(19) Japan Patent Office (JP)
`
`(12) Laid-open Patent Application Gazette (A)
`
`
`
`(51) Int. Cl. A
`A 61 K 35/60
`
`ID Code
`ACB
`
`(11) Laid—open Application No. 863—23819
`(43) Date of Laid—open Publication: Feb. 1, 1988
`Internal Control No.
`8615—4C
`
`Examination: Not Requested Yet No. of Claims: 1
`
`(Total 4 pages)
`
`(54) Title of Invention: Platelet Aggregation Inhibitor
`(21) Application No.: S61—167540
`(22) Application Date: July 16, 1986
`(72) Inventor: Shoichi MURATA, Sugamata Heights #504, 3—1—1 Imaizumi, Utsunomiya City,
`Tochigi Prefecture
`(72) Inventor: Kenji HARA, 1022—53 Nagashitsu—cho, Utsunomiya City, Tochigi Prefecture
`(71) Applicant: KAO Corporation, 1—14—10 Nihonbashi Kayaba—cho, Chuo—ku, Tokyo
`(74) Agent: Mitsuyuki ARIGA, Patent Agent, and two others
`
`SPECIFICATION
`
`1.
`
`Title of Invention
`
`Platelet Aggregation Inhibitor
`
`2.
`
`What Is Claimed Is:
`
`A platelet aggregation inhibitor containing a krill organic solvent extract as an
`1.
`active ingredient.
`2.
`The platelet aggregation inhibitor of claim 1, wherein the krill organic solvent
`extract is a phospholipid fraction.
`
`Detailed Description of the Invention
`3.
`Industrial Field of Application
`The present invention relates to a platelet aggregation inhibitor, and more specifically
`relates to a platelet aggregation inhibitor that has few side effects and high stability and that is
`obtained by extracting it from krill using an organic solvent.
`
`Prior Art
`
`It is known that when a thrombus forms in a blood vessel, blood flow is greatly impaired
`and serious injury is caused to tissue. In the pathology of diseases caused by thrombus formation,
`i.e.
`thrombosis, three factors act as thrombogenic factors: the condition of the vascular wall,
`blood flow speed, and blood components; it is known that these interact with one another and
`play an important role. Among these, the role of platelets, which are one component of blood, is
`extremely important. The possibility of inducing thrombosis through platelet rebound has been
`
`145
`
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`
`

`

`experimentally and epidemiologically verified. Recently, in conjunction with clarifying the
`causative mechanism of arteriosclerosis, it has become clear that stage one of the onset of
`arteriosclerosis is platelet aggregation at injured vascular endothelial cells. Therefore, in recent
`years thrombosis has been treated and prevented by the administration of drugs which are
`platelet aggregation inhibitors, such as aspirin, indomethacin, phenylbutazone, clofibrate, dextran
`sulfate, papaverine, and heparin, and polyunsaturated fatty acids such as eicosapentaenoic acid,
`either orally or by intravenous injection.
`
`Problems the Invention Is to Solve
`
`Nevertheless, all of the abovementioned drugs are not completely satisfactory in some
`aspect, such as side effects, efficacy, or stability, so there is a need for the development of a
`platelet aggregation inhibitor with no side effects and improved efficacy and stability to replace
`these. Also, it is necessary that this platelet aggregation inhibitor can be administered orally so
`that it can be administered daily.
`
`Means for Solving the Problems
`In consideration of these facts, the present inventors performed diligent research in order
`to obtain a platelet aggregation inhibitor that would satisfy the abovementioned requirements. As
`a result, they discovered that a krill organic solvent extract has a platelet aggregation inhibition
`effect, and that this substance has few side effects and improved stability, and moreover can be
`administered orally, and so completed the present invention.
`Therefore, the present invention provides a platelet aggregation inhibitor containing a
`krill organic solvent extract as an active ingredient.
`The krill used in the present invention may be any of the Euphausia genus such as
`superba, crystallorophias, frigida, triacantha, valentini, longirostris, lucens, similis, spinifera, or
`recurva, or any of the Thysanoessa genus such as macarura, vicina, or gregaria, and is not limited
`to a particular species.
`Furthermore, the krill that is the starting material is distributed through the oceans of the
`world, and is plentiful around the South Pole in particular, where its biomass is said to range
`from hundreds of millions of tons to two billion tons. It appears to be possible to catch
`50,000,000 to 70,000,000 tons/year, which is comparable to the current annual catch of fish
`worldwide, so in terms of supplying the raw material, a stable supply should be possible.
`Extraction from krill using an organic solvent is performed in the normal manner. For
`example, krill or a powder thereof is put in an organic solvent such as a non—polar solvent such
`as chloroform, benzene, butanol, or ether or a mixture of a non—polar solvent and a polar solvent
`such as chloroform—methanol, ether—ethanol, or butanol—water. Preferably, it is stirred for 2—24
`hours at 15—60°C, and filtered. Preferred organic solvents are chloroform, chloroform—methanol,
`and butanol—water.
`
`The krill organic solvent extract obtained in this manner can be used as—is as a platelet
`aggregation inhibitor, or can be concentrated or dried. But it can also be used by obtaining a
`phospholipid fraction from this extract. Typical methods of obtaining a phospholipid fraction are
`to condense the abovementioned extract, and then drip a small amount gradually into a large
`amount of cold acetone, and thereby cause a phospholipid fraction to precipitate, for example, or
`to separate and collect it by thin—layer chromatography.
`The platelet aggregation inhibitor of the present invention is manufactured by combining
`the krill organic solvent extract obtained as described above or a phospholipid fraction obtained
`
`146
`
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`
`

`

`therefrom with a known pharmaceutical carrier as required. Furthermore, when using the krill
`organic solvent extract, the organic solvent in the extract is preferably removed by replacement
`with water.
`
`The platelet aggregation inhibitor of the present invention obtained in this manner is
`preferably administered orally in the amount of l—20 g/day in terms of the amount of lipids in the
`extract or phospholipid fraction, for adult males, but it is possible to further increase the dose
`according to the degree of symptoms.
`Furthermore, the extract or phospholipid fraction that is the active ingredient in the
`platelet aggregation inhibitor of the present invention has extremely high safety, as indicated by
`the fact that LD50 (oral) in rats of the phospholipids contained in these is 25 g/kg.
`
`Operation
`The mechanism of the platelet aggregation inhibition effect of the krill organic solvent
`extract of the present invention has not been explicated in detail, but it appears to derive from the
`phospholipids having large amounts of polyunsaturated fatty acids such as eicosapentaenoic acid
`that are contained in the krill organic solvent extract.
`
`Effect of the Invention
`
`As described above, the krill organic solvent extract of the present invention and in
`particular a phospholipid fraction derived from this exhibit an excellent platelet aggregation
`inhibition effect in oral administration, and have no toxicity or side effects, and so are an
`extremely superior platelet aggregation inhibitor.
`
`Embodiments
`
`The present invention is described more specifically in the following embodiments.
`
`Embodiment l
`
`Freeze—dried krill (Euphausia superba) was finely pulverized, 500g of this pulverized
`material was added to a butanol—water (65:35) mixture, 1000 ml, and while stirring at 50°C for
`20 hours, the lipids were extracted, and a butanol—water extraction solution was obtained by
`filtering.
`The filtered butanol—water extraction solution was concentrated under reduced pressure
`and the butanol was removed, after which additional concentration was performed to produce
`40g of the butanol—water extraction solution (water content 28g).
`
`Embodiment 2
`
`Freeze—dried krill (Euphausia superba) was finely pulverized, 500g of this pulverized
`(I)
`material was added to 1000 ml of chloroform, and while stirring at 40°C for 20 hours, the lipids
`were extracted, and a chloroform extraction solution was obtained by filtering.
`(II)
`The filtered chloroform extraction solution was concentrated under reduced pressure and
`solidified, and then 50 ml of a water—ethanol (lzl) solution was added, and the dried material was
`
`dissolved. This was again concentrated under reduced pressure and the ethanol was removed,
`producing 37g of the krill chloroform extraction solution (water content 25g).
`
`Embodiment 3
`
`147
`
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`
`

`

`A chloroform extraction solution prepared in the same manner as in Embodiment 2(I)
`was concentrated under reduced pressure to about 10 ml, and then added dropwise to 2000 ml of
`acetone with stirring, and a phospholipid fraction was precipitated. The precipitate was filtered
`and collected under reduced pressure, and then dissolved in 30 ml of a water—ethanol 1:1 mixed
`solution, and the ethanol was removed by reduced—pressure concentration. 20g of a phospholipid
`fraction of the krill chloroform extraction solution was produced (water content 15g).
`
`Embodiment 4
`
`Tests were performed on the platelet aggregation inhibition effect of the krill extracts and
`the phospholipid fractions thereof obtained in Embodiment l, Embodiment 2, and Embodiment
`3. Specifically, krill extracts and phospholipid fractions were administered daily for two weeks
`to male Wistar rats (body weight 200g), 10 rats per group, 0.5 ml per dose, into the stomach
`using a probe. On the final day of the experiment, under Nembutal anesthesia, blood was
`collected from the lower abdominal artery, with a 3.8% sodium citrate solution added in the
`amount 1/ 10. The collected blood was centrifuged at 500g, 22°C, for 6 hours to make the
`supernatant a PRP (Platelet Rich Plasma). The remaining blood was centrifuged at 1000 g, 22°C,
`for 15 hours to make the supernatant a Platelet Poor Plasma (PPP). Platelet aggregation activity
`was measured using an ERMA Aggretec TE—500, and shown as maximum aggregation ratio and
`maximum aggregation time. Furthermore, platelet aggregation activity was studied with the PRP
`diluted with PPP so that the number of platelets became 5—7 x 107 per 200 ul, and 20 ul of a
`saline solution with ADP 20 umol was added as the aggregation initiating substance. Also, rats
`administered only water were used as the control group. The results are shown in Table 1.
`
`
`Table 1
`
`Administration group
`Maximum aggregation ratio
`Maximum aggregation time
`
`(070)
`(min)
`59.8
`3.16
`Krill butanol—water extract
`
`Krill chloroform extract
`60.3
`3.14
`
`
`
`Krill phospholipid fraction
`
`52.8
`
`2.89
`
`As shown by these results, it is clear that the phospholipid fractions in the krill organic
`solvent extracts, etc. have a platelet aggregation inhibition effect.
`
`Formulation Example
`Composition:
`100 mg
`Krill phospholipid*
`(D
`100 mg
`Lactose
`®
`50 mg
`Aluminum silicate
`(3
`5 mg
`Magnesium stearate
`@
`* Powder with extraction solvent completely removed (Embodiment 2)
`Manufacturing Method:
`Mix ®—@, and press into tablets.
`
`The End
`
`148
`
`RIMFROST EXHIBIT 1122 Page 0004
`RIMFROST EXHIBIT 1122 Page 0004
`
`

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`RIMFROST EXHIBIT 1122 Page 0008
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