WO2020139300A2 - A combination comprising granulocyte colony stimulating factor - Google Patents
A combination comprising granulocyte colony stimulating factor Download PDFInfo
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- WO2020139300A2 WO2020139300A2 PCT/TR2019/051223 TR2019051223W WO2020139300A2 WO 2020139300 A2 WO2020139300 A2 WO 2020139300A2 TR 2019051223 W TR2019051223 W TR 2019051223W WO 2020139300 A2 WO2020139300 A2 WO 2020139300A2
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- WIPO (PCT)
- Prior art keywords
- pharmaceutical combination
- acid
- combination according
- sodium
- metformin
- Prior art date
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- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 title claims abstract description 41
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 title claims abstract description 41
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 25
- 229940123208 Biguanide Drugs 0.000 claims abstract description 19
- -1 biguanide compound Chemical class 0.000 claims abstract description 16
- 238000002512 chemotherapy Methods 0.000 claims abstract description 14
- 238000002626 targeted therapy Methods 0.000 claims abstract description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 32
- 229960003105 metformin Drugs 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002539 nanocarrier Substances 0.000 claims description 7
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 5
- VKZRWSNIWNFCIQ-UHFFFAOYSA-N 2-[2-(1,2-dicarboxyethylamino)ethylamino]butanedioic acid Chemical compound OC(=O)CC(C(O)=O)NCCNC(C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-UHFFFAOYSA-N 0.000 claims description 4
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 4
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
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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
-
- 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a pharmaceutical combination comprising granulocyte- colony stimulating factor (G-CSF) and a biguanide compound for treating a patient with cancer with a targeted therapy in combination with chemotherapies.
- G-CSF granulocyte- colony stimulating factor
- Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These abnormal cells are termed cancer cells, malignant cells, or tumor cells. Treatment protocols vary according to the type and stage of cancer. Most treatment protocols are designed to fit the individual patient's disease. However, most treatments include at least one of the following and may include all: surgery, chemotherapy, and radiation therapy.
- Chemotherapy is the use of anticancer drugs designed to slow or stop the growth of rapidly dividing cancer cells in the body. But like other treatments, it causes side effects.
- One of the most common adverse effects is myelosuppression including a significant drop in circulating neutrophil numbers (neutropenia). Myelosuppression is associated with potentially dangerous outcomes such as severe infections that can increase the duration of hospitalization. It also can result in temporary cessation or dose reductions of chemotherapy, even it can ultimately reduce the overall treatment efficacy.
- G-CSF granulocyte colony-stimulating factor
- G-CSF Granulocyte colony stimulating factor
- E. coli. Escherichia coli
- the protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli. Because G-CSF is produced in E. coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.
- G-CSF is supplied in either vial or in prefilled syringes.
- the product is available in single use vials and prefilled syringes.
- the single use vials contain either 300 meg or 480 meg G-CSF at a fill volume of 1 , 0 ml or 1 , 6 ml respectively.
- the single use prefilled syringes contain either 300 meg or 480 meg G-CSF at a fill volume of 0, 5 ml or 0, 8 ml respectively.
- the recombinant human G-CSF synthesized in an E. coli. the expression system is called filgrastim.
- the structure of filgrastim differs slightly from the natural glycoprotein. Most published studies have used filgrastim and it was the first form of G-CSF to be approved for marketing.
- G-CSF The recombinant production of G-CSF has been described in the patent literature for the first time in 1987, in WO 87/01132 A1.
- the formulation of the product contains filgrastim, acetate, sorbitol, polysorbate 80, sodium and water in a form suitable for intravenous and subcutaneous administration.
- the patent application WO2016146629 A1 discloses a process of isolating and purifying granulocyte colony stimulating factor (G-CSF) from a G-CSF-producing microorganism.
- G-CSF granulocyte colony stimulating factor
- the strategy is to improve the current state of an adjunctive cancer treatment with combination therapy.
- the strategy to improve the current state of cancer treatment and chemoprevention is to combine therapies. Furthermore, there is no combination of G-CSF with biguanides, in the prior art.
- biguanide refers to a group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver, improving the body’s sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines. Biguanide is the organic compound with the formula HN(C(NH)NH2)2 .
- the examples of biguanide are metformin, phenformin, buformin.
- metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other biguanides.
- epidemiological studies have been published with regard to the preventive and therapeutic effects of metformin on various cancers.
- Metformin is an antidiabetic having an orally-administrated biguanide structure.
- Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
- Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg.
- metformin hydrochloride 1 ,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
- metformin when metformin is administered to a p53 gene-deficient cancer patient, the treatment of metformin leads to changes in the energy metabolic pathway of cancer cells and an anticancer activity increases proportionally to a dose of metformin, thus showing that metformin is effective for the treatment of cancer at a normal dose for the treatment of diabetes mellitus.
- combining more than one molecule in one dosage form increases the patient’s compliance. However, while this combination increases the patients’ quality of life, combining more than one molecule in one dosage form also reduces chemotherapy symptoms which can be neutropenia.
- the main object of the present invention is to combine granulocyte-colony stimulating factor (G-CSF) with a biguanide compound to eliminate chemotherapy symptoms, to provide rapid and effective treatment and to bring additional advantages over the relevant prior art.
- G-CSF granulocyte-colony stimulating factor
- Another object of the present invention is to provide decreased toxicities, improved solubility and stability and site-specific delivery of therapeutic agents.
- Another object of the present invention is to obtain a stable combination formulation with a synergistic effect for use in cancer treatment.
- biguanide refers to metformin or phenformin or buformin.
- metalformin refers to not only metformin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
- the combination comprises simultaneous administration of the agents in the same or different dosage form, or separate administration of the agents (e.g., sequential administration).
- the agents can be formulated for separate administration and administered concurrently or sequentially.
- concurrent or sequential administration preferably results in the agents being simultaneously present in treated patients.
- a pharmaceutical combination comprising granulocyte-colony stimulating factor (G-CSF) and a biguanide compound.
- G-CSF granulocyte-colony stimulating factor
- the biguanide compound is metformin or phenformin or buformin.
- the biguanide compound is metformin or a pharmaceutically acceptable salt, solvate or polymorph thereof.
- metformin and G-CSF may generate a synergistic effect.
- the combination is co-administered concomitantly or sequentially with chemotherapy.
- the combination comprising both metformin and G-CSF in accordance with the present invention has excellent pharmacological effects and is capable of achieving medication convenience of patients.
- This combination helps to reduce the risks associated with neutropenia after chemotherapy so, the combination provides supportive treatment for cancer treatment.
- the cancer is selected from the group comprising head and neck cancers, esophagus cancer, gastric cancer, colorectal cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cancer, urothelial cancer, prostate cancer, testicular tumor, osteosarcoma, soft-tissue sarcoma, leukemia, myelodysplastic syndrome, malignant lymphoma, adult T-cell leukemia, multiple myeloma, skin cancer, brain tumor, pleural mesothelioma, and unknown primary cancer.
- the biguanide compound is metformin hydrochloride or metformin butyrate or metformin glycinate or metformin pamoate.
- the weight ratio of metformin to G-CSF is 0.1 - 8.0, preferably 0.3 - 2.0.
- a pharmaceutical combination of treating cancer in a human individual in need of treatment for cancer comprises metformin and G-CSF, wherein the metformin and G-CSF are administered in an effective amount.
- the pharmaceutical combination comprises G-CSF in an amount of between 0.2 mg/ml and 1.0 mg/ml, preferably between 0.6 mg/ml and 0.96 mg/ml.
- the pharmaceutical combination comprises metformin in an amount of between 0.1 mg/ml and 1.5 mg/ml, preferably between 0.3 mg/ml and 1.2 mg/ml.
- the pharmaceutical combination further comprises pharmaceutically acceptable excipients are selected from the group comprising buffering agents, stabilizers, diluents, chelating agents, nanocarriers, preservatives, solubilizers or mixtures thereof.
- Suitable buffering agents are selected from the group comprising alkali metal citrate, citric acid, sodium citrate, tartaric acid, fumaric acid, sorbic acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, sodium hydroxide or mixtures thereof.
- Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium chloride, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, polysorbates 20 and 80, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or mixtures thereof.
- Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
- Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid (EDTA) or ethylenediamine-N,N'-disuccinic acid (EDDS) or mixtures thereof. It may be added at levels safe for administration to improve storage stability.
- EDTA ethylenediamine tetraacetic acid
- EDDS ethylenediamine-N,N'-disuccinic acid
- Nanocarriers are colloidal drug carrier systems having submicron particle size typically ⁇ 500 nm. Nanocarriers, owing to their high surface area to volume ratio, have the ability to alter the basic properties and bioactivity of drugs. Improved pharmacokinetics and biodistribution, decreased toxicities, improved solubility and stability, controlled release and site-specific delivery of therapeutic agents are some of the features that nanocarriers can incorporate in drug delivery systems.
- Suitable nanocarriers are selected from the group comprising gold nanoparticles, polylactic acid, poly(cyano)acrylates, polyethyleneimine, block copolymers, polycaprolactone or mixtures thereof.
- Suitable preservatives are selected from the group comprising alcohol, quaternary ammonium compounds, benzethonium chloride, benzoxonium chloride, benzododecinium bromide, alkyltrimethilammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and esters and salts thereof, methyl 4-hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyl toluene, butylated hydroxyanisole, cetylpyridinium chloride, cetrimide, propylparaben or methylparaben; alkyl acids, potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine chloride, 2-phenoxyethanol, boric acids, phenols, 4-chlorocresol, 4-chloroxyleno
- Suitable solubilizers are selected from the group comprising propanol, 1-butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1-pentanol, 1-propanol, 2-propanol, methylene chloride, acetone, ethanol, dichloromethane, n-hexane, dioxane or mixtures thereof.
- compositions for parenteral administration that comprise a solution or suspension of metformin and G-CSF dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.
- the parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- the stability of the active ingredients in the final product is a major concern to the formulator.
- drug substances are less stable in aqueous media than in solid dosage forms, and it is important to properly stabilize and preserve liquid aqueous formulations.
- Acid-base reactions, acid or base catalysis, oxidation and reduction can occur in these products. Such a reaction may result from drug substance-component interactions, component-component interactions or vessel-product
- the pH value of the composition is buffered and within the range of from 4.0 to 6.0.
- the pharmaceutical combination is for use in the treatment of cancer.
- the pharmaceutical combination is for use treating a human patient with cancer with a targeted therapy in combination with chemotherapies.
- the invention relates to a pharmaceutical kit comprising G-CSF and a biguanide, metformin, in same unit dosage forms, said forms being suitable for administration separately, sequentially or simultaneous in effective amounts.
- the package comprises instructions for use.
- the kit may optionally further include polyester coil packing material and humectant.
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Abstract
The present invention relates to a pharmaceutical combination comprising granulocyte-colony stimulating factor (G-CSF) and a biguanide compound for treating a patient with cancer with a targeted therapy in combination with chemotherapies.
Description
A COMBINATION COMPRISING GRANULOCYTE COLONY STIMULATING FACTOR
Field of the invention
The present invention relates to a pharmaceutical combination comprising granulocyte- colony stimulating factor (G-CSF) and a biguanide compound for treating a patient with cancer with a targeted therapy in combination with chemotherapies.
Background of the invention
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These abnormal cells are termed cancer cells, malignant cells, or tumor cells. Treatment protocols vary according to the type and stage of cancer. Most treatment protocols are designed to fit the individual patient's disease. However, most treatments include at least one of the following and may include all: surgery, chemotherapy, and radiation therapy.
Chemotherapy is the use of anticancer drugs designed to slow or stop the growth of rapidly dividing cancer cells in the body. But like other treatments, it causes side effects. One of the most common adverse effects is myelosuppression including a significant drop in circulating neutrophil numbers (neutropenia). Myelosuppression is associated with potentially dangerous outcomes such as severe infections that can increase the duration of hospitalization. It also can result in temporary cessation or dose reductions of chemotherapy, even it can ultimately reduce the overall treatment efficacy.
A major advance in dealing with neutropenia is the routine use of hemopoietic growth factor support using recombinant forms of granulocyte colony-stimulating factor (G-CSF). Administration of G-CSF can increase neutrophils after chemotherapy by promoting mobilization of bone marrow-derived cells (BMDCs), thus reducing both the severity and duration of neutropenia. (Voloshin T., Gingis-Velitski S., Bril R., Benayoun L, Munster M., Milsom C., Man S., Kerbel R. S., and Shaked Y., Blood, 2011 Sep 22; 118(12): 3426-3435)
Granulocyte colony stimulating factor (G-CSF) is175 amino acid protein manufactured by recombinant DNA technology. G-CSF is produced by Escherichia coli (E. coli.) bacteria into which has been inserted into the human granulocyte colony-stimulating factor gene. The protein has an amino acid sequence that is identical to the natural sequence predicted from
human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E. coli. Because G-CSF is produced in E. coli, the product is non-glycosylated and thus differs from G-CSF isolated from a human cell.
G-CSF is supplied in either vial or in prefilled syringes. The product is available in single use vials and prefilled syringes. The single use vials contain either 300 meg or 480 meg G-CSF at a fill volume of 1 , 0 ml or 1 , 6 ml respectively. The single use prefilled syringes contain either 300 meg or 480 meg G-CSF at a fill volume of 0, 5 ml or 0, 8 ml respectively.
The recombinant human G-CSF synthesized in an E. coli. the expression system is called filgrastim. The structure of filgrastim differs slightly from the natural glycoprotein. Most published studies have used filgrastim and it was the first form of G-CSF to be approved for marketing.
The recombinant production of G-CSF has been described in the patent literature for the first time in 1987, in WO 87/01132 A1. The first commercially available G-CSF preparation on the basis of recombinant G-CSF was admitted in Germany in 1991 and is produced and distributed by Amgen under the trade name Neupogen®. The formulation of the product contains filgrastim, acetate, sorbitol, polysorbate 80, sodium and water in a form suitable for intravenous and subcutaneous administration.
The patent application WO2016146629 A1 discloses a process of isolating and purifying granulocyte colony stimulating factor (G-CSF) from a G-CSF-producing microorganism.
There is no known completely a cure for cancer until now. Current treatments typically focus on accelerating patient’s recovery after chemotherapy, restraining chemotherapy symptoms. G-CSF alone does not provide adequate treatment. In the present invention, the strategy is to improve the current state of an adjunctive cancer treatment with combination therapy.
Laboratory models, however, provide independent impressive evidence for the activity of biguanides in both cancer treatment and chemoprevention. (Michael Poliak, Cancer Prev. Res (Phila). 2010 Sep; 3(9): 1060-1065)
In the present invention, the strategy to improve the current state of cancer treatment and chemoprevention is to combine therapies. Furthermore, there is no combination of G-CSF with biguanides, in the prior art.
The term biguanide refers to a group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver, improving the body’s sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines. Biguanide is the organic compound with the formula HN(C(NH)NH2)2. The examples of biguanide are metformin, phenformin, buformin.
The results of numerous preclinical, epidemiological and clinical studies suggested that metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other biguanides. During the last decade, numerous epidemiological studies have been published with regard to the preventive and therapeutic effects of metformin on various cancers.
Metformin is an antidiabetic having an orally-administrated biguanide structure. Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg.
The lUPAC (International Union of Pure and Applied Chemistry) name of metformin hydrochloride is 1 ,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
Formula I
it has been found that when metformin is administered to a p53 gene-deficient cancer patient, the treatment of metformin leads to changes in the energy metabolic pathway of cancer cells and an anticancer activity increases proportionally to a dose of metformin, thus showing that metformin is effective for the treatment of cancer at a normal dose for the treatment of diabetes mellitus.
In this invention, combining more than one molecule in one dosage form increases the patient’s compliance. However, while this combination increases the patients’ quality of life, combining more than one molecule in one dosage form also reduces chemotherapy symptoms which can be neutropenia.
Detailed description of the Invention
The main object of the present invention is to combine granulocyte-colony stimulating factor (G-CSF) with a biguanide compound to eliminate chemotherapy symptoms, to provide rapid and effective treatment and to bring additional advantages over the relevant prior art.
Another object of the present invention is to provide decreased toxicities, improved solubility and stability and site-specific delivery of therapeutic agents.
Another object of the present invention is to obtain a stable combination formulation with a synergistic effect for use in cancer treatment.
The term "biguanide” as used throughout the specification refers to metformin or phenformin or buformin.
The term "metformin" as used throughout the specification refers to not only metformin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
As used herein, the combination comprises simultaneous administration of the agents in the same or different dosage form, or separate administration of the agents (e.g., sequential administration). For example, the agents can be formulated for separate administration and administered concurrently or sequentially. Such concurrent or sequential administration preferably results in the agents being simultaneously present in treated patients.
According to an embodiment of the present invention, a pharmaceutical combination comprising granulocyte-colony stimulating factor (G-CSF) and a biguanide compound.
According to an embodiment of the present invention, the biguanide compound is metformin or phenformin or buformin. Preferably, the biguanide compound is metformin or a pharmaceutically acceptable salt, solvate or polymorph thereof.
The combined use of metformin and G-CSF may generate a synergistic effect. The combination is co-administered concomitantly or sequentially with chemotherapy.
Further, the combination comprising both metformin and G-CSF in accordance with the present invention has excellent pharmacological effects and is capable of achieving medication convenience of patients.
This combination helps to reduce the risks associated with neutropenia after chemotherapy so, the combination provides supportive treatment for cancer treatment.
According to an embodiment of the present invention, the cancer is selected from the group comprising head and neck cancers, esophagus cancer, gastric cancer, colorectal cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cancer, urothelial cancer, prostate cancer, testicular tumor, osteosarcoma, soft-tissue sarcoma, leukemia, myelodysplastic syndrome, malignant lymphoma, adult T-cell leukemia, multiple myeloma, skin cancer, brain tumor, pleural mesothelioma, and unknown primary cancer.
According to an embodiment of the present invention, the biguanide compound is metformin hydrochloride or metformin butyrate or metformin glycinate or metformin pamoate.
According to an embodiment of the present invention, the weight ratio of metformin to G-CSF is 0.1 - 8.0, preferably 0.3 - 2.0.
According to an embodiment of the present invention, a pharmaceutical combination of treating cancer in a human individual in need of treatment for cancer comprises metformin and G-CSF, wherein the metformin and G-CSF are administered in an effective amount.
According to an embodiment of the present invention, the pharmaceutical combination comprises G-CSF in an amount of between 0.2 mg/ml and 1.0 mg/ml, preferably between 0.6 mg/ml and 0.96 mg/ml.
According to an embodiment of the present invention, the pharmaceutical combination comprises metformin in an amount of between 0.1 mg/ml and 1.5 mg/ml, preferably between 0.3 mg/ml and 1.2 mg/ml.
According to an embodiment of the present invention, the pharmaceutical combination further comprises pharmaceutically acceptable excipients are selected from the group comprising buffering agents, stabilizers, diluents, chelating agents, nanocarriers, preservatives, solubilizers or mixtures thereof.
Suitable buffering agents are selected from the group comprising alkali metal citrate, citric acid, sodium citrate, tartaric acid, fumaric acid, sorbic acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, sodium hydroxide or mixtures thereof.
Suitable stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium chloride, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, polysorbates 20 and 80, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or mixtures thereof.
Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid (EDTA) or ethylenediamine-N,N'-disuccinic acid (EDDS) or mixtures thereof. It may be added at levels safe for administration to improve storage stability.
Nanocarriers are colloidal drug carrier systems having submicron particle size typically <500 nm. Nanocarriers, owing to their high surface area to volume ratio, have the ability to alter the basic properties and bioactivity of drugs. Improved pharmacokinetics and biodistribution, decreased toxicities, improved solubility and stability, controlled release and site-specific
delivery of therapeutic agents are some of the features that nanocarriers can incorporate in drug delivery systems.
Suitable nanocarriers are selected from the group comprising gold nanoparticles, polylactic acid, poly(cyano)acrylates, polyethyleneimine, block copolymers, polycaprolactone or mixtures thereof.
Suitable preservatives are selected from the group comprising alcohol, quaternary ammonium compounds, benzethonium chloride, benzoxonium chloride, benzododecinium bromide, alkyltrimethilammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and esters and salts thereof, methyl 4-hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyl toluene, butylated hydroxyanisole, cetylpyridinium chloride, cetrimide, propylparaben or methylparaben; alkyl acids, potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine chloride, 2-phenoxyethanol, boric acids, phenols, 4-chlorocresol, 4-chloroxylenol, dichlorophene, hexachlorophene or mixtures thereof.
Suitable solubilizers are selected from the group comprising propanol, 1-butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1-pentanol, 1-propanol, 2-propanol, methylene chloride, acetone, ethanol, dichloromethane, n-hexane, dioxane or mixtures thereof.
Any combination of the above-described excipients in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by the context.
The pharmaceutical combination can be administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. Thus, the invention provides compositions for parenteral administration that comprise a solution or suspension of metformin and G-CSF dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.
The parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
The stability of the active ingredients in the final product is a major concern to the formulator. In general, drug substances are less stable in aqueous media than in solid dosage forms, and it is important to properly stabilize and preserve liquid aqueous formulations. Acid-base reactions, acid or base catalysis, oxidation and reduction can occur in these products. Such a reaction may result from drug substance-component interactions, component-component interactions or vessel-product interactions. In the case of pH-sensitive compounds, any such interactions can alter the pH and cause precipitation.
According to an embodiment of the present invention, the pH value of the composition is buffered and within the range of from 4.0 to 6.0.
According to an embodiment of the present invention, the pharmaceutical combination is for use in the treatment of cancer.
According to an embodiment of the present invention, the pharmaceutical combination is for use treating a human patient with cancer with a targeted therapy in combination with chemotherapies.
In a further embodiment, the invention relates to a pharmaceutical kit comprising G-CSF and a biguanide, metformin, in same unit dosage forms, said forms being suitable for administration separately, sequentially or simultaneous in effective amounts. Also, the package comprises instructions for use. The kit may optionally further include polyester coil packing material and humectant.
Claims
1. A pharmaceutical combination comprising granulocyte-colony stimulating factor (G- CSF) and a biguanide compound.
2. The pharmaceutical combination according to claim 1 , wherein the biguanide compound is metformin or phenformin or buformin.
3. The pharmaceutical combination according to claim 2, wherein the biguanide compound is metformin or a pharmaceutically acceptable salt, solvate or polymorph thereof.
4. The pharmaceutical combination according to claim 3, wherein the biguanide compound is metformin hydrochloride or metformin butyrate or metformin glycinate or metformin pamoate.
5. The pharmaceutical combination according to claim 4, wherein the weight ratio of metformin to granulocyte-colony stimulating factor is 0.1 - 8.0, preferably 0.3 - 2.0.
6. The pharmaceutical combination according to claim 1 , wherein granulocyte-colony stimulating factor is present in an amount of between 0.2 mg/ml and 1.0 mg/ml, preferably between 0.6 mg/ml and 0.96 mg/ml.
7. The pharmaceutical combination according to claim 5, wherein metformin or a pharmaceutically acceptable salt thereof is present in an amount of between 0.1 mg/ml and 1.5 mg/ml, preferably between 0.3 mg/ml and 1.2 mg/ml.
8. The pharmaceutical combination according to any preceding claim, wherein further comprising pharmaceutically acceptable excipients are selected from the group comprising buffering agents, stabilizers, diluents, chelating agents, nanocarriers, preservatives, solubilizers or mixtures thereof.
9. The pharmaceutical combination according to claim 8, wherein the buffering agents are selected from the group comprising alkali metal citrate, citric acid, sodium citrate, tartaric acid, fumaric acid, sorbic acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, sodium hydroxide or mixtures thereof.
10. The pharmaceutical combination according to claim 8, wherein the stabilizers are selected from the group comprising citric acid, fumaric acid, tartaric acid, sodium citrate, sodium chloride, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, polysorbates 20 and 80, arginine, lysine, meglamine, ascorbic acid, gallic acid esters or mixtures thereof.
11. The pharmaceutical combination according to claim 8, wherein the diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose- maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
12. The pharmaceutical combination according to claim 8, wherein the chelating agents are selected from the group comprising ethylenediamine tetraacetic acid (EDTA) or ethylenediamine-N,N'-disuccinic acid (EDDS) or mixtures thereof
13. The pharmaceutical combination according to claim 8, wherein the nanocarriers are selected from the group comprising gold nanoparticles, polylactic acid, poly(cyano)acrylates, polyethyleneimine, block copolymers, polycaprolactone or mixtures thereof.
14. The pharmaceutical combination according to claim 8, wherein the preservatives are selected from the group comprising alcohol, quaternary ammonium compounds, benzethonium chloride, benzoxonium chloride, benzododecinium bromide, alkyltrimethilammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and esters and salts thereof, methyl 4- hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyl toluene, butylated hydroxyanisole, cetylpyridinium chloride, cetrimide, propylparaben or methylparaben; alkyl acids, potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine chloride, 2-phenoxyethanol, boric acids, phenols, 4- chlorocresol, 4-chloroxylenol, dichlorophene, hexachlorophene or mixtures thereof.
15. The pharmaceutical combination according to claim 8, wherein the solubilizers are selected from the group comprising propanol, 1-butanol, 2-butanol, ethyl acetate, ethyl ether, heptane, pentane, 1-pentanol, 1-propanol, 2-propanol, methylene chloride, acetone, ethanol, dichloromethane, n-hexane, dioxane or mixtures thereof.
16. The pharmaceutical combination according to any preceding to claim, wherein the composition is administered parenterally.
17. The pharmaceutical combination according to any preceding claims, for use in the treatment of cancer.
18. The pharmaceutical combination according to any preceding claims, for use treating a human patient with cancer with a targeted therapy in combination with chemotherapies.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2018/20952 | 2018-12-28 | ||
| TR2018/20952A TR201820952A2 (en) | 2018-12-28 | 2018-12-28 | GRANULOCYTE COLONY A COMBINATION WITH A STIMULATING FACTOR |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2020139300A2 true WO2020139300A2 (en) | 2020-07-02 |
| WO2020139300A3 WO2020139300A3 (en) | 2020-12-24 |
Family
ID=71128855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2019/051223 WO2020139300A2 (en) | 2018-12-28 | 2019-12-26 | A combination comprising granulocyte colony stimulating factor |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201820952A2 (en) |
| WO (1) | WO2020139300A2 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0603252D0 (en) * | 2006-02-17 | 2006-03-29 | Axcess Ltd | Dissolution aids for oral peptide delivery |
| BR112014001346A8 (en) * | 2011-07-19 | 2018-05-08 | Stc Unm | nanotransport compound, method, pharmaceutical compound and use of a |
| WO2016140714A1 (en) * | 2015-03-05 | 2016-09-09 | The General Hospital Corporation | Novel compositions and uses of metformin agents |
-
2018
- 2018-12-28 TR TR2018/20952A patent/TR201820952A2/en unknown
-
2019
- 2019-12-26 WO PCT/TR2019/051223 patent/WO2020139300A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020139300A3 (en) | 2020-12-24 |
| TR201820952A2 (en) | 2020-07-21 |
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