buffer, and this solution packed in the container, wherein said G-CSF has following character:
(i) molecular weight: carrying out electrophoresis in coagulating by dodecyl sodium sulfate-polyacrylamide, to record molecular weight be 19,000 ± 1000;
(ii) isoelectric point, IP: have at least one in the following isoelectric point, IP.
pI=5.5±0.1,pI=5.8±0.1,pI=6.1±0.1。
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP169489/86 | 1986-07-18 | ||
JP16948886 | 1986-07-18 | ||
JP16948986 | 1986-07-18 | ||
JP169487/86 | 1986-07-18 | ||
JP169486/86 | 1986-07-18 | ||
JP16948786 | 1986-07-18 | ||
JP16948686 | 1986-07-18 | ||
JP169488/86 | 1986-07-18 |
Publications (2)
Publication Number | Publication Date |
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CN87104963A CN87104963A (en) | 1988-02-24 |
CN1033738C true CN1033738C (en) | 1997-01-08 |
Family
ID=27474266
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Application Number | Title | Priority Date | Filing Date |
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CN87104963A Expired - Lifetime CN1033738C (en) | 1986-07-18 | 1987-07-18 | Stable pharmaceutical preparation containing granulocyte colony stimulating factor and process for producing same |
Country Status (24)
Country | Link |
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KR (1) | KR930004597B1 (en) |
CN (1) | CN1033738C (en) |
AT (1) | AT402259B (en) |
AU (1) | AU611856B2 (en) |
BE (1) | BE1000253A3 (en) |
CA (1) | CA1297007C (en) |
CH (1) | CH671157A5 (en) |
DE (1) | DE3723781C2 (en) |
DK (1) | DK171308B1 (en) |
ES (1) | ES2010226A6 (en) |
FR (1) | FR2601591B1 (en) |
GB (1) | GB2193631B (en) |
GR (1) | GR871067B (en) |
HK (1) | HK64893A (en) |
HU (1) | HU198627B (en) |
IE (1) | IE60290B1 (en) |
IL (1) | IL83220A (en) |
IT (1) | IT1218927B (en) |
NL (1) | NL192917C (en) |
NO (1) | NO171828C (en) |
PT (1) | PT85343B (en) |
SE (1) | SE503312C2 (en) |
SG (1) | SG64393G (en) |
YU (1) | YU47543B (en) |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4929442A (en) * | 1986-09-26 | 1990-05-29 | Exovir, Inc. | Compositions suitable for human topical application including a growth factor and/or related materials |
US4847325A (en) * | 1988-01-20 | 1989-07-11 | Cetus Corporation | Conjugation of polymer to colony stimulating factor-1 |
NO179479C (en) * | 1988-03-11 | 1996-10-16 | Teikoku Seiyaku Kk | Process for the preparation of an intravaginal pharmaceutical preparation |
US5981485A (en) | 1997-07-14 | 1999-11-09 | Genentech, Inc. | Human growth hormone aqueous formulation |
GB8824591D0 (en) * | 1988-10-20 | 1988-11-23 | Royal Free Hosp School Med | Fractionation process |
US6132763A (en) * | 1988-10-20 | 2000-10-17 | Polymasc Pharmaceuticals Plc | Liposomes |
US5349052A (en) * | 1988-10-20 | 1994-09-20 | Royal Free Hospital School Of Medicine | Process for fractionating polyethylene glycol (PEG)-protein adducts and an adduct for PEG and granulocyte-macrophage colony stimulating factor |
US5104651A (en) * | 1988-12-16 | 1992-04-14 | Amgen Inc. | Stabilized hydrophobic protein formulations of g-csf |
EP0459516A1 (en) * | 1990-06-01 | 1991-12-04 | Kirin-Amgen, Inc. | Oral dosage form of biologically active proteins |
JP3249147B2 (en) * | 1990-06-01 | 2002-01-21 | キリン−アムジエン・インコーポレーテツド | Oral preparation containing bioactive protein |
FR2686899B1 (en) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | NOVEL BIOLOGICALLY ACTIVE POLYPEPTIDES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2686900B1 (en) * | 1992-01-31 | 1995-07-21 | Rhone Poulenc Rorer Sa | NOVEL POLYPEPTIDES HAVING GRANULOCYTE COLONY STIMULATION ACTIVITY, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2693907B1 (en) * | 1992-07-23 | 1994-09-02 | Rhone Poulenc Rorer Sa | A method of administering granulocyte colony stimulating factor solutions. |
EP0582932A1 (en) * | 1992-08-11 | 1994-02-16 | F. Hoffmann-La Roche Ag | Therapeutic system for the parenteral administration of hematopoietic growth factors |
DE4242919A1 (en) * | 1992-12-18 | 1994-06-23 | Boehringer Mannheim Gmbh | Process for the preparation of storage-stable aqueous pharmaceutical preparations of G-CSF |
DE4242863A1 (en) * | 1992-12-18 | 1994-06-23 | Boehringer Mannheim Gmbh | Stable lyophilized pharmaceutical preparations of G-CSF |
US20030053982A1 (en) | 1994-09-26 | 2003-03-20 | Kinstler Olaf B. | N-terminally chemically modified protein compositions and methods |
US5824784A (en) | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
WO1996024369A1 (en) * | 1995-02-06 | 1996-08-15 | Genetics Institute, Inc. | Formulations for il-12 |
TW434021B (en) * | 1995-03-15 | 2001-05-16 | Kirin Brewery | Methods for preventing adsorption of thrombopoietin (TPO), and stable TPO-containing compositions |
TW434020B (en) * | 1995-03-15 | 2001-05-16 | Kirin Brewery | Methods for preventing adsorption of thrombopoietin (TPO), and stable top-containing compositions |
GB9526733D0 (en) | 1995-12-30 | 1996-02-28 | Delta Biotechnology Ltd | Fusion proteins |
US20030190307A1 (en) | 1996-12-24 | 2003-10-09 | Biogen, Inc. | Stable liquid interferon formulations |
WO1999044630A1 (en) * | 1998-03-06 | 1999-09-10 | Chugai Seiyaku Kabushiki Kaisha | Protein-free preparations |
US6979442B1 (en) * | 1998-08-17 | 2005-12-27 | Pfizer Inc. | Stabilized protein compositions |
ATE389414T1 (en) | 1999-09-08 | 2008-04-15 | Chugai Pharmaceutical Co Ltd | STABLE PROTEIN SOLUTION BOTTLED IN A CONTAINER MADE OF HYDROPHOBIC RESIN AND A METHOD FOR STABILIZING THE SAME |
EP1260230A4 (en) * | 2000-02-29 | 2008-08-06 | Chugai Pharmaceutical Co Ltd | Preparations stabilized over long time |
PT1129720E (en) * | 2000-02-29 | 2004-08-31 | Pfizer Prod Inc | STABILIZED GRANULOCYTE COLONY STIMULATOR FACTOR |
US6946134B1 (en) | 2000-04-12 | 2005-09-20 | Human Genome Sciences, Inc. | Albumin fusion proteins |
CA2747325A1 (en) | 2000-04-12 | 2001-10-25 | Human Genome Sciences, Inc. | Albumin fusion proteins |
CA2420850A1 (en) * | 2000-09-01 | 2003-02-28 | Chugai Seiyaku Kabushiki Kaisha | Solution formulations having long-term stability |
US8435939B2 (en) | 2000-09-05 | 2013-05-07 | Biokine Therapeutics Ltd. | Polypeptide anti-HIV agent containing the same |
US7507413B2 (en) | 2001-04-12 | 2009-03-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
ES2425738T3 (en) | 2001-12-21 | 2013-10-17 | Human Genome Sciences, Inc. | Albumin Fusion Proteins |
WO2004020462A1 (en) | 2002-08-27 | 2004-03-11 | Fujii, Nobutaka | Cxcr4 antagonist and use thereof |
EP1598074B1 (en) | 2003-02-28 | 2019-01-02 | Chugai Seiyaku Kabushiki Kaisha | Stabilized protein-containing formulations |
DE202006020194U1 (en) | 2006-03-01 | 2007-12-06 | Bioceuticals Arzneimittel Ag | G-CSF liquid formulation |
CA2673719C (en) | 2006-12-21 | 2018-07-24 | Biokine Therapeutics Ltd. | T-140 peptide analogs having cxcr4 super-agonist activity for bone marrow recovery |
EP2396023A2 (en) | 2009-02-11 | 2011-12-21 | Yeda Research and Development Co. Ltd. | Short beta-defensin-derived peptides |
AU2011207915B2 (en) | 2010-01-19 | 2013-07-11 | Hanmi Science Co., Ltd. | Liquid formulations for long-acting G-CSF conjugate |
EP2399572A1 (en) | 2010-06-22 | 2011-12-28 | Sandoz AG | Long-term storage of non-glycosylated recombinant human G-CSF |
BR112018000903A2 (en) | 2015-07-16 | 2018-09-11 | Biokine Therapeutics Ltd. | compositions and methods for cancer treatment |
KR102033920B1 (en) | 2016-02-23 | 2019-10-18 | 바이오라인알엑스 리미티드 | How to treat acute myeloid leukemia |
WO2018138267A1 (en) | 2017-01-27 | 2018-08-02 | Cinfa Biotech S.L. | Method for determining the efficacy of a g-csf containing composition |
EP3797752A4 (en) * | 2018-05-21 | 2022-03-02 | Chugai Seiyaku Kabushiki Kaisha | Lyophilized formulation sealed in glass vial |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2652636A1 (en) * | 1976-11-19 | 1978-05-24 | Hans Uwe Dr Rer Nat Wolf | Stabilising protein during separation, purification and storage - by adding amphiphilic cpds., esp. lipid(s), ionic and or nonionic detergents |
AU523077B2 (en) * | 1978-03-20 | 1982-07-08 | Green Cross Corporation, The | Hgi glycoprotein |
DE3380726D1 (en) * | 1982-06-24 | 1989-11-23 | Japan Chem Res | Long-acting composition |
JPS60228422A (en) * | 1984-04-26 | 1985-11-13 | Suntory Ltd | Stabilized preparation of physiologically active substance |
JPS61227526A (en) * | 1984-07-25 | 1986-10-09 | Chugai Pharmaceut Co Ltd | Novel csf and method of collecting same |
JPS6191131A (en) * | 1984-10-09 | 1986-05-09 | Chugai Pharmaceut Co Ltd | Method and composition for preventing adsorption of pharmaceutical |
ATE80894T1 (en) * | 1985-02-05 | 1992-10-15 | Cetus Oncology Corp | PURIFICATION OF NATURAL COLONY STIMULATING FACTOR-1. |
US4810643A (en) * | 1985-08-23 | 1989-03-07 | Kirin- Amgen Inc. | Production of pluripotent granulocyte colony-stimulating factor |
JPH0618778B2 (en) * | 1985-10-04 | 1994-03-16 | 中外製薬株式会社 | Leukopenia treatment |
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1987
- 1987-07-08 GR GR871067A patent/GR871067B/en unknown
- 1987-07-10 IT IT67594/87A patent/IT1218927B/en active
- 1987-07-13 NL NL8701640A patent/NL192917C/en not_active IP Right Cessation
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