US20080207947A1 - Use Of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases - Google Patents

Use Of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases Download PDF

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Publication number
US20080207947A1
US20080207947A1 US11/913,994 US91399406A US2008207947A1 US 20080207947 A1 US20080207947 A1 US 20080207947A1 US 91399406 A US91399406 A US 91399406A US 2008207947 A1 US2008207947 A1 US 2008207947A1
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oil
use according
dha
weight
pharmaceutical composition
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Joan Carles Domingo Pedrol
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Brudy Technology SL
PROTECTO EMPRESARIAL BRUNDY SL
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PROTECTO EMPRESARIAL BRUNDY SL
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Assigned to PROYECTO EMPRESARIAL BRUNDY, S.L. reassignment PROYECTO EMPRESARIAL BRUNDY, S.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DOMINGO PEDROL, JOAN CARLES
Publication of US20080207947A1 publication Critical patent/US20080207947A1/en
Assigned to PROYECTO EMPRESARIAL BRUDY, S.L. reassignment PROYECTO EMPRESARIAL BRUDY, S.L. CORRECTIVE ASSIGNMENT TO CORRECT THE SPELLING OF NAME OF ASSIGNEE PREVIOUSLY RECORDED ON REEL 020094 FRAME 0611. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST. Assignors: DOMINGO PEDROL, JOAN CARLES
Assigned to BRUDY TECHNOLOGY, S.L. reassignment BRUDY TECHNOLOGY, S.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PROYECTO EMPRESARIAL BRUDY, S.L.
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to use of an acid enriched in docosahexaenoic acid for manufacturing a drug for the treatment of a tumorous disease.
  • omega-3 fatty acids and especially the long-chain polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present in fish and in oils derived therefrom inhibit carcinogenesis and show potential anti-tumour activity.
  • PUFAs long-chain polyunsaturated fatty acids
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the omega-3 PUFAs principally DHA, reduce the growth of various types of tumorous cells, including breast, bowel, pancreas, and in chronic myeloid leukaemia and melanoma.
  • omega-3 PUFAs selectively inhibit the proliferation of tumorous cells, being less toxic towards normal cells. This different sensitivity to the omega-3 PUFAs cannot be explained simply by differences in the take-up of fatty acids.
  • Various mechanisms have been proposed by which the omega-3 fatty acids might alter the carcinogenic process, notably the following: suppression of biosynthesis of eicosanoids deriving from arachidonic acid (ARA); alterations in the activity of transcription factors, regulation of gene expression and intracellular marking; alteration of oestrogen metabolism; alteration of the generation of free radicals and reactive oxygen species and modifications in membrane fluidity.
  • ARA arachidonic acid
  • the ARA-derived eicosanoids have been associated with tumour development.
  • the omega-3 PUFAs compete with the omega-6 PUFAs as substrates of the desaturases and elongases, the omega-3 PUFAs having greater affinity for said enzymes.
  • the omega-3 fatty acids inhibit cycloxygenase-2 at transcriptional level and compete with the omega-6 fatty acids as substrates of the cycloxygenases in formation of the eicosanoids.
  • omega-3 PUFAs and their metabolytes can exercise some of their anti-tumour effects by affecting the expression of various genes or the activities of the signal-transmission molecules involved in controlling growth, differentiation, cellular apoptosis, angiogenesis and metastasis.
  • the most important are the activated receptor of peroxysomal proliferation, that of nuclear transcription factor KB, the ras oncogene, protein kinase C, co-enzyme-A-3-hydroxyl-3-methylglutaril reductase, cycloxygenase-2, lipoxygenases and the nitric oxide synthase. It has been shown that the treatment of colon carcinoma cells with DHA alters the characteristics of the cellular membrane and reduce its metastasic capacity.
  • tumour cells have a deficit of anti-oxidant defense systems in comparison with the healthy cells and are thus more susceptible to oxidation damage.
  • the PUFAs are the main intracellular substrates in lipid peroxidation, whether it be by causing damage to the cell membranes, altering cellular composition or the assembly of the cytoskeleton, altering the membrane transport systems or the activity of their enzymes, or inhibiting the reactions of the polymerase. It is therefore reasonable to consider the DHA-enriched cells of the tumour as being more susceptible to oxidative damage.
  • omega-3 fatty acids have an effect on the cell cycle.
  • DHA In vitro treatment with DHA leads to a stoppage in the G 1 /S or G 2 /M phase during the cell cycle in tumorous cells of breast and melanoma.
  • the administration of fish oil rich in omega-3 to rats implanted with a breast tumorous line can prolong replication of the DNA of the tumorous cells thereby delaying progression through the synthesis phase.
  • omega-3 PUFAs can increase the cytotoxicity of several anti-neoplasic agents and the anti-carcinogenic effects of radiotherapy. These effects are possibly mediated by incorporation of the fatty acids into the tumour cell membranes, thus altering physical and functional characteristics.
  • the therapeutic efficacy achieved depends on several factors, such as the bioavailability of the fatty acid, which is in turn related with the chemical structure of which it forms part, the type of omega-3 PUFA used (ALA, EPA or DHA) and the interaction availability between the PUFA and the target cell.
  • omega-3 PUFA used ALA, EPA or DHA
  • DHA is the omega-3 PUFA that provides most effective anti-tumour protection, exceeding that of EPA. This result has also been confirmed in combined EPA+DHA anti-tumour treatments, where the presence of EPA has been observed to diminish the efficacy of the DHA.
  • intratumour administration is the preferred route for the treatment of gliomas. It is essential in this respect that the PUFAs be administered to the patients in such a way as to be easily taken up by the tumorous cells.
  • parenteral administration for example, which is suitable for the treatment of hepatomas, it is essential to have a carrier system such as an emulsion with the additional objective of limiting bonding of the PUFAs to the serum albumin that suppresses their tumour cytotoxicity.
  • a carrier system such as an emulsion with the additional objective of limiting bonding of the PUFAs to the serum albumin that suppresses their tumour cytotoxicity.
  • oral administration suitable for the treatment of lymphomas, following processing and intestinal absorption the PUFAs are transported to the target tissue incorporated into the kilomicrons in the form of triglycerides.
  • the present invention concerns the unexpected discovery that oils with a high content of DHA incorporated into a glyceride, in particular with a content exceeding 50% by weight, present an anti-tumour efficacy greater than the same concentration of DHA in any other chemical form.
  • An object of the present invention is therefore the use of an oil enriched in docosahexaenoic acid (hereinafter also referred to as “DHA”) which is incorporated into a glyceride, for manufacturing a pharmaceutical composition for the treatment of a tumorous disease, with said oil being enriched by a concentration of up to 70% by weight in relation to the total weight of said pharmaceutical composition and with said docosahexaenoic acid being incorporated into a glyceride in a percentage of at least 50% by weight in relation to the total fatty acids in said oil.
  • DHA docosahexaenoic acid
  • oil enriched in docosahexaenoic acid means natural or synthetic derivatives of glycerol containing 50-100% by weight of the docasohexaenoyl group based on the total content of fatty acids.
  • docosahexaenoic acid incorporated into a glyceride is taken to mean a glycerol with the three positions esterified with docosahexaenoic acid.
  • the expression “up to 70% by weight of said enriched oil” means that 70% of the total weight of the pharmaceutical composition corresponds to the DHA-enriched oil.
  • the expression “at least 50% in relation to the total fatty acids” means that the DHA represents at least 50% by weight of the total fatty acids of said enriched oil.
  • the inventors of the present invention have found that using an amount of at least 50% of DHA doubles or even quintuples the anti-tumour effect of said DHA, thereby achieving a high specific tumourous cytotoxic activity without the existence of side-effects.
  • said pharmaceutical composition is in emulsion form.
  • the emulsions can be prepared under apyrogenic and sterile conditions with sufficient physical and chemical stability for administration thereof, including parenteral administration, by means of methods well-known to an expert in the art.
  • the mean diameter of the microemulsion is less than 200 nm.
  • this mean diameter permits parenteral application, thereby administering an effective dose of DHA greater than that obtained by oral administration, and therefore increasing the bioavailability of said acid. This is due to avoiding the loss inherent to intestinal absorption. Furthermore, high concentrations of DHA can be administered by the parenteral route.
  • said pharmaceutical composition in emulsion form is administered by parenteral route.
  • the doses to be administered depend on the type and severity of the pathology to be treated, and there are no dietary restrictions (interactions with foods).
  • the emulsions of the invention can also be administered orally, sublingually, intravenously, intramuscularly, topically, subcutaneously, rectally or even simply by bringing the active ingredient of the emulsion of the invention into contact with the olfactory organs situated at the entrance to the airways in liquid or vapour form. Administration can thus be carried out by spraying, nebulising or atomising the emulsions or by inhalation.
  • said pharmaceutical composition is administered by intramuscular injection.
  • said DHA-enriched oil also includes ecosapentaenoic acid (also referred to as EPA) in a percentage by weight of up to 30% in relation to the total fatty acids in said oil.
  • ecosapentaenoic acid also referred to as EPA
  • the concentration of DHA-enriched oil is in the range of 10-70%, preferably in the range of 10-30% in relation to the total weight of the pharmaceutical composition.
  • the percentage by weight of DHA in relation to the total weight of fatty acids of said enriched oil ranges between 50-100%, preferably between 70 and 90%, and more preferably said percentage by weight of DHA is 70%.
  • the inventors of the present invention have further found that when a pharmaceutical composition in accordance with the present invention is administered, there are no interactions with the components of the anti-neoplasic regime being administered to the patient, since said composition is not metabolised in pathways common to those of metabolisation of the anti-neoplasic drugs.
  • said composition is administered concomitantly with at least one anti-neoplasic drug.
  • anti-neoplasic drug is taken to mean an active ingredient or drug designed for the treatment of a pathology of tumorous or cancerous origin.
  • the invention relates to a stable, non-detergent composition in microemulsion form for administration to human beings, comprising:
  • the initial emulsion is homogenised repeatedly at high pressure to a suitable size and the pH is adjusted to a hysiological value (between 6.5-7) with sodium hydroxide (Sigma & Aldrich). Once adjusted to the final volume, the microemulsion is sterilised by filtration (0.22 ⁇ m, Millipore) in its definitive glass receptacle.
  • KG-1a cells derived from an acute myeloid leukaemia which are moreover MDR+, ATCC CCL-246.1
  • Jurkat cells derived from an acute type-T lymphoma, TIB-152
  • HeLa and KB3.1 cells derived from a human epithelial carcinoma, CCL-2
  • HT-29 cells derived from a human colon tumour, HTB-38
  • 435 cells derived from a human breast tumour, MDA-MB-435
  • SH-SY5Y cells derived from a human neuroblastoma, CRL-2266
  • NP-18 cells derived from a human pancreal tumour.
  • the non-tumorous model used was Foreskin cells (non-differentiated epidermis fibroblasts, CRL-1635) and REPTC cells (renal proximal tubule cells, DPK-KTEC-H). All the cellular lines ere obtained from the American Type Culture Collection, except for the NP-18 cells which were ceded by the Merck Pharm and Chemistry Bioresearch Laboratory and the REPTCs which were acquired from Dominion Pharmakine. The cell cultures were kept under suitable growth conditions: temperature (37° C.), CO 2 concentration (5%) and humidity (95%) in a special incubator for this purpose. The cells were kept growing in culture bottles, but were transferred to 96-well plates to allow the experiment to be carried out.
  • This method consists of adding the MTT reagent (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide), Sigma & Aldrich), soluble in aqueous medium, to the incubation medium.
  • the viable cells metabolise this compound and it is converted into formazan salt.
  • This salt is a calorimetric compound insoluble in aqueous medium, soluble in DMSO and usable as a measure of cell viability.
  • the method consists of adding 20 ⁇ l per well of an MTT solution of 7.5 mg/ml (in excess). It is incubated for one hour at 37° C.
  • IC 50 defined as the concentration of DHA necessary to reduce the viability of the culture to 50% in relation to control.
  • the first aspect to be studied to determine the action of the DHA as an anti-tumour agent is the specificity of its cytotoxic activity.
  • the model used was little-differentiated Foreskin cells and human renal proximal tubule cells (RPTEC), and the results obtained are shown in Table 1.
  • the cytotoxicity of the product resides in the presence of DHA, since a reduction of the proportion of said acid reduces the cytotoxic power (compare the results of TG-70, TG-50 and TG-20), with the threshold concentration necessary to obtain a therapeutic development being estimated as at least a 50% of content in DHA, although an optimum therapeutic effect is achieved with a DHA concentration of 70%.
  • the second aspect studied was the applicability spectrum of the DHA as an anti-tumour drug, with its chemical structure and the nature of the pathological process at which it is directed being deemed as variables, and maintaining the DHA content at 70%.
  • the results obtained are shown in Table 2.
  • cytotoxic potency which follows the order TG>FA>EE in all the models used, interdependently of their origin. From the results obtained we might stress, firstly, the greater sensitivity to the DHA (5-8 times greater) for tumorous processes of a haematological nature (Jurkat and KG-1a) as against the solid tumours (the rest). As an exception that confirms the rule, great sensitivity is observed in cells derived from a pancreatic tumour (NP18).
  • cytotoxicity of the microemulsions is very much greater in a tumorous line (HeLa cells) than in a normal one (Foreskin cells), depending directly on the concentration of DHA in the glyceride. Moreover, the toxicity observed is attributable solely to the DHA and not to the carrier system (emulsion), since an emulsion of the same characteristics prepared with an oleic acid triglyceride is entirely innocuous.
  • the cytotoxic efficacy of the DHA microemulsions against the different tumorous lines was also analysed, and the results obtained are shown in Table 4, using once again as control a microemulsion of oleic acid prepared under the same conditions as the DHA microemulsion.
  • the results obtained confirm that the emulsions of DHA are at least as effective in their anti-tumour activity as DHA incorporated into a free glyceride.
  • the efficacy is 1.5-3 times greater.
  • the non-toxicity of the carrier system (emulsion) is likewise confirmed, since an emulsion of the same characteristics prepared with an oleic acid triglyceride is entirely innocuous.

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US11/913,994 2005-05-12 2006-04-26 Use Of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases Abandoned US20080207947A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ESP-200501141 2005-05-12
ES200501141A ES2264886B1 (es) 2005-05-12 2005-05-12 Utilizacion de acido docosahexaenoico para el tratamiento de enfermedades tumorales.
PCT/EP2006/061833 WO2006120120A1 (en) 2005-05-12 2006-04-26 Use of docosahexaenoic glycerides for the treatment of tumorous diseases

Related Parent Applications (2)

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PCT/EP2006/061833 A-371-Of-International WO2006120120A1 (en) 2005-05-12 2006-04-26 Use of docosahexaenoic glycerides for the treatment of tumorous diseases
PCT/EP2006/061844 A-371-Of-International WO2006114429A2 (de) 2005-04-27 2006-04-26 Kunststoffgegenstände zur metallisierung mit verbesserten formgebungseigenschaften

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US12/550,780 Continuation US9271954B2 (en) 2005-05-12 2009-08-31 Use of docosahexaenoic glycerides for the treatment of tumorous diseases

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US11/913,994 Abandoned US20080207947A1 (en) 2005-05-12 2006-04-26 Use Of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases
US12/550,780 Active US9271954B2 (en) 2005-05-12 2009-08-31 Use of docosahexaenoic glycerides for the treatment of tumorous diseases
US15/005,181 Abandoned US20170333381A9 (en) 2005-05-12 2016-01-25 Use of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases

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US12/550,780 Active US9271954B2 (en) 2005-05-12 2009-08-31 Use of docosahexaenoic glycerides for the treatment of tumorous diseases
US15/005,181 Abandoned US20170333381A9 (en) 2005-05-12 2016-01-25 Use of Docosahexaenoic Glycerides For The Treatment Of Tumorous Diseases

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US (3) US20080207947A1 (no)
EP (1) EP1881824B1 (no)
JP (2) JP5893235B2 (no)
CA (1) CA2614192C (no)
DK (1) DK1881824T3 (no)
ES (2) ES2264886B1 (no)
HK (1) HK1113319A1 (no)
IL (1) IL187274A (no)
NO (1) NO336953B1 (no)
NZ (1) NZ563301A (no)
PL (1) PL1881824T3 (no)
PT (1) PT1881824E (no)
WO (1) WO2006120120A1 (no)

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ES2264886B1 (es) * 2005-05-12 2008-02-01 Proyecto Empresarial Brudy, S.L. Utilizacion de acido docosahexaenoico para el tratamiento de enfermedades tumorales.
CA2614473C (en) * 2005-07-08 2016-05-03 Martek Biosciences Corporation Polyunsaturated fatty acids for treatment of dementia and pre-dementia-related conditions
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ES2277557B1 (es) 2005-12-21 2008-07-01 Proyecto Empresarial Brudy, S.L. Utilizacion de acido docosahexaenoico para el tratamiento del daño celular oxidativo.
US8343753B2 (en) 2007-11-01 2013-01-01 Wake Forest University School Of Medicine Compositions, methods, and kits for polyunsaturated fatty acids from microalgae
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EP2599485B1 (en) * 2010-07-26 2019-02-20 FUJIFILM Corporation Fat-containing composition and oral formulation containing same
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KR101665253B1 (ko) 2015-06-19 2016-10-25 순천향대학교 산학협력단 도코사헥사에노산 및 트리아신 씨를 포함하는 것을 특징으로 하는 자궁내막암 치료 및 예방용 조성물

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EP1881824A1 (en) 2008-01-30
PT1881824E (pt) 2015-03-26
NO336953B1 (no) 2015-11-30
DK1881824T3 (en) 2015-02-23
NZ563301A (en) 2010-08-27
CA2614192A1 (en) 2006-11-16
JP5893235B2 (ja) 2016-03-23
US9271954B2 (en) 2016-03-01
JP6038841B2 (ja) 2016-12-07
ES2264886A1 (es) 2007-01-16
IL187274A (en) 2011-11-30
JP2008540484A (ja) 2008-11-20
CA2614192C (en) 2014-03-18
ES2264886B1 (es) 2008-02-01
NO20076382L (no) 2008-02-08
JP2014208677A (ja) 2014-11-06
IL187274A0 (en) 2008-06-05
EP1881824B1 (en) 2014-12-24
HK1113319A1 (en) 2008-10-03
US20160193175A1 (en) 2016-07-07
US20090318553A1 (en) 2009-12-24
PL1881824T3 (pl) 2015-06-30
WO2006120120A1 (en) 2006-11-16
US20170333381A9 (en) 2017-11-23
ES2531599T3 (es) 2015-03-17

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