HK1069327B - Use of ginkgo biloba extracts for preparing a medicine for treating sarcopenia - Google Patents

Description

Use of ginkgo biloba extract for the preparation of a medicament for the treatment of sarcopenia

The present patent application relates to the use of ginkgo biloba extracts for the preparation of a medicament for the treatment of sarcopenia (sarcopenia).

Sarcopenia is a muscular disease affecting most elderly people and presenting with a decrease in muscle mass with age (see, e.g., Chumlea et al, Nutrition, Health & Aging, 1(1), 7-12). No satisfactory treatment for such lesions has been found to date.

Indeed, given that treatment methods such as with Growth Hormone (GH) have been shown to increase muscle mass, this very expensive treatment still exhibits some undesirable side effects (wherein the treatment can even shorten the life expectancy of the treated patient).

The applicant has now found that: administration of ginkgo biloba extracts can prevent sarcopenia or slow down its progression in elderly patients already suffering from this disease.

The invention therefore mainly relates to the use of ginkgo biloba extracts for the preparation of a medicament for preventing sarcopenia or slowing down the progression thereof in elderly patients already suffering from this disease.

In fact, according to the invention, when treating elderly patients with ginkgo biloba extract, the relationship R obtained by dividing their muscle mass Mm by their total body weight Mt tends to remain stable or, in most cases, to increase. Preferably, the increase in R thus obtained after a treatment period of at least one month is greater than or equal to 5%, and more preferably greater than or equal to 6% or even 8% or 10%.

The ginkgo extracts which can be used according to the invention are those comprising at least flavone glycosides and/or one or more ginkgolides (ginkgolide). Preferably, the content of flavone glycosides and/or one or more bilobalides in the ginkgo extract used for the preparation of the medicament according to the invention amounts to a level of at least 25% by weight, more preferably to a level of at least 30% by weight and still more preferably to a level of at least 50% by weight. Furthermore, the proportion of alkylphenol compounds in the ginkgo extract used according to the invention is preferably below 10ppm, more preferably below 5ppm and still more preferably below 1 ppm. If appropriate, one or more of the bilobalides may be replaced by acetylated homologues thereof, alkoxylated homologues or glycosylated homologues thereof (such as, for example, the compounds of general formula (I) described below).

Preferably, the ginkgo extract used for preparing the medicament of the present invention is rich in flavone glycosides and/or bilobalide. It may be, for example, EGb 761^*And (3) a type extract. According to another embodiment of the present invention, the ginkgo extract used for preparing the medicament of the present invention is any ginkgo extract containing flavonoid glycoside, bilobalide and bilobalide, such as CP 401 extract.

EGb 761^*The extract refers to EGb 761 with standard composition^*The standard extract EGb 761 of the above-mentioned plant, and the extract of the above-mentioned plant has substantially the same composition^*In particular, it has been defined in the following articles: drieu, La presse mcale, 31, 25.9.1986, Ginkgo biloba extract (EGb 761)^*) Supplement, 1455-; or as already defined in patents EP 431535 and EP 431536; thus EGb 761^*The extract specifically contains 20-30% of flavone glycoside, 2.5-4.5% of ginkgolides A, B, C and J, 2-4% of bilobalide, and less than 10% of original flower colorGinkgo extract comprising proanthocyanidins and less than 10ppm (preferably less than 5ppm and still more preferably less than 1ppm) of alkylphenols, preferably means a ginkgo extract comprising from 22% to 36% of flavone glycosides, from 2.5% to 3.5% in total of ginkgolides A, B, C and J, from 2.5% to 3.5% of bilobalide, less than 8% of proanthocyanidins and less than 10ppm (preferably less than 5ppm and still more preferably less than 1ppm) of alkylphenols, especially a ginkgo extract comprising about 24% of flavone glycosides, from 3.1% in total of ginkgolides A, B, C and J, from 2.9% of bilobalide, from 6.5% of proanthocyanidins and less than 1ppm of alkylphenols.

CP 401 type extracts refer to extracts as those listed in patent US 5,389,370, especially ginkgo extracts comprising 5.5% to 8% in total of ginkgolides A, B, C and J, 40% to 60% of flavone glycosides and 5% to 7% of bilobalides, preferably ginkgo extracts comprising 6.5% to 7.5% in total of ginkgolides A, B, C and J, 45% to 55% of flavone glycosides and 5.5% to 6.5% of bilobalides, and especially extracts comprising about 7% in total of bilobalide A, B, C and J, 50% of flavone glycosides and 6% of bilobalides.

In extension, EGb 761 wherein the ginkgolide is replaced by a homologue of formula (I) as described below^*Type or CP 401 extract is also combined with EGb 761^*Or CP 401 type extract.

According to one embodiment of the invention, at least a portion of one or more bilobalides may be replaced by a compound of formula (I),

wherein W, X, Y and Z each represent H, OH, straight-chain or branched alkoxy or O-G_sGroup, G_s-OH represents a monosaccharide or a disaccharide, or one of their derivatives or analogues, at least one of W, X, Y or Z being known to represent O-G_sA group.

Preferably, the aforementioned compound of formula (I) is a compound wherein X represents OH or O-G_sGroup, G_s-OH represents a monosaccharide or a disaccharide, or one of their derivatives or analogues, and:

w represents OH or O-G_sThe radical, Y represents H and Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents H and Z represents OH or O-G_sA group;

-or W represents H, Y represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents a linear or branched alkoxy radical and Z represents H.

For the preparation of compounds of the general formula (I), the person skilled in the art is referred to PCT patent application WO 98/52959.

The pharmaceutical composition comprising the ginkgo extract may be in solid form, such as a powder, granules, tablets, gelatin capsules, liposomes, suppositories, or patches (patch). Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone and waxes.

The pharmaceutical composition comprising the ginkgo biloba extract may also be present in liquid form, such as a solution, emulsion, suspension or syrup. Suitable liquid carriers may be, for example, water, organic solvents such as one or more glycols, and mixtures thereof in varying proportions in water.

Administration of the medicament of the present invention may be carried out by topical, oral or parenteral routes, by injection (intramuscular, subcutaneous, intravenous, etc.), and the like.

The expected daily dose of ginkgo extract is between 0.1mg and 10g, depending on the concentration of the active ingredient in the extract and the severity of the sarcopenia of the patient. The final decision may be made by the attending physician or veterinarian.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, all patents, and all other documents mentioned herein are incorporated by reference.

In order to show the superiority of the above ginkgo biloba extract for the treatment of sarcopenia, the following experiments may be performed. To achieve the same result, other experiments aimed at, for example, determining body composition and, in particular, the relationship between fat and non-fat mass can also be carried out (see Chumlea et al, Nutrition, Health & Aging, 1(1), 7-12).

Pharmacological moieties

Comparative determination of weight gain and soleus muscle mass gain in rats:

method 1

3 groups of rats were set up: one group was 12 young Wistar rats (4 months old) and the other two groups were aged Wistar rats (22 months old), wherein one group consisted of 11 rats receiving normal drinking water for 5 weeks, and the other group consisted of 12 rats receiving standard ginkgo extract EGb 761 containing 75mg/kg^*Rat composition of drinking water. After weighing, young Wistar rats were sacrificed at 4 months of zero 2 weeks of age and older Wistar rats were sacrificed at 22 months of zero 3 weeks of age. In all groups, the plantar muscle (right muscle) was weighed and frozen for structural family analysis (typing analysis) of possible changes in muscle fibers and mitochondria (left muscle).

The therapeutic effect, expressed as the mean increase in the weight of the plantar muscles of the treated rats compared to the untreated rats, and the increase in the weight of the plantar muscles relative to the total weight of the rats, were determined.

Method 2

Two groups of rats were set up for the experiment, 30 to 45 male Fischer 344 strain rats per group. At the beginning of the experiment, rats in group 1 were 12 months of age and rats in group 2 were 24 months of age.

Rats in each group were divided into 3 subgroups. Each subgroup 1 rat was orally administered EGb 761 at a daily dose of 100mg/kg^*Treatment; each subgroup 2 rat was orally administered EGb 761 at a daily dose of 50mg/kg^*Treatment; finally, rats of the 3 rd subgroup did not receive any treatment. All rats were weighed at the start of treatment and their body weights recorded. After one month of treatment and survival under the same conditions, the final weighing was performed before the rats were sacrificed by decapitation. Their soleus muscles were then removed for weighing.

For administration of EGb 761^*Or no EGb 761^*The increase in total weight of treated rats was compared. For administration of EGb 761^*Or no EGb 761^*The soleus muscle mass of the treated rats was also compared. These comparisons led to EGb 761^*The beneficial effects of the therapy are highlighted. Indeed, the latter reduces age-related muscle loss in treated subjects compared to untreated subjects.

Results obtained in the case of method 1:

the treated animals had less weight gain than untreated animals (the control aged rats had a 23% weight gain within 5 weeks and the treated aged rats had a 13.5% weight gain within the same time period).

Measurement of the weight of the plantar muscle at the end of the study period provided the following results:

young rat	Untreated rats for the elderly	Old-aged rat treatment
			334.63±17.82	273.00±16.12	296.50±21.81

Finally, it is pointed out that: the weight of the metatarsal muscles in treated rats was increased by 8.60% compared to untreated rats, while the relationship of the weight of the muscles in treated rats relative to the total weight was increased by 26.19%.

The results show that: using standard ginkgo biloba extract EGb 761^*The treatment performed does result in a reduction of muscle mass loss in elderly subjects.

Claims (10)

1. Use of a ginkgo extract comprising at least a flavonoid glycoside and/or one or more bilobalides in the manufacture of a medicament for the prevention or treatment of sarcopenia.

2. Use according to claim 1, characterized in that: the content of flavone glycosides and/or one or more bilobalides in the ginkgo extract used for the preparation of the medicament is at least up to a level of 25% by weight.

3. Use according to claim 1, characterized in that: the ginkgo extract comprises 20% to 30% flavone glycosides, 2.5% to 4.5% total of ginkgolides A, B, C and J, 2% to 4% bilobalide, less than 10% proanthocyanidins, and less than 10ppm alkylphenol compounds.

4. Use according to claim 3, characterized in that: the ginkgo extract contains less than 5ppm of alkylphenol compounds.

5. Use according to claim 3 or 4, characterized in that: at least a portion of ginkgolides A, B, C and J are replaced by a compound of formula (I),

wherein W, X, Y and Z each represent H, OH, straight-chain or branched alkoxy or O-G_sGroup, G_s-OH represents a monosaccharide or a disaccharide, or one of their derivatives or analogues, with the proviso that at least one of W, X, Y or Z represents O-G_sA group.

6. Use according to claim 5, characterized in that: compounds of the general formula (I) are those in which X represents OH or O-G_sThe group, Gs-OH, represents a monosaccharide or a disaccharide, or one of their derivatives or analogues, and:

w represents OH or O-G_sThe radical, Y represents H and Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents H and Z represents OH or O-G_sA group;

-or W represents H, Y represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents a linear or branched alkoxy radical and Z represents H.

7. Use according to claim 1, characterized in that: the ginkgo extract comprises 5.5% to 8% total of ginkgolides A, B, C and J, 40% to 60% flavonoid glycosides, and 5% to 7% bilobalide.

8. Use according to claim 7, characterized in that: the ginkgo extract comprises 6.5% to 7.5% total of ginkgolides A, B, C and J, 45% to 55% flavonoid glycosides, and 5.5% to 6.5% bilobalide.

9. Use according to claim 7 or 8, characterized in that: at least a portion of ginkgolides A, B, C and J are replaced by a compound of formula (I),

wherein W, X, Y and Z each represent H, OH, straight-chain or branched alkoxy or O-G_sGroup, G_s-OH represents a monosaccharide or a disaccharide, or one of their derivatives or analogues, with the proviso that at least one of W, X, Y or Z represents O-G_sA group.

10. Use according to claim 9, characterized in that: compounds of the general formula (I) are those in which X represents OH or O-G_sGroup, G_s-OH represents a monosaccharide or a disaccharide or one of its derivatives or analogues, and:

w represents OH or O-G_sThe radical, Y represents H and Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents H;

-or W represents OH or O-G_sThe radical, Y, represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents H and Z represents OH or O-G_sA group;

-or W represents H, Y represents OH or O-G_sAnd Z represents OH or O-G_sA group;

-or W represents OH or O-G_sThe radical Y represents a linear or branched alkoxy radical and Z represents H.