AU611204B2

AU611204B2 - Treatment of lipoprotein disorders associated with cholesterol metabolism

Info

Publication number: AU611204B2
Application number: AU23433/88A
Authority: AU
Inventors: Manfred Berger; Daniele Spielmann; Helmut Traitler
Original assignee: Societe des Produits Nestle SA; Nestle SA
Current assignee: Societe des Produits Nestle SA
Priority date: 1987-10-16
Filing date: 1988-10-05
Publication date: 1991-06-06
Anticipated expiration: 2008-10-05
Also published as: JPH075471B2; JPH01132530A; DE3868827D1; EP0311866B1; ES2036650T3; IE61682B1; EP0311866A1; CA1314229C; AU2343388A; GR3003990T3; IE882989L; CH673223A5; ATE72987T1

Abstract

Blackcurrant seed oil has been found particularly effective in the treatment of lipoprotein anomalies linked to cholesterol metabolism. Its administration makes it possible to increase significantly the cholesterol in high-density lipoproteins while reducing cholesterol in low-density lipoproteins, and thus reduces the cardiovascular risk.

Description

:'-...~=arnu=irnruL-- COMMONWEALTH OF AUSTRALIA FORM PATENTS ACT 1952 r0 M P T, F T I RP T F T r T T N R QIF AT1 FOR OFFICE USE: Class Int.Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: &Z 1' 0 priority: .eiLated Art: *0:

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S'Nne of Applicant: *.Ad.dress of Applicant: Actual Inventor: SOCIETE DES PRODUITS NESTLE S.A.

Vevey, Switzerland Manfred Berger, Daniele Spielmann, and Helmut Traitler ease *:'AQlress for Service: SHELSTON WATERS, 55 Clarence Street, Sydney :.:Complete Specification for the Invention entitled: "TREATMENT OF LIPOPROTEIN DISORDERS ASSOCIATED WITH CHOLESTEROL METABOLISM" The following statement is a full description of this invention, including the best method of performing it known to us:- 1 Fee: $145.00 I la- Treatment of lipoprotein disorders associated with cholesterol metabolism 1 This invention relates to the use of a lipid of the blackcurrant in the treatment of lipoprotein disorders associated with cholesterol metabolism.

Lipids circulate in the blood in the form of lipoproteins soluble in aqueous medium which consist of a lipidic nucleus of cholesterol esterified by fatty acids and triglycerides surrounded by a layer of proteins, phospholipids and free cholesterol. The arrangement of the various components.characterizes the type of lipoprotein. Numerous :0 epidemiological studies have demonstrated the preponderant role played by the lipoproteins in the development of atherosclerosis.

In simple terms, it is known that certain lipoproteins, known as low-density lipoproteins (LDL) represent a cardiovascular risk factor because there is a positive correlation between their presence at high levels in the bloodstream and 0* atherosclerosis. By contrast, high-density lipoproteins (HDL.) represent an anti-cardiovacular risk factor because there is a negative correlation between their levels and the disease. There is thus a "good cholesterol" transported by the HDL which drain the cholesterol from the arterial wall and return it to the liver where it is catabolized. By contrast, the LDL deposit the cholesterol on the arterial wall.

It is known that oils rich in polyunsaturated fatty acids have the effect of reducing the total plasmatic cholesterol level However, studies have shown that the fall in the TC is due either to a concomitant reduction in the cholesterol of the LDL (CLDL) and the cholesterol of the HDL (CHDL) or to a reduction in the CLDL with no modification of the CHDL. According to D.V. Horrobin et al in Lipids, Vol. 18, No. 8, pages 558-561, this last case i- _L I C E form for guidance in ne Applicant would be entitled to have the patent assigned to completngthis part it if a patent were granted to the actual inventors 4. The basic Application(s) referred to in paragraph 2 of this Declaration was/were the first Application(s) made in a Convention country In respect of the invention, the subject of the Application.

DECLAREDat y Switzerland DECLARED at and this day of p e tember... 19 88 h) Personal Signature of Declarant no seal, 2 would be that of evening primrose oil.

We have surprisingly found that the administration of blackcurrant seed oil produced a reduction in the CLDL while significantly increasing the CHDL.

Accordingly, the present invention relates to a method for treating lipoprotein disorders associated with cholesterol metabolism in a mammal which comprises the step of administering a pharmaceutically effective amount of a composition comprising a lipid of blackcurrant in combination with a pharmaceutically acceptable carrier to a mammal in need thereof.

In the context of the invention, lipoprotein disorders associated with cholesterol metabolism are understood to include: essential hypercholesterolemia (type IIa) characterized by a normal triglyceride level an increase in the TC corresponding to an increase in the CLDL and to a reduction in, or normal level of, the CHDL, mixed hyperlipidemia (type IIb) characterized by an increase in, or normal level of, the TG, an increase in, or normal level of, the TC corresponding to an increase in the CLDL and to a reduction in the CHDL, dys-beta-lipoproteinemia (type III) characterized by o* an increase the TG and in the TC, the latter being distinctly less frequent than the other two, the anomaly corresponding to a low level of HDL.

In the context of the invention, lipid of the blackcurrant is understood to be i i- the oil of blackcurrant seeds (Ribes nigrum) obtained by extraction from blackcurrant residues and refining, for example as described in European patent 92 085 or European patent application 137 862, a mixture of fatty acids emanating from the hydrolysis or fractionation of blackcurrant seed oil and obtained, for example, in accordance with European patent application no. 178 442 or in accordance with European patent application 271 747.

a pharmaceutically acceptable salt of the fatty acids 1 I r 3 1 mentioned above, an oil obtained by re-esterification of such a mixture of fatty acids with glycerol, a mixture of the lipids mentioned above.

The blackcurrant lipid may advantageously be protected against oxidation by a liposoluble antioxidant, for example ascorbyl palmitate, tocopherols or a mixture of such antioxidants.

The dietetic compositions may be formulated as emulsions, for example sauces, mayonnaises or margarines.

The pharmaceutical compositions may be made up in S various forms according to the method of administration, for example oral, enteral, rectal or parenteral. For example, it is possible to prepare capsules, gelatin-coated :S~:.-tablets, suppositories or syrups. In the case of enteral or parenteral administration, the compositions are formulated m@ as physically and chemically stabilized, apyrogenic and sterile solutions or emulsions.

The dose administered depends upon the type and serious- 2. ness of the anomaly to be treated. It may comprise from 1 to 25 g blackcurrant lipid and preferably from 2 to 5 g blackcurrant oil daily in a single dose or preferably in two to three separate doses.

The invention is illustrated by the following Example t in which the parts and percentages are by weight, unless otherwise indicated.

Example Experimental conditions Patients having an initial TC level of more than 300 mg/dl are treated for 12 weeks with an average daily dose of six gelatin capsules containing either 450 mg blackcurrant seed oil BCO') and 200 ppm (parts per million) ascorbyl palmitate or 450 mg grapeseed oil (GSO) and 200 ppm ascorbyl palmitate.

BCOconsists of triglycerides of the following fatty 4 I acids (by weight): linoleic acid, C 1 8:2,n-6 gamma-linolenic acid, C18:3,n-6 17% with 38% in the beta-position alpha-linolenic acid, C1 8 3 n-3 13% with 17% in the beta-position S stearidonic acid, C 18 :4 n- with 32% in the beta-position 0*e3 Gamma-linolenic acid is the reaction product of delta-6desaturase with linoleic acid.

Stearidonic acid is the reaction product of delta-Sdesaturase with alpha-linolenic acid.

GSO contains approximately 70% by weight linoleic acid, 1 to 2% by weight alpha-linolenic acid, but no gammalinolenic acid or stearidonic acid.

All the patients were given an information sheet of dietetic recommendations.

The group receiving the BCO consisted of 5 patients comprising 3 females and 2 males with an average age of 61 years (from 36 to 76). The group receiving the GSO consisted of 7 patients, 4 females and 3 males, with an average age of 55 years (from 48 to 62). In the two groups, the initial TC was similar. In the two groups, the majority of patients were of the IIb type defined above.

Blood samples were taken at intervals of 0, 4, 8 and 12 weeks for analysis of the parameters.

Results Table 1 below shows the mean values of the parameters indicated and the standard deviations (SD) for each visit and the probability of the statistical test (T test) 1. -r 1 -r 1 5 1 for the two groups. The T test provides an answer to the question: is there any difference between the means of the groups studied and that for each visit? The significant cases (probability 0.05) are underlined.

The TC (mg/dl) is measured enzymatically from the serum by colorimetry using the enzymes cholesterolesterase, cholesteroloxidase and the indicator 4-aminophenazine.

The CHDL (mg/dl) is measured in the same way as the TC on the fraction containing the HDL collected after ultracentrifugation of the serum at 12,000 r.p.m.

The CLDL (mg/dl) is deduced from the value of the CHDL in accordance with Friedewald and Fredrickson.

see

V*%

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•e 0 e *oS *See e Table I GROUPS CT CHLCLDL 12 0" 4 8 112 0 4 a 12 1 309.20 293,40 279,20 261.00"~ 42.80 50M0 56.40 61.40,- 270.20 260.00 234.20 206.60 BCO UI -SO 51, 4.49 3.94 6.27 9.57" 1.91 2.04 1.92 1.43: 13,73 12.30 14.21 17.82

GSO

7 SD 7 I Is 304.43 4.63 295.00 298.43 293.71:11 40.86

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7.12 6.27 9.57i 1.91 11 39.71 42.71 39.57:1 276.57 2,04 1.92 1,4311 13.73 273.00 267.14 271.28 12.29 14,21 17.82 Probability 11 0,492 0,865 0,079 0.033 a' 0,526 0,130 0.029 0,001,, 0,790 0,593 0,191 0.021 0 0 *0 4 a 0 0 0 a 0 a 0 sf0 0 4 4 4 a 0 C S .0= 'C 4 0 0 0 0 0

A

-7- I Table 2 relates to the probabilities of the paired T tests between the visits V 4

V

8

V

12 and V o The object of these statistical tests is to find the differences between the visit V 0 and the successive visits V 4

V

8 and V 12 for each group taken separately, i.e. the evolution of the phenomenon as a function of time. Once again the significant cases are underlined (probability 0.05).

4 I 9 VP V Table 2 ECO GROUP P ar'ameters CHDL CLDL Between visits V -V V -V -i"V V V -V V -V V to 4 0 8% V 1 2 0 4 0 8 0 12 V4 o V8- V1a V It If GSQ GROUP ProbabilPity in=7 0.045 0.219 0.143:: lb 0.030 0.40 0.33: 0.303 0.028 0.393 If a a a a *aa ease a a a 3 a a a a a a a 5 @9 a a e.g a a a a a a a a a a a a a a a a a a aaa a a a a a a a a a a a a a.

a. a. a a a aaa 9 1 Table 3 below studies the CLDL ratio known as the

CHDL

"standard atherogenicity risk" and the probabilities of the T test. Table 4 below shows the probabilities of the paired T tests. The significant cases are underlined.

Table 3 Groups CLDL/CHDL n 0 4 8 12 5X 5 6.34 5.63 4.24 3.48 BCO SD "5 0.44 0.95 0.34 0.38 44 *4 II 5 7 6.85 6.97 6.35 6.93

II

i5 GSO SD !7 0.45 0.42 0.49 0.56 4 *4 Probability 0.445 0.184 0.010 0.010 ,4 Table 4 BCO group Between visits V 4 aV o

V

8

V

o

V

12

-V

o 444 II Probability iin=5 0.259 <0.001 <0.001 GSO group Probability nn7 0.298 0.155 0.740 Conclusions In the BCO group, the mean of the CHDL increased distinctly the means of the CLDL and the TC decreased and respectively) and the mean of the standard atherogenicity risk factor decrease' from 6.34 to 3.48 w_ I during the treatment.

By comparison, the corresponding values of the GSO group were: CHDL CLDL TC The mean of the standard atherogenicity risk factor showed hardly any change (from 6.86 to 6.93).

It can thus be seen that the administration of BCO leads to a reduction in the TC due solely to a decrease in the CLDL without participation of the CHDL which, by contrast, increases substantially. The standard atherogenicity risk thus decreases considerably.

By contrast, the administration of GSO produces no a improvement in the pathological state of the patients.

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Claims

1. A method for treating lipoprotein disorders associated with cholesterol metabolism in a mammal which comprises the step of administering a pharmaceutically effective amount of a composition comprising a lipid of blackcurrant in combination with a pharmaceutically acceptable carrier to a mammal in need thereof.

2. A method according to claim 1 wherein the composition is administered orally, rectally, enterally or parenterally.

3. A method according to claim 1 or 2 wherein the composition is administered in an amount providing a daily dose of 1 to 25 g blackcurrant lipid.

4. A method according to claim 5 wherein the composition is administered in an amount providing a daily dose of 2 to 5 g blackcurrant seed oil. DATED this 20th day of MARCH, 1991 SOCIETE DES PRODUITS NESTLE S.A. Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS *0 *a 3 0 tou 9 4 4 4O 4.. 44St 44 44 44 40 4g 4 4 4a 4 44 4 4 4* 6 I