IE871933L - Stable pharmaceutical preparation containing granulocyte¹colony stimulating factor - Google Patents
Stable pharmaceutical preparation containing granulocyte¹colony stimulating factorInfo
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- IE871933L IE871933L IE871933A IE193387A IE871933L IE 871933 L IE871933 L IE 871933L IE 871933 A IE871933 A IE 871933A IE 193387 A IE193387 A IE 193387A IE 871933 L IE871933 L IE 871933L
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- stimulating factor
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- polyoxyethylene
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- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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Abstract
A stable granulocyte colony stimulating factor-containing pharmaceutical preparation contains, in addition to the active agent, at least one substance selected from a pharmaceutically acceptable surfactant, saccharide, protein and high-molecular weight compound.
[DE3723781A1]
Description
60290 STABLE PHARMACEUTICAL PREPARATION CONTAINING GRANULOCYTE COLONY STIMULATING FACTOR AND PROCESS FOR PRODUCING THE SAME The present invention relates to a pharmaceutical 5 preparation containing a granulocyte colony stimulating factor™ In particularf the present invention relates to a stabilised pharmaceutical preparation containing a granulocyte colony stimulating factor that is protected against loss or inactivation of the active component (i.e., granulo-10 cyte colony stimulating factor) due to adsorption on the wall of a container in which the preparation is putP or to association* polymerization or oxidation of said component.
Chemotherapy has been undertaken as one method for treating a variety of infectious diseases but it has 15 recently been found that chemotherapy causes some serious clinical problems such as the generation of drug-resistant organisms, change of causative organisms^ and high side effects., In order to avoid these problems associated with chemotherapy involving the use of therapeutic agents such as 20 antibiotics and bactericides» attempts are being made to use a substance that activates the prophylactic capabilities of the host of an infection-causing organism and thereby providing a complete solution to the aforementioned problems of chemotherapy™ Of the various prophylactic capabilities of 25 the host f the phagocytic bactericidal action of leucocytes is believed to cause the strongest influence in the initial period of bacterial infection and it is therefore assumed to be important to enhance the infection protecting capabilities of the host by promoting the growth of neutrophiles and their differentiation into the mature state. A granulocyte colony stimulating factor (G-CSF) is one of the very useful substances that exhibit such actions and the same assignee of the present invention previously filed a patent applica-5 tion on an infection protecting agent using G-CSF (Japanese Patent Application No. 23777/19 85).
As mentioned abovechemotherapy as currently practiced involves various unavoidable problems and intensive efforts are being made to use a drug substance that is 10 capable of activating the prophylactic functions of the host or the person who has been infected.
Needless to sayf G-CSF displays by itself the ability to activate the prophylactic functions of the host and it has also been found that G-CSF exhibits greater therapeutic 15 effects in"clinical applications if it is used in combination with a substance that activates th^prophylactic capabilities of the host * G-CSF is used in a very small amount and a pharmaceutical preparation containing 0„ 1 - 500 fig (preferably 20 5 - 50 fug) of G-CSF is usually administered at a dose rate of 1 - 7 times a week per adult. However, G-CSF has a tendency to be adsorbed on the wall of its container such as an ampule for injection or a syringe™ Therefore, if the drug is used as an injection in such a form as an aqueous 25 solution,, it will be adsorbed on the wall of its container such as an ampule or a syringe., This either results in the failure of G-CSF to fully exhibit its activity as a pharmaceutical agent or necessitates the incorporation of G-CSF in a more-than-necessary amount making allowance for its possible loss due to adsorption.
In addition, G-CSF is liable and highly susceptible to environmental factors such as 5 temperature, humidity, oxygen and ultraviolet rays. By the agency of such factors, G-CSF undergoes physical or chemical changes such as association, polymerization and oxidation and suffers a great loss in activity.
These phenomenon make it difficult to ensure complete 10 accomplishment of a therapeutic act by administering a very small amount of G-CSF in a very exact manner.
It is therefore necessary to develop a stable pharmaceutical preparation of G-CSF that is fully protected against a drop in the activity of its 15 effective component.. This is the principal object of the present invention which provides a stable pharmaceutical preparation of G-CSF., The present inventors conducted intensive studies in order to enhance the stability of a G-CSF containing 20 pharmaceutical preparation and found that this object can effectively be attained by addition of a pharmaceutically acceptable surfactant, saccharide, protein or other high-molecular weight compound-According to the present invention, there is 25 provided a stable granulocyte colony stimulating factor containing pharmaceutical preparation that contains, in addition to the granulocyte colony stimulating factor present as the effective ingredient, at least one substance selected from pharmaceutically acceptable 30 surfactants, saccharides, proteins and other high- molecular weight compounds such as natural polymers or synthetic polymers; wherein the granulocyte colony stimulating factor has the following physicochemical properties: (i) molecular weight: about 19,000 ± 1,000 as measured by electrophoresis -5. - through a sodium dodecylsulfate-polyacrylamide gel; (ii) isoelectric point: having at least one of the 5 three isoelectric points, pi = 5.5 ± 0.1, pi = 5.8 ± 0.1, and pi = 6.1 ± 0.1; (iii) ultraviolet absorption: having a maximum absorption at 280 nm and a minimum 10 absorption at 250 ran; (iv) amino acid sequence of the 21 residues from JSI terminus: H2N-Thr-Pro-Leu-Glv-Pro-Ala-Ser-Ser-Leu~Pro-Gln-Ser-Phe-Leu~Leu-Lys-Cys-Leu-Glu~Gln-Val-. 15 The present invention also provides a process for producing a stable granulocyte colony stimulating factor containing pharmaceutical preparation, which process comprises mixing granulocyte colony stimulating factor (G-CSF) with at least one substance selected 20 from pharmaceutically acceptable surfactants, saccharides, proteins and other high molecular weight substances such as natural polymers and synthetic polymers, dissolving the resulting mixture in a buffer solution, and charging a container with the solution; 25 wherein said G-CSF has the following properties: (i) molecular weight: about 19,000 ± 1,000 as measured by electrophoresis through a sodium dodecylsulfate-30 polyaerylamide gel; (ii) isoelectric point: having at least one of the three isoelectric points, pi = 5.5 ± 0.1, pi = 5.8 ± 0.1, and pi = 6.1 ± 0.1; 35 (iii) ultraviolet absorption: having a maximum absorption at 280 nm and a minimum absorption at 250 nm; (iv) amino acid sequence of the 21 residues from .N terminus: H,N-Thr-Pro~Leu~Gly-Pro~Ala~Ser~Ser-Leu-Pro-Gln-5 Ser-Phe-Leu-Leu-Lys-Cys-Leu-Glu~Gln-Val~.
For details of the method for preparing the G-CSF to be used in the present invention,, see the specifications of Japanese Patent Application 23os. 153273/1984, 259455/1985, 269456/1985, 270838/1985 and 10 270839/1985, all having been filed by the assignee of the present invention.
The human G-CSF containing solution obtained may be stored in a frozen state after being further purified and concentrated, as required, by any known 15 technique. Alternatively, the solution may be stored after being dehydrated by such means as freeze-drying.
The human G-CSF thus prepared can be processed as specified by the present invention in order to attain stable G-CSF containing pharmaceutical preparations. 20 Typical examples of the surfactant that is used to attain the stable G-CSF containing pharmaceutical preparation of the present invention are listed below: nonionic surfactants with HLB of 6 -18 such as sorbitan aliphatic acid esters (e.g. sorbitan monocaprylate, 25 sorbitan aionolaurate and sorbitan monopalmitate), glycerin aliphatic acid esters (e.g. glycerin monocaprylate, glycerin monomyristate, and glycerin monostearate), polyglycerin aliphatic acid esters (e.g. decaglyceryl monostearate, decaglycervl distearate and 30 decaglyceryl monolinoleate), polyoxvethylene sorbitan aliphatic acid esters (e.g. polyoxyethylene sorbitan monolauratef polyoxyethylene sorbitan monooleatet, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitatepolyoxyethylene sorbitan trioleatet, and polyoxyethylene sorbitan tristearate), polyoxyethylene 5 sorbitol aliphatic acid esters (e.g. polyoxyethylene sorbitol tetrastearate and polyoxyethylene sorbitol tetraoleate)t polyethylene glycerin aliphatic acid esters (e.g. polyoxyethylene glyceryl monostearate), polyethylene glycol aliphatic acid esters (e .g., polyethylene glycol distearate) £. 10 polyoxyethylene alkyl ethers (e.g. polyoxyethylene lauryl ether), polyoxyethylene polyoxypropylene alkyl ethers (e„g* polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl etherr and polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkylphenyl 15 ethers (e-'g- polyoxyethylene nonylphenyl ether) , polyoxy-ethylated castor oilt, polvoxyethylated fe^rdened castor oil (polyoxyethylated hydrogenated castor oil), polyofyethylated beeswax derivatives (e.g. polyoxyethylated sorbitol beeswax)? polyoxyethylene lanolin derivatives (e.g. polyoxyethylene 20 lanolin), and polyoxyethylene aliphatic acid amides (e.g. polyethylene stearic acid amide); nonionic surfactants such as alkyl sulfuric acid salts having a - C1g alkyl group (e.g. sodium cetyl sulfate, sodium lauryl sulfate and sodium oleyl sulfate), polyoxyethylene alkyl ether sulfuric acid 25 salts wherein the average molar number of ethylene oxide addition is 2 - 4 and the alkyl group has 10 - 18 carbon atoms (e„g, polyoxyethylene sodium lauryl sulfate), salts of alkyl sulfosuccinate esters wherein the alkyl group has 8 - 18 carbon atoms (e„g. sodium lauryl sulfosuccinate ester); and natural surfactants such as lecithin, glycerophospho-lipidr sphingophospholipid (e.g. sphingomyelin), and sucrose aliphatic acid esters wherein the aliphatic acid has 12-18 5 carbon atoms. These surfactants may of course be used either independently or in admixture.
The surfactants listed above are preferably used in amounts of 1 - 10#000 parts by weight per part by weight of G-CSF„ The saccharide to be used in making the stable G-CSF containing pharmaceutical preparation of the present invention may be selected from among monosaccharides, oligosaccharides , and polysaccharides,, as well as phosphate esters and nucleotide derivatives thereof so long as they 15 are pharmaceutically acceptable™ Typical examples are listed belows trivalent and higher suga^ alcohols such as glycerin, erythritol,» arahitolL, xylitol, sorbitoland mannitol; acidic sugars such as glucuronic acid, iduronic acid, neuraminic acidt galacturonic acid, gluconic acid 20 mannuronic acidketoglycolic acid# ketogalactonic acid and ketogulonic acid; hyaluronic acid and salts thereofe chon-droitin sulfate and salts thereof., heparin, inulinr chitin and derivatives thereof, chitosan and derivatives thereof? dextrin, dextran with an average molecular weights of 5000 25 - 150l?0002 and alginic acid and salts thereof. All of these saccharides may be used with advantage either independently or in admixture. -g- The saccharides listed above are preferably used in amounts of 1 - 10^000 parts by weight per part by weight of G-CSF.
Typical examples of the protein to be used in making 5 the stable G-CSF containing pharmaceutical preparation of j the present invention include human serum albumin, human serum globulin, gelatin, acid-treated gelatin (average mol. wt. = 7,000 - 100,000), alkali-treated gelatin (average mol. wt. = 7,000 - 100,000), and collagen™ Needless to say, 10 these proteins may be used either independently or in admixture.
The proteins listed above are preferably used in amounts of 1 - 20,000 parts by weight per part by weight of G-CSF.
Typical examples of the high-molecular weigh compound to be used in making the stable G-CSF containing pharmaceutical preparation of the present invention include*; natural polymers such as hydroxypropyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl 20 cellulose; and synthetic polymers such as polyethylene glycol (mol. wt. = 300 - 6,000), polyvinyl alcohol (mol- wt„ - 20,000 - 100,000), and polyvinylpyrrolidone (mol. wt. = 20,000 - 100,000). Heedless to say, these high-molecular weight compounds may be used either alone or in combination. 25 The high-molecular weight compounds listed above are desirably used in amounts of 1 - 20,000 parts by weight per part by weight of G-CSF.
In addition to the surfactant, saccharide, protein or high-molecular weight compound described above, at least one member selected from the group consisting of an amino acid, a sulfureous reducing agent and an antioxidant may also be 5 incorporated in making the G-CSF containing pharmaceutical preparation of the present invention. Illustrative amino acids include glycine, threonine, tryptophan, lysine, hydroxylysine, histidine, arginine, cysteine, cystine, and methionine. Illustrative sulfureous reducing agents 10 include: ^-acetylcysteine, N-acetylhomocysteine, thioctic acid , thiodiglvcol, thioethanolamine, thioglycerol, thio-sorbitol, thioglycolic acid and salts thereofr sodium thio-sulfate, sodium hvdrogensulfite, sodium pyrosulfite, sodium sulfite, thiolacfcic acid, dithiothreitol, glutathione, and a 15 mild sulfureous reducing agent having a sulfhydryl group such as a C^ - C^ thioalkanoic acid,- Illustrative antioxidants include erythorbic acid, dibutylhydroxytoluene, bu.tv 1 hydroxyanisolef di--e-tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbic acid palmitate 20 L-ascorbic acid stearate, triamyl gallate, propyl gallate and chelating agents such as disodium ethylenediamine-tetraacetate (EDTA), sodium pyrophosphate and sodium me taphosphat e *, The above-listed amino acids, sulfureous reducing 25 agents and antioxidants or mixtures thereof are preferably used in. amounts of 1 - 10,000 parts by weight per part by weight of G-CSF, For the purpose of formulating the stable G-CSF containing preparation of the present invention in a suitable dosage form? one or more the following agents maybe incorporated; a diluent, a solubilising aid? an isotonic 5 agent, an excipient* a pH modifier*, a soothing agentr and a buffer.
The stabilized G-CSF pharmaceutical preparation of the present invention may be formulated either for oral administration or for parenteral administration such as by 10 injection applied in various ways, and a variety of dosage forms may be employed depending upon the specific mode of administration™ Typical dosage forms include: those intended for oral administration such as tablets, pills, capsules, granules and suspensions.; solutions, suspensions 15 and freese^arled preparations principally intended for intravenous injection, intramuscular injection, subcutaneous injection and intracutaneous injection; and those /intended for transmucosal administration such as rectal supposito-ries, nasal drugs, and vaginal suppositories. 20 According to the present invention, at least one substance selected from the group consisting of a surfactant,. a saccharide, a protein or a high-molecular weight compound is added to a G-CSF containing pharmaceutical preparation so that it is prevented from being adsorbed on 25 the wall of its container or a syringe while at the same timet it remains stable over a prolonged period of time.
The detailed mechanism by which the substances mentioned above stabilised G-CSF or prevent it from being adsorbed is yet to be clarified,, In the presence of a surfactant, the surface of G-CSF which is a hydrophobic protein would be covered with the surfactant to become solubilised so that the G-CSF present in a trace amount is 5 effectively prevented from being adsorbed on the wall of its container or a syringe, h saccharide or hydrophilic high-molecular weight compound would form a hydrated layer between G-CSF and the adsorptive surface of the wall of its container or a syringe, thereby preventing adsorption 10 of G-CSF in an effective manner.,, ft protein would compete with G-CSF for adsorption on the wall of its container or a syringe, thereby effectively inhibiting adsorption of G-CSF.
Besides the prevention of G-CSF adsorption^ the 15 substances~mentioned above would also contribute to the prevention of association or polymerization molecules of G-CSF. In the presence of a surfactant, saccharide, protein or high-molecular weight compound, the individual molecules of G-CSF are dispersed in these substances and 20 the interaction between the G-CSF molecules is sufficiently reduced to cause a significant decrease in the probability of their association or polymerization™ In addition? these substances would retard the autoxidation of G-CSF that is accelerated under high temperature or humidity or prevent 25 G-CSF from being associated or polymerized as a result of its autoxidation. These effects of retarding autoxidation of G-CSF or preventing it from being associated or polymerized would be further enhanced by addition of an amino - 13 r acid, a sulfurous reducing agent, or an antioxidant.
The problems described above are particularly noticeable in solutions for injecting and in suspensions but they also occur during the process of 5 formulating G-CSF in other dosage forms such as tablets. The addition of surfactants, saccharides, proteins or high-molecular weight compounds is also effective in this latter case.
Through the addition of at least one substance 10 selected from the group consisting of a surfactant, saccharide, protein and a high-molecular weight compound, G-CSF is highly stabilised and maintains its activity for a prolonged period of time, as will be demonstrated in the examples that follow. To attain 15 these results, the following ranges of the amount of each of these substances are desirable: 1 - 10,000 parts by weight of surfactant, 1 - 10,000 parts by weight of saccharide, 1-20F000 parts by weight of protein, and 1 - 20,000 parts by weight of high-20 molecular weight compound, per 1 part by weight of G~ CSF.
According to the present invention, a surfactant, a saccharide, a protein and/or a high-molecular weight compound is used in a specified concentration and this 25 is effective not only in preventing G-CSF from being adsorbed on the wall of its container or a syringe but also in enhancing the stability of a G-CSF containing pharmaceutical preparation. As a result, it becomes possible to ensure the administration of a small but 30 highly precise dose of G-CSF to patients? since G-CSF is costly, its efficient utilization will lead to lower costs for the production of G-CSF containing pharmaceutical preparations.
The following examples are provided for the purpose of further illustrating the present invention but are in no 5 sense to be taken as limiting. In these examples, the residual activity of G-CSF was determined by one of the following methods. (a) Soft acrar method using mouse bone marrow cells: A horse serum (0.4 ml), 0.1 ml of the sample, 0.1 ml 10 of a C3H/He (female) mouse bone marrow,cell suspension (0,5 - 1 x 105 nuclear cells), and 0.,4 ml of a modified McCoy's 5A culture solution containing 0.75% of agar were mixed, poured into a plastic dish for tissue culture (35 mm0) r coagulated, and cultured for 5 days at 37°C in 5% C09/95% 15 air and at~100% humidity. The number of colonies formed was counted (one colony consisting of at le^t 50 cells) and the activity was determined with one unit being the acrtivity for forming one colony.
The modified McCoy9 s 5A culture solution used in the 20 method (a) was prepared by the following procedures.
Modified McCoy's 5A culture solution (double concentration) Twelve grams of McCoy's 5A culture solution (Gibco) e 2.55 g of MEM amino acid-vitamin medium (Nissui Seiyaku Co., Ltd-)* 2.18 g of sodium bicarbonate and 50,000 units of 1 25 potassium penicillin G were dissolved twice in 500 ml of distilled water and the solution was aseptically filtered through a Millipore filter (0.22 f*m). (b) Reverse-phase high-performance liquid chromatography; Using a reverse-phase C8 column (4.6 mm x 300 mm; 5 |im) and an n-propanol/trifluoroacetic acid mixture as a mobile phase,, the residual activity of G-CSF (injected in an amount equivalent to 1 fig) was determined under the following gradient conditions: Time (sec) Solvent (A) Solvent (B) Gradient 0 100% 0% linear 0% 100% linear 25 100% 0% } } Solvent (A); 30% n-propanol and 0.1% trifluoroacetic acid Solvent (B): 60% n-propanol and 0.1% trifluoroacetic acid Detection was conducted at a wavelength of 210 nm and the percentage of the residual G-CSF activity was calculated 15 by the following formulas the residual, amount of G-CSF Residual G-CSF _ after the lapse of a given time activity (%) the initial amount of G-CSF x The residual amount of G-CSF as determined by this method correlated very well with the result attained in measurement by the soft agar method (a) using mouse bone marrow cells.
Example 1 To 5 fig of G-CSFr one of the stabilizing agents listed in Table 1 was added and the mixture was aseptically dissolved in a 20 mM buffer solution (containing 100 mM sodium chloride; pH 7.4) to make a pharmaceutical prepara- tion containing 5 (jg of G-CSF per mlSJ which was then freeser-dried. The time-dependent change in G-CSF activity was measured by method (a) and the results are shown in Table 1» The term "activity (%)CT in the table represents the residual activity of G-CSF relative to the initial unit and is defined by the following formula: activity unit after Acti vitv m = - the lapse of a given time ' Act-viuy Io) initial activity unit Freeze-drying was conducted by the following procedures: The G-CSF solution containing a stabilizing agent was put into a sterile sulfa-treated glass vial, frozen at -40°C or below for 4 hours, subjected to primary drying by heating 10 from -40°C to 0°C over a period of 48 hours with the pressure increased front 0„03 to 0.1 torr, then to secondary during by heating from 0°C to 20®C for a period of 12 hours with the pressure increased from 0.03 to 0.08 torri thereafter ,, the interior of the vial was fil3s%d with a sterile 15 dry nitrogen gas to attain an atmospheric pressure5' and the vial was plugged with a freeze-drying rubber stopper, then sealed with an aluminum cap.
% Table 1 Stabilizing agent Amount (parts by weight) Activity (%) After storage at 4°C for 6 months After storage at 37°C for 1 month xylitol ,000 92 86 mannitol ,000 91 85 glucuronic acid ,000 86 82 hyaluronic acid 2,000 92 89 dextran (m.w. 40,000) 2,000 95 90 heparin ,000 85 80 chitosan 2> 000 93 91 alginic acid 2,000 90 90 human serum albumin 1,000 98 99 human serum globulin ■ 1,000 98 95 acid-treated gelatin 2,000 97 95 alkali-treated gelatin 1,000 QQ •S a' 96 collagen 2,000 95 90 polyethylene glycol (m„w. 4,000) ,000 94 90 hydroxypropyl cellulose 1,000 98 94 sodium carboxymethyl cellulose 1,000 88 80 hydroxymethyl cellulose ,000 92 90 polyvinyl alcohol (m„w„ 50,000) 2,000 96 95 polvv inylpyr rolidone (m.w. 5 0,000) 2,000 95 94 human serum albumin mannitol cysteine 2,000 2,000 100 100 97 Table 1 (cont'd) Stabilizing agent Amount (parts by weight) Activity (%) After storage at 4°C for 6 months After storage at 37°C for 1 month human serum albumin polyoxyethylene sorbitan monolaurate mannitol 2,000 100 2,000 99 96 human serum albumin hydroxypropyl cellulose dextran (m.w. 40,000) 2 r 000 500 2,000 98 92 polyoxyethylene sorbitan monolaurate sorbitol ' 100 2 ? 0 0 0 98 96 polyoxyethylated hardened castor oil dextran (m.w. 40,000) 100 2,000 94 92 not added - ■8% 74 58 Example 2 To 10 fig of G-CSFf one of the stabilizing agents listed in Table 2 was added and the mixture was aseptically dissolved in a 20 mM phosphate buffer solution (containing 5 100 mM sodium chloride; pH, 7.4) to make a pharmaceutical preparation containing 10 fig of G-CSF per ml. The preparation was aseptically charged into a sulfa-treated glass vial and sealed to make a G-CSF solution. The time-dependent change in the activity of G-CSF in this solution was 10 measured by the same method as used in Example 1 and the results are shown in Table 2.
Table 2 Stabilizing agent Amount (parts by weight) Activity (%) After storage at 4 ®C for 7 days After storage at 40 C for 2 months After storage at RT for 1 month raannitol ,000 91 87 82 hyaluronic acid 2,000 93 87 70 dextran (m.w. 40,000) 2,000 96 95 85 glycerin ,000 90 90 88 neuraminic acid ,000 93 91 84 chitin 2,000 95 92 86 dextrin 2,000 90 92 87 human serum albumin 1,000 99 95 92 human serum globulin 1,000 98 94 90 acid-treated gelatin 2,000 97 96 87 alkali-treated gelatin 500 99 95 92 collagen 2,000 QQ 9 4 88 polyethylene glycol (m.w• 4 , 000) ,000 94 89 90 hydroxypropyl cellulose 2,000 98 95 92 sodium carboxymethyl cellulose 2,000 92 91 80 hydroxyethyl cellulose 4,000 92 94 90 polyvinyl alcohol (m.w. 50,000) 4,000 97 93 90 polyvinylpyrrolidone (m.w. 50,000) 4,000 95 95 92 sorbitan monolaurate 400 97 96 95 polyoxyethylene sorbitan monolaurate 400 100 96 94 Table 2 (cont'd) Stabilizing agent Amount (parts by weight) Activity (%) After storage at V* for 7 days After storage at 4°C for 2 months After storage at RT for 1 month polyoxyethylene sorbitan monostearate 400 98 97 94 polyoxyethylene polyoxypropylene glycol ether 400 100 94 93 polyoxyethylated hardened castor oil 400 QQ y 98 90 sodium lauryl sulfate 2,000 97 93 87 lecithin 2;»000 97 94 90 human serum albumin mannitol cysteine 2,000 2,000 100 100 99 97 human serum albumin polyoxyethylene sorbitan monolaurate mannitol 2,000 100 2,000 99 97 95 human serum albumin hydroxypropyl cellulose dextran (m.w. 40,000) 1,000 500 2,000 99 97 95 polyoxyethylene sorbitan monopalmitate sorbitol 100 2,000 96 96 93 polyoxyethylated hardened castor oil dextran (m.w. 40,000) 100 2,000 95 92 92 not added - 72 61 A 7 •8 / Example 3 To 10 jig of G-CSF,, one of the stabilizing agents listed in Table 3 was added and the mixture was aseptically dissolved in a 20 mM phosphate buffer solution (containing 100 mM sodium chloride? pHi? 7,4) to make a pharmaceutical preparation containing 10 s*g of G-CSF per ml- One milliliter of the preparation was charged into a sulfa-treated silicone-coated glass vial and left at 4°C- The effectiveness of each stabilising agent in preventing G-CSF adsorption was evaluated by measuring the residual activity of G-CSF in the solution after 0„51, 2 and 24 hours. The measurement was conducted by method (b) using reverse-phase high-performance liquid chromatography. The results are shown in Table 3., Table 3 Stabilising agent Amount (parts by weight) Residual activity (%) initial 0.5 h 2 h 24 h monnitol ,000 100 93 90 91 hyaluronic acid 2,000 100 97 92 92 dextran (m.w. 40,00 0) 2,000 100 98 95 96 glycerin ,000 100 94 91 90 heparin 2,000 100 92 90 90 glucuronic acid ,000 100 96 90 91 ketoglycolic acid ,000 100 92 88 90 human serum albumin 1,000 100 100 101 99 human serum globulin 1,000 100 98 100 98 alkali-treated gelatin 500 100 99 98 99 acid-treated gelatin 2,000 100 99 97 97 collagen 2,000 100 100 98 99 polyethylene glycol "(m.w. 4,000) o o o o rH 100 100 100 i 99 hydroxypropyl cellulose 2,000 100 100 100 99 sodium carboxymethyl cellulose 2,000 100 98 96 95 hydroxyethyl cellulose 4,000 100 96 93 92 polyvinyl alcohol (m.w. 5 0,000) 4,000 100 99 100 98 polyvinylpyrrolidone (m„w. 50,000) 4,000 100 98 98 96 sorbitan monocaprylate 400 100 100 100 98 polyoxyethylene sorbitan monostearate 400 100 100 98 100 polyoxye t hylated hardened castor oil 400 100 99 101 99 Table 3 (cont'd) Stabilizing agent Amount (parts by weight) Residual activity (%) initial l XI in 8 o 2 h 24 h sodium lauryl sulfate 2,000 100 100 99 97 lecithin 2,000 100 99 100 98' human serum albumin mannitol cysteine 2,000 2,000 100 100 100 100 101 human serum albumin polyoxye thy1ene sorbitan monolaurate mannitol 2,000 100 2,000 100 100 98 99 human serum albumin hydroxypropyl cellulose dextran (m.w. 40 r000) 1,000 500 2,000 100 101 99 100 polyoxyethylene sorbitan monolaurate sorbitol 100 2,000 . 100^ 100 99 99 polyoxyethylated hardened castor oil dextran (m.w. 40,000) 100 2,000 100 100 j 98 97 not added - 100 91 72 73
Claims (13)
1. CLAIMS 1„ A stable granulocyte colony stimulating factor containing pharmaceutical preparation that contains, in addition to the granulocyte colony 5 stimulating factor present as the effective ingredient , at least one substance selected from pharmaceutically acceptable surfactants, saccharides, proteins and other high-molecular weight compounds such as natural polymers or synthetic polymers p wherein the granulocyte 10 colony stimulating factor has the following physicochemical propertiess (i) molecular weights about 19,000 ± 1,000 as measured by electrophoresis through a sodium 15 dodecylsulfate- polyacrylamide gel; (ii) isoelectric point;; having at least one of the three isoelectric points, pi = 5.5 ± 0.1, pi = 5.8 ± 20 0.1, and pi = 6.1 ± 0.1; (iii) ultraviolet absorptions having a maximum absorption at 280 nm and a minimum absorption at 250 nm; (iv) amino acid sequence of the 21 residues from N 25 terminus:
2. H2M-Thr-Pro-Leu-Gly~Pro-Ala-Ser-Ser-Leu-Pro-Gln-Ser-Phe-Leu-Leu-Lys-Cys-Leu-Glu-Gln-Val-. 2. A preparation according to claim 1 which contains the surfactant in an amount of 1 - 10,000 30 parts by weight per part by weight of the granulocyte colony stimulating factor-
3. „ A preparation according to claim 1 or 2 wherein said surfactant is a nonionic surfactant, an anionic surfactant or a natural surfactant; the 35 nonionic surfactant being a sorbitan aliphatic acid ester, a glycerin aliphatic acid ester, a polyglycerin - 25 - aliphatic acid ester, a polyoxyethylene sorbitan aliphatic acid ester, a polyoxyethylene sorbitol aliphatic acid ester, a polyoxyethylene glycerin aliphatic acid ester, a polyethylene glycol aliphatic 5 acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene polyoxypropylene alkyl ether, a polyoxyethylene alkylphenyl ether, a polyoxyethylated hardened castor oil, a polyoxyethylated beeswax derivative, a polyoxyethylene lanolin derivative, or a 10 polyoxyethylene aliphatic acid amidep the anionic surfactant being an alkyl sulfate salt, a polyoxyethylene alkyl ether sulfate salt , or an alkyl sulfosuccinate ester salt? and the natural surfactant being lecithin, glycerophospholipid, 15 sphingophospholipid, or a sucrose aliphatic acid ester-
4. A preparation according to claim 1 which contains the saccharide in an amount of 1 - 10f000 parts by weight per part by weight of the granulocyte colony stimulating factor. 20
5. A preparation according to Claim 1 or 4 wherein said saccharide is at least one of glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, glucuronic acid, iduronic acid, galacturonic acid, neuraminic acid, glyconic acid, mannuronic acid, 25 ketoglycolic acid, ketoga1actonic acid, ketogulonic acid, hyaluronic acid and, salts thereof, chondroitin sulfate and salts thereof, heparin, inulin, chitin and derivatives thereof, chitosan and derivatives thereof, dextrin, dextran with an average molecular weight of 30 5,000 - 150,000 and alginic acid and salts thereof.
6. A preparation according to claim 1 which contains the protein in an amount of 1 - 20,000 parts by weight per part by weight of the granulocyte colony stimulating factor. 35
7. A preparation according to claim 1 or 6 wherein said protein is at least one of human serum - 26 - albumin, human serum globulinf gelatin, acid- or alkali-treated gelatin with an average molecular weight of 7?000 - 100,000, and collagen,,
8. h preparation according to claim 1 which 5 contains the high-molecular weight compound in an amount of 1 » 20 e, 000 parts by weight per part by weight of the granulocyte colony stimulating factor,,
9. » A preparation according to claim 1 or 8 wherein said high-molecular weight compound is at least 10 one of hydroxypropyl cellulose, hydroxymethvl cellulose,, sodium carboxymethyl cellulose, hydroxy ethyl cellulose,, polyethylene glycol with a molecular weight of 300 - 6,0001, polyvinyl alcohol with a molecular weight of 201. 000 - 100,000, and polyvinylpyrrolidone 15 with a molecular weight of 20,000 - 100,000.
10. A process for producing a stable granulocyte colony stimulating factor containing pharmaceutical preparation„ which process comprises mixing granulocyte colony stimulating factor (G-CSF) with at least one 20 substance selected from pharmaceutically acceptable surfactants, saccharides, proteins and other high molecular weight substances such as natural polymers and synthetic polymers, dissolving the resulting mixture in a buffer solution; and charging a container 25 with the solution; wherein said G-CSF has the following-properties : (i) molecular weights about 19,000 ± 1,000 as measured by electrophoresis through a sodium 30 dodecylsulfate™ polvacrylamide gel? (ii) isoelectric points having at least one of the three isoelectric points, pi = 5„5 i 0.1, pi = 5«,8 ± 35 0.1, and pi = 6,1 ± 0.1; (iii) ultraviolet absorption: having a maximum - 27 - absorption at 280 rjn and a minimum absorption at 250 run; (iv) amino acid sequence of the 21 residues from S3 terminus: 5 H2N-Thr~Pro-Leu-Gly-Pro-Ala-Ser-Ser-Lau-Pro-Gln- Ser-Phe-LeU"-Leu-Lys~Cys~Leu-Glu-Gln-¥al-™
11. » A preparation according to claim 1,, substantially as hereinbefore described in any of the Examples.
12. A process according to claim 10f substantially as hereinbefore described in any of the Examples.
13. - A stable granulocyte colony stimulating factor containing pharmaceutical preparation, when produced by a process according to claim 10 or 12. Dated this 17th day of July9 1987. BY:- TOMKINS & CO., Applicants' Agents, (Signed) 53 Dartmouth Road, DUBLIN 6. 10 15
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16948986 | 1986-07-18 | ||
| JP16948686 | 1986-07-18 | ||
| JP16948786 | 1986-07-18 | ||
| JP16948886 | 1986-07-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE871933L true IE871933L (en) | 1988-01-18 |
| IE60290B1 IE60290B1 (en) | 1994-06-29 |
Family
ID=27474266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE193387A IE60290B1 (en) | 1986-07-18 | 1987-07-17 | "Stable pharmaceutical preparation containing granulocyte colony stimulating factor and process for producing the same" |
Country Status (24)
| Country | Link |
|---|---|
| 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) |
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| 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 |
| NZ228285A (en) * | 1988-03-11 | 1991-08-27 | Teikoku Seiyaku Kk | Pharmaceutical composition comprising a polypeptide and adapted for intravaginal administration |
| US5981485A (en) | 1997-07-14 | 1999-11-09 | Genentech, Inc. | Human growth hormone aqueous formulation |
| 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 |
| GB8824591D0 (en) | 1988-10-20 | 1988-11-23 | Royal Free Hosp School Med | Fractionation process |
| US5104651A (en) * | 1988-12-16 | 1992-04-14 | Amgen Inc. | Stabilized hydrophobic protein formulations of g-csf |
| 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 |
| EP0459516A1 (en) * | 1990-06-01 | 1991-12-04 | Kirin-Amgen, Inc. | Oral dosage form of biologically active proteins |
| 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 |
| DE4242863A1 (en) * | 1992-12-18 | 1994-06-23 | Boehringer Mannheim Gmbh | Stable lyophilized pharmaceutical preparations of G-CSF |
| DE4242919A1 (en) * | 1992-12-18 | 1994-06-23 | Boehringer Mannheim Gmbh | Process for the preparation of storage-stable aqueous 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 |
| AU695129B2 (en) * | 1995-02-06 | 1998-08-06 | Genetics Institute, Llc | 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 |
| EP1060746A4 (en) * | 1998-03-06 | 2002-06-19 | Chugai Pharmaceutical Co Ltd | Protein-free preparations |
| US6979442B1 (en) * | 1998-08-17 | 2005-12-27 | Pfizer Inc. | Stabilized protein compositions |
| AU6875900A (en) * | 1999-09-08 | 2001-04-10 | Chugai Seiyaku Kabushiki Kaisha | Protein solution preparation and method of stabilizing the same |
| DK1129720T3 (en) * | 2000-02-29 | 2004-09-27 | Pfizer Prod Inc | Stabilized granulocyte colony stimulating factor |
| JP4683810B2 (en) * | 2000-02-29 | 2011-05-18 | 中外製薬株式会社 | Long-term stabilized preparation |
| CA2405557C (en) | 2000-04-12 | 2013-09-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| US6946134B1 (en) | 2000-04-12 | 2005-09-20 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| AU8260701A (en) * | 2000-09-01 | 2002-03-13 | Chugai Pharmaceutical Co Ltd | Solution preparations stabilized over long time |
| 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 |
| EP2261250B1 (en) | 2001-12-21 | 2015-07-01 | Human Genome Sciences, Inc. | GCSF-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 |
| DE102006009437A1 (en) | 2006-03-01 | 2007-09-13 | Bioceuticals Arzneimittel Ag | G-CSF liquid formulation |
| EP3011961B1 (en) | 2006-12-21 | 2020-11-11 | Biokine Therapeutics LTD. | 4f-benzoyl-tn14003 for the mobilisation of hematopoietic progenitor cells in view of transplantation |
| WO2010092571A2 (en) | 2009-02-11 | 2010-08-19 | Yeda Research And Development Co. Ltd. | Short beta-defensin-derived peptides |
| BR112012017979B1 (en) | 2010-01-19 | 2021-10-13 | Hanmi Science Co., Ltd. | LIQUID FORMULATIONS FOR LONG-TERM G-CSF CONJUGATE |
| EP2399572A1 (en) | 2010-06-22 | 2011-12-28 | Sandoz AG | Long-term storage of non-glycosylated recombinant human G-CSF |
| US10786547B2 (en) | 2015-07-16 | 2020-09-29 | Biokine Therapeutics Ltd. | Compositions, articles of manufacture and methods for treating cancer |
| 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 |
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| 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 |
| SE451844B (en) * | 1978-03-20 | 1987-11-02 | Morinaga Milk Industry Co Ltd | GLYCOPROTEIN, PROCEDURE FOR PREPARING THEREOF AND THERAPEUTIC AGENTS INCLUDING THE 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 |
| DE3686794T2 (en) * | 1985-02-05 | 1993-03-04 | Cetus Oncology Corp | CLEANING THE 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 |
-
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
- 1987-07-14 AT AT0177587A patent/AT402259B/en not_active IP Right Cessation
- 1987-07-15 DK DK368387A patent/DK171308B1/en not_active IP Right Cessation
- 1987-07-15 BE BE8700787A patent/BE1000253A3/en not_active IP Right Cessation
- 1987-07-15 AU AU75665/87A patent/AU611856B2/en not_active Expired
- 1987-07-15 CA CA000542239A patent/CA1297007C/en not_active Expired - Lifetime
- 1987-07-16 PT PT85343A patent/PT85343B/en unknown
- 1987-07-16 CH CH2727/87A patent/CH671157A5/en not_active IP Right Cessation
- 1987-07-16 NO NO872966A patent/NO171828C/en not_active IP Right Cessation
- 1987-07-17 SE SE8702907A patent/SE503312C2/en not_active IP Right Cessation
- 1987-07-17 DE DE3723781A patent/DE3723781C2/en not_active Expired - Lifetime
- 1987-07-17 ES ES8702106A patent/ES2010226A6/en not_active Expired
- 1987-07-17 IE IE193387A patent/IE60290B1/en not_active IP Right Cessation
- 1987-07-17 FR FR878710156A patent/FR2601591B1/en not_active Expired - Lifetime
- 1987-07-17 GB GB8716904A patent/GB2193631B/en not_active Expired - Lifetime
- 1987-07-17 HU HU873268A patent/HU198627B/en unknown
- 1987-07-17 IL IL83220A patent/IL83220A/en not_active IP Right Cessation
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- 1987-07-18 CN CN87104963A patent/CN1033738C/en not_active Expired - Lifetime
- 1987-07-18 KR KR1019870007804A patent/KR930004597B1/en not_active IP Right Cessation
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1993
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