Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• the present invention relates to a novel pharmaceutical combination of 1-(2- tetrahydrofuryl)-5-fluorouracil and phenolic compound for oral treating of tumors; in particular, it relates to the unexpected synergistic antitumor effect of a combination of phenolic compound and the antitumor agent in the treatment of cancer; and to processes for preparing the composition and its use for oral chemotherapy of tumors, especially malignant tumors.
• Background Art
• Cancer is the uncontrolled growth and spread of cells that may affect almost any tissue of the body. Lung, colorectal and stomach cancer are among the five most common cancers in the world for both men and women. Among men, lung and stomach cancer are the most common tumors worldwide. For women, the most common cancers are breast and cervical cancer.
• TEGAFUR i.e. 1-(2-tetrahydrofuryl)-5- fluorouracil
• GB 1 168 391 INHT ORGANOCHESKOGO SINTEZA, published 22.10.1969
• 5-FU 5-Fluorouracil
• TEGAFUR is metabolized to 5-FU in vivo, predominantly in the liver, and has been reported to be less toxic and to have a higher therapeutic index than 5-FU (see “Cancer Research” 1995, vol.1 , p.839-845).
• US 4 328 229 discloses an anti-cancer composition containing TEGAFUR and uracil.
• the composition is used for delivery of 5-FU to a tumor which is sensitive to 5-FU in a warm-blooded animal. It is disclosed therein that the composition can be co-administered in a variety of dosage forms including an oral dosage form.
• Caffeic acid phenethyl ester is a phenolic compound contained in propolis, which is the generic name of a resinous product derived from the bark of conifer trees and carried by honeybees to their hives (see CHIAO, C. "Apoptosis and altered redox state induced by CAPE in transformed rat fibrolast cells", published in “Cancer Research” 1995, vol.55, no.3576, p.3583). The biological activities of propolis and CAPE have been studied, and it has been shown that CAPE also has an antitumor activity.
• US 5008441 discloses a method for producing CAPE and a method which substantially inhibits the growth of transformed cells without substantially inhibiting the growth of normal cells. This process comprises treating a population of cells with an effective inhibiting amount of CAPE so as to substantially inhibit the growth human breast carcinoma cells, human melanoma cells, colon or renal carcinoma cells.
• MASAHIKO W., et al., "CAPE Induces Apoptosis by Inhibition of NF- ⁇ B and Activation of Fas in Human Breast Cancer MCF-7 Cells", published in "Journal of Biological Chemistry” 2004, vol.279, no.7, p.
• CAPE is described as a phenolic compound, which is a biologically active ingredient of honeybee propolis and strongly inhibits NF- ⁇ B activation. Furthermore, it was demonstrated that apoptosis is induced by CAPE in various cancer cell lines - e.g. human breast cancer MCF-7 cells. It was found by TAKEMA, N., et al., in "Selective antiproliferative activity of CAPE analogues on highly liver-metastatic murine colon 26-L5 carcinoma cell line", published in "Bioorganic&Medicinal Chemistry 2002, vol.10, p.3351-3359, that CAPE possesses selective antiproliferative activity toward a highly metastatic murine colon 26-L5 carcinoma cell line.
• WO 03/090681 discloses synergistic effects of nuclear transcription factor NF- ⁇ B inhibitors and antineoplastic agents in the treatment of cancer.
• NF- ⁇ B inhibitors As an NF- ⁇ B inhibitor CAPE and as an anti-neoplastic agent 5-FU is mentioned.
• 5-FU an anti-neoplastic agent.
• the human breast cancer cell lines MDA-MB 435 and MCF-7 were treated with an NF- ⁇ B inhibitor and an antineoplastic agent.
• WO 2005/105 086 discloses a combination of three drugs TEGAFUR, 2,4-dihydroxy-5-chloropyridine and oxonic acid or a pharmaceutically acceptable salt thereof in a mole ratio of 1 :0.4:1 , which is available as capsules (trade name: S-1).
• SUZUKI IKUKATSU et al. Antitumor and Anticytopenic Effects of Aqueous Extracts of Propolis in Combination with Chemotherapeutic Agents. Cancer Biotherapy&Radiopharmaceuticals. 2002, vol.17, no.5, p.553-562.
• CWSP crude water-soluble propolis
• 5-FU 5-FU
• a pharmaceutical combination of TEGAFUR and CAPE By using a pharmaceutical combination of TEGAFUR and CAPE the following advantageous effects are attained: ⁇ a pharmaceutical combination of TEGAFUR and phenolic compound, like CAPE had high antimetastatic activity in contrast to individual components or pharmaceutical combination of 5-Fu and CAPE at equimolar doses; ⁇ pharmaceutical combination of TEGAFUR and CAPE possessed pronounced synergistic antimetastatic efficacy.
• the unit dosage form is selected according to the purpose of treatment. Examples thereof are oral dosage form such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, etc. These dosage forms can be manufactured by conventional pharmaceutical procedures known in this field.
• the carrier for shaping into the form of tablets there can be employed various excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.; binders such as simple syrup, glucose solution, starch solution, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene-sorbitan fatty acid esters, sodium lauryl sulphate, stearic acid monoglyceride, starch, lactose, etc.; antidisintegrators such as sucrose, stearic acid, cacao butter, hydrogenated oil, etc.; absorption promoters such as quaternary ammonium bases, sodium lauryl sulphate, etc.; humectants such as
• the tablets may be in the form of coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layer tablets, etc.
• the carrier for shaping into the form of pills includes, for example, various excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, gum tragacanth powder, gelatin, etc.; and disintegrators such as laminaran, agar, etc.
• the carrier for shaping into the form of suppositories includes, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.
• Capsules are manufactured by mixing the phenolic compound, like CAPE with
• TEGAFUR TEGAFUR, with any of the carriers mentioned above and encapsulating the mixture in hard gelatin capsule, soft capsule or other capsules.
• a diluent such as, for example, white petrolatum, paraffin, glycerol, cellulose derivatives, polyethylene glycols, silicone, bentonite, etc.
• Example 1 The pharmaceutical activity of orally administrated 5-FU, Tegafur, CAPE and combinations thereof were studied using a spontaneous metastasis model produced by intramuscular injection of Lewis lung carcinoma (LLC) in synergeneic
• LLC Lewis lung carcinoma
• the antitumor activities of 5-FU, Tegafur, CAPE or combinations thereof were determined by their administration to female C57BI/6 mice (weight 19-21 g, age 2 to 2.5 months). Dosage of Tegafur and 5-FU was chosen in suboptimal range as known for 5-FU in ISHIKAWA , T., et al. Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. International Journal of
• mice were randomly divided into 6 groups of 11 mice each: 1 st group: Control group treatment with vehicle, composed of 4.8% ethanol, 7.5%
• 3 rd group TEGAFUR 0.06 mmol/kg in vehicle; 4 th group: CAPE 0.18 mmol/kg and TEGAFUR 0.06 mmol/kg in vehicle.
• Treatment includes oral administration (by probe) of test articles (or their combinations) on 5 consecutive days followed by 2 drug-free-days (5-days-a-week schedule) during 3 weeks (14 administrations) beginning in two days after cancer cells inoculation.
• the size of metastatic nodules and their number on the surface of five lung lobules of each mouse were determined by using a binocular with dimension glass.
• Nonparametric Mann-Whitney U test was used for comparative statistical analysis. A two-tailed p value less than 0.05 was considered as statistically significant.
• the anticancer efficacy of test articles in terms of metastases volume inhibition (MVI) coefficient was calculated using the following formula:
• V met control
• V m et that is the value of metastases volume
• TEGAFUR and CAPE possessed high antimetastatic activity; it inhibited the total volume of metastases by more than 70%.
• Antitumor effect of against LLC could be considered a synergetic one since neither TEGAFUR nor CAPE showed significant antimetastatic efficacy.
• the parenteral solution was prepared according to the above formula.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
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• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Emergency Medicine (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2009
  • 2009-09-15 WO PCT/EP2009/061948 patent/WO2010031766A1/en not_active Ceased
  • 2009-09-15 EP EP09783031A patent/EP2331091A1/de not_active Withdrawn
  • 2009-09-15 GE GEAP200912190A patent/GEP20135872B/en unknown
  • 2009-09-15 UA UAA201103225A patent/UA100294C2/uk unknown
  • 2009-09-15 EA EA201100493A patent/EA019408B1/ru not_active IP Right Cessation

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