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Title:
A COMBINATION COMPRISING GRANULOCYTE COLONY STIMULATING FACTOR
Document Type and Number:
WIPO Patent Application WO/2020/139300
Kind Code:
A2
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.

Inventors:
TOKSOZ ZAFER (TR)
YENICE IREM (TR)
KACAR TURGAY (TR)
Application Number:
PCT/TR2019/051223
Publication Date:
July 02, 2020
Filing Date:
December 26, 2019
Export Citation:
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Assignee:
ARVEN ILAC SANAYI VE TICARET ANONIM SIRKETI (TR)
International Classes:
A61K38/19; C07C279/26; C08G12/14
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Claims:
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.

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.