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Title:  Mixture of primary fatty acids obtained from sugar cane wax

United States Patent:  6,486,205

Issued:  November 26, 2002

Inventors:  Gonzales Bravo; Luis (Habana, CU); Marrero Delange; David (Habana, CU); Laguna Granja; Abilo (Habana, CU); Mas Ferreiro; Rosa Maria (Habana, CU); de Lourdes Arruzazabala Valmana; Maria (Habana, CU); Carbajal Quintana; Daysi (Habana, CU); Cora Medina; Mirian (Habana, CU); Menendez Soto del Valle; Roberto (Habana, CU)

Assignee:  Laboratorios Dalmer SA (Habana, CU)

Appl. No.:  402292

Filed:  January 19, 2000

PCT Filed:  April 1, 1998

PCT NO:  PCT/IB98/00870

371 Date:  January 19, 2000

102(e) Date:  January 19, 2000

PCT PUB.NO.:  WO98/43631

PCT PUB. Date:  October 8, 1998

Abstract

A new natural mixture of primary fatty acids of high molecular weight ranging from 24 to 38 carbon atoms, especially those ranging between 26 and 36 carbon atoms and more especially those of straight chain of 26, 28, 29, 30, 31, 32, 33, 34, 35 and 36 carbon atoms. This mixture has a relative composition of each fatty acid that is highly reproducible batch to batch and it is extracted from sugar cane (Saccharum officinarum, L.) wax. This mixture of fatty acids has specific pharmacological properties that supports its use as an active component of pharmaceutical formulations used as hypocholesterolemic and against hypercholesterolaemia type II, as antiplatelet, anti-thrombotic and anti-ischemic. This mixture of primary fatty acids is also effective in the inhibition of the development of gastric ulcers induced by different agents.

Description of the Invention

This invention relates to a new mixture of primary fatty acids with straight chains of 26, 28, 29, 30, 31, 32, 33, 34, 35 and 36 carbon atoms. This mixture shows a relative composition of the fatty acids that is highly reproducible from batch to batch and it is extracted from sugar cane (Saccharum officinarum L.) wax, and can be used for the treatment of type II hypercholesterolemia, as antiplatelet agent, as anti-thrombotic, as anti-ischemic agent as well as protective and/or curative agent against gastric ulcers.

There are other mixtures of fatty acids that has reported biological properties, such is the case of the one reported in U.S. Pat. No. 5,284,873 in which is claimed a pharmaceutical composition for combatting prostate affections, in which the active principle is a fraction of fatty acids obtained from the fruits of Sabal Serrulata, with oleic acid as the main one, followed by lauric and palmitic acids, being the one with the greater number of carbon atom eicosenoic. In the U.S. Pat. No. 5,502,045 is claimed a method of reducing the cholesterol levels in serum using an ester formed by a-sitostanol and a 2 fatty acid from 2 to 22 carbon atoms. Also, claims a method of formation of such esters, being the effective daily dose of 0.2 to 20 g of the ester. Although, in the U.S. Pat. No. 5,444,054 is reported a method of treating ulcerative colitis in which one of the fractions used is an oil that contains certain fatty acids from 18 to 22 carbon atoms, but unsaturated. Not close to this patent application are the U.S. Pat. Nos. 4,505,933 and 4,687,783 in which are claimed mixtures of fatty aldehydes derived from fatty acids, for the treatment of patients with multiple sclerosis as well as neurological and dermatological diseases, the inventors claims a daily dose of 100-400 mg/kg of body weight of the patients.

In the last decade, numerous patent have appeared which report the omega-3-poly-unsaturated fatty acids have an effect on serum cholesterol and blood platelet aggregation, such is the case of U.S. Pat. No. 4,526,902 where it is claimed a pharmaceutical composition for the treatment of thrombo-embolic conditions in which the active principle are unsaturated eicosapentaenoic and docohexacnoic fatty acids together with linoleic acid, linolenic acid and its derivatives. Also, in the U.S. Pat. No. 5,502,077 is claimed a composition of fatty acids for the treatment or prophylaxis of multiple risk factors for cardiovascular diseases, where the 80% in weight corresponds with omega-3 fatty acids, its salts or derivatives thereof, being the main ones eicosapentaenoic and docohcxacnoic acids. In EPO patent 0 422 490 A2 it is claimed a pharmaceutical composition for inhibiting the absorption of cholesterol, containing triglycerides formed, preferably, by a mixture of saturated fatty acids from 20 to 24 carbon atoms, but they should be administered in a daily dose of 2 to 10 g. Also, in the Japanese patents 55092316 A and 56115736 A. of Tokiwa Shizeru et al, is reported the demonstration as well as the isolation and purification of an agent for diminishing cholesterol composed by a mixture of highly unsaturated fatty acids, especially eicosatrienoic and docosatertraenoicacids. In other Japanese patents (publication # 1290625 A, 02053724 A, 02243622 A and 04169524 A) claimed different pharmaceutical formulations, such as an improver of cerebral function or for the treatment of degenerative disease, or for lowering cholesterol in blood and for having Serum lipid-improving activity in which are presents as active principle, mixtures of fatty acids, especially eicosapentaenoic and docosahexacnoic acids, in a daily dose that varies from 500 mg/kg of body weight to 0.5-30 g.

As it has been shown, these patents claims mixture of fatty acid with specific biological properties, some of them closely related with the ones claimed in the present patent application. But, the composition of these mixtures significantly differs from the one claimed in these patent application and, also, the proposed daily dose to be used in these treatments in higher than the one claimed in the present patent application.

The present invention is related mainly with the pharmaceutical industry, particularly with the development of pharmaceutical formulations with specific properties, because them could be used as hypocholesterolaemic and hypolypoproteinaemic, anti-platelet anti-thrombotic, anti-ischemic drugs as well as in the prevention of gastric and duodenal ulcers induced by different agents.

These formulations contains, as active principle, a natural mixture of primary fatty acids of high molecular weight ranging from 24 to 38 carbon atoms, especially those ranging from 26 to 36 carbon atoms and more especially those of straight chain of 26, 28,29,30,31,32,33,34,35 and 36 carbon atoms, obtained from sugar cane wax (named MFASCW).

Drugs with specific pharmacological properties, based in the uses of primary fatty acids of high molecular weight (from 26 to 36 carbon atoms) obtained from, vegetable or animal waxes as active principles has not been reported previously, but it is known that primary fatty alcohols of high molecular weight obtained from sugar cave wax shows the same pharmacological properties. In EPO patent 0 488 928 A2 is claimed a mixture of fatty alcohols of high molecular weight for the treatment of hypercholesterolaemia and hyperlypoproteinaemia, type II that., also, in patent WO 94/07830 is claimed the use of the same mixture as antiplatelet agent, anti-ischemic, anti-thrombotic as well as in the prevention of gastric and duodenal ulcers induced by different agents.

The procedure for the obtention of this mixture of primary fatty acids of high molecular weight in the present invention is based in an homogeneous saponification of sugar cane wax with concentrated solutions of alkaline and earth-alkaline hydroxides, especially those of low molecular weight and more especially those of sodium, potassium and calcium. The concentration of the alkaline solution must be such that the ratio in weight of the corresponding hydroxide with that of the wax to be processed must be over 5% on, especially from 8 to 25% and more specifically from 15 to 25%. Saponification process lasts for a period over 30 min and more especially between 1 to 5 hours. The solid, obtained in this step, is processed using a conventional solid-liquid extractor, where the M.F.A.S.C.W., in salt form, is isolated from the rest of the components by extracting these components using the adequate organic solvent choose among ketones from 3 to 8 carbon atoms, alcohols from 1 to 5 carbon atoms, hydrocarbons from 5 to 8 carbon atoms, haloforms as well as aromatic compounds including mixtures of them. Some preferred solvents used in the present invention are the following: acetone, methyl-ethyl ketone, pentanone, hexanone, terbutanol, ethanol, methanol, 2-propanol, butanol, hexane, pentane, isopentane, ciclohexane, heptane, chloroform, 1,2 dichloroethane, dichloromethane, trichloroethane, trichloromethane, 1,2,3 trichloropropane, benzene, toluene, phenol, p-methyl toluene and others.

The mixture of primary fatty acids of high molecular weight in salt form is purified by succesive recristalizations in an adequate organic solvents or in aqueous solutions, choosen among ketones from 3 to 8 carbon atoms, alcohols from 1 to 5 carbon atoms, hydrocarbons from 5 to 8 carbon atoms, as well as aromatic compounds, including mixtures of them. Some preferred solvents used in this step of the process acetone, methyl-ethyl ketone, pentanone, hexanone, terbutanol, ethanol, methanol, 2-propanol, butanol, hexane, pentane, heptane, octane, ciclohexane, benzene, toluene, phenol, p-methyl toluene and water between others.

An step in the purification of this mixture of primary fatty acids of high molecular weight consist in refluxing the components in an adequate organic solvent, choose among ketones from 3 to 8 carbon atoms, alcohols from 1 to 5 carbon atoms, hydrocarbons from 5 to 8 carbon atoms as well as aromatic compounds including mixtures of them and, immediately, hot filtering the fatty acids salts.

In the final step of this process the free fatty acids are regenerated using an acid solution, that could be prepared using mineral acids and/or organic acids to be choose among hydrochloric acid, sulphuric acid, nitric acid, perchloric acid, acetic acid and oxalic acid among others. The yield of fatty acid is between 10 to 40%, while the purity of the M.F.A.S.C.W. is in the general range from 85 to 100%, more especially between 90 to 99%, determined using gas chromatography and/or volumetric chemical analysis.

The M.F.A.S.C.W. obtained in the present invention is a mixture of primary fatty acids of high molecular weight ranging from 26 to 36 carbon atoms, more especially the one of 26, 28, 29, 30, 31, 32, 33, 34, 35 and 36 carbon atoms. In Table I is reported the qualitative and quantitative composition of this M.F.A.S.C.W.

 

                             TABLE I
    Qualitative and quantitative composition of the M.F.A.S.C.W.
          Component             Percent in the mixture (%)
          1-hexacosanoic                  0.3-1.5
          1-octacosanoic                 25.0-50.0
          1-nonacosanoic                  1.0-3.0
          1-triacontanoic                15.0-30.0
          1-hentriacontanoic               0.8-3.0
          1-dotriacontanoic              10.0-22.0
          1-tritriacontanoic               1.0-3.0
          1-tetratriacontanoic              10.0-22.0
          1-pentatriacontanoic               0.5-1.5
          1-hexatriacontanoic               2.0-9.0



The daily dose of M.F.A.S.C.W. to be used for the treatment of the different diseases has been established between 1 to 100 mg per day and the most adequate route of administration is oral solid dosage-form such as tablets, gragees or capsules. Also, this drug could be administered orally or parenterally or topically considering the uses claimed in the present invention.

The pharmaceutical formulation, used in the oral route contains as active principle from 0.5 to 25.0% in weight of M.F.A.S.C.W. This dose is obtained by mixing M.F.A.S.C.W. with different excipients such as disintegrators, agglutinants, lubricants, sliders or just fillers.

One of the objects of the present invention is to isolate and purify the natural mixture of primary fatty acis with high molecular weight ranging from 26 to 36 carbon atoms from sugar cane wax, especially the mixture of straight chain fatty acids of 26, 28, 29, 30, 31, 32, 33, 34, 35 and 36 carbon atoms.

Other of the objects of this invention is to use this natural mixture of fatty acids, in relatively low doses, as a component of pharmaceutical formulations used as hypocholesterolemic and hypolipidaemic drugs. Also, one of the objects of the present invention is the development of pharmaceutical formulations that contains M.F.A.S.C.W. as active principle in order to be used as anti-ischemic and anti-thrombotic drugs, administered orally, topically or parenterally.

Finally, in a whole picture of M.F.A.S.C.W. profile, and proposed as active principle for pharmaceutical formulations, this mixture is innocuos, and very well tolerated, representing an important advantage. Thus, results obtained in toxicological assays carried out in rodents report absence of toxicity related with the M.F.A.S.C.W.. No side effects have been detected in subjects treated with the product which is object of the present invention.

Claim 1 of 19 Claims

What is claimed is:

1. A pharmaceutically beneficial composition of primary fatty acids consisting of a mixture of:

(a) 1-hexacosanoic acid;

(b) 1-octacosanoic acid;

(c) 1-nonacosanoic acid;

(d) 1-triacontanoic acid;

(e) 1-hentriacontanoic acid;

(f) 1-dotriacontanoic acid;

(g) 1-tritriacontanoic acid;

(h) 1-tetratriacontanoic acid;

(i) 1-pentatriacontanoic acid; and,

(j) 1-hexatriacontanoic acid;

wherein said pharmaceutically beneficial composition of primary fatty acids are a natural mixture obtained from a homogeneous saponification of sugar cane wax and substantially free of other fatty acids having 24 to 38 carbon atoms.
 


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