AU656681B2 - Oily preparation and method of production thereof - Google Patents

Description

L, -iri Our Ref: 473870 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT

'CCC

44 C Applicant(s): Address for Service: Invention Title: Emiyo Niwa 31-17, Asahi-machi TOSA-SHIMIZU Kouchi

JAPAN

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Levrl 10, 10 'arrack Street SYDNEY NSW 2000 Oily preparation and method of production thereof The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 Oily preparation and method of produaction- Lherpof J BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oily Preparation and its production mC-rbod, and particularly to an oily preparation uontaining, as efctive cumponents, substances which~ suppress pr-oduction of reactive oxygen and lipid peroxidle In human bodies.

Hereinafter, these substances will he referred to as antioxidant substances.

2. Related Art Statement Recently, atteniLion has been attracted to antioxidant substances which exhibit excellent cffects when used for preventing and treating- various inflammuations and inveterate dlsea .s such as chronic arthrorheumatisat, tbrombophiebitis, progressive systemic sclcrema, Bluerger s disease, Raynaud's disease, intractable dermatoulcer and the like oaused by destruction of cellular organiization by reactive oxygen and lipid peroxide prodiia.d in human bodies.

CCIIIt has been clariffied according to a sLudy by the present inycntors Lhat tbe above-mentioned C artioxidaniL clubstiances comrprise low molecular wecight subs~tances siich as fiavonoids. polyphenois, tanniris, tocopherols, vitamiln R, and the like contained in a plant body, and by taking them orally as a medlic or a heal.th food, the production *of above-mentioncd reactive oxygen and lipid peroxide in the body is suppieassed (see JTournal of Jrapan Pharmacist Association, No. 39, Vol. 12, supplement, "Nloavailability of SOD (Superoxide Disinutase) and. crude drUg", PP. 1097-1119, published on December 1. 1987).

Coventionally, as preparations containing such antioxidant substances, a. votanIcal nutrient of Japancse Patent No. 13~66268, and an antioxidant compositlon A ~described in 'Niwa's Japaneso Unexamined PatefiL Application Laid-opeii No. 63-79834 have been iown.

The votanical nutrient of' No. 1366268 is obtained by midxing green tea powder with powder of baked unpolished rice and soybean,. powder; adding a small amount of koji fungus to the mixture; immersing, then, this powder mixture in a mixture of sesame oil and *oybean oil for about 4 days to extract e--ffective components; removing precipi Cates by centrifugation; and enclosing rem~ained oiJly substance In a capsule mrade of gel-tin or the like.

The antioxidant composition of -No. 63-7U834 is obtained by mildly heating plant seeds or germs thereof not to p)roduce scorch:, subsequentlyl brewing ttiese heated 3 4

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pl1ant materials by adding a microorganism; and adding thereto a plant oil obtained from a plant which was also mildly heated. Optionally, vita~min C, vitamino C derivatives or a plant body containing them is added to the compositi~on.

As plant seeds, iS Used A. seed which contains antioxidant substanceq such as above-mcntioned flavonoids, polyphenols, tannins, tocopherols, vitaminl 1, and the i111c, incluiding rice, wheat, barley, soybean.

adzuki bean, corn, -atoniligj. (pearl barley). pea. As plant oil, is used sesame oil, soybean oil, cotton seed oil, corn oil, safflower oil, eveing primrose oil, rice bran oil, rapc oil. olive oil. and the like.

However, the votanical nutrient of No. 16208 Is low In Its antioxidant activity, because of its method o1' processing the raw plant material.

The antioxidant composition of Siwa, No. 63- 79834 obviated such a problem by remarkably increasing the activity of antioxidanit substancps by mildly heating the raw plant material not to prodioe scorch with far- Infrared radiation, thus preventing deactivation of axitioxidant substances due to high temperature, liberating and converting the raw material to the low molecular weight eff'ective components, and by bren-iig thus-heat treated material -to promote further liberation

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It*C C, St CS C S SI t *5 4'4 and conversion to the low molecular weight effective s ubstanocs However, according tb the study by the present inventors since then,. It ha been clarified that although above- men tioned antioxidant substancec 1'emar;Nabiy Ruppresses the production of the reanctive oxygen and lipid peroxide In test tube, the antioxidant atvivities are not exhibited in human bodies siurficient ly.

It Is considered that, in orcler to allow the antioxidant substances ro ar-rive at the inside of cells suffering a disease such as an inflammatory reaction or the like due to reactive oxygen and lipid po-roxide, It is necessary to pass through cell membranes which cover *surface.5~ of the cells. liowever. thn cell membrane of limnan is abundant with oil and fat components, uand hence it has such a property that only oily substances are allowed to pass through, so that above-mentioned antioxidant composition havIng a low content of oily substances has a low ability to pass through the cel membrane to penetrate into the Insid~e of tho cell.

Tlius,, the present inventors have i-"peat~id studies 1in order to Improve the cell. membr'ane- passing ability of the antioxidant compos;itlon, While maiakng f urth er improvement In selcu.tion' of plant species as a raw material and its processing method. Consequerltly, there has been, obtained an) oily preparation Di which the K activity of the antioxidant substances as effectivo compronents high ai)d the penetrating ability into the inside of the cell1 suffering a disease is high, completing the present Invention.

D1SCLOSL:RE OF InvENTrION It is an objcct of the present invention to I provide an oily preparation and its production. method In which thAe activity of antioxidant substances as effective components is high and the penetratingr ahitly he Inside of the cell at a dfqpease place, is high.

Method of producing the oily preparation of the j: present invention nornpsises: heating rice germ and/or wheat germ, and soybean at a temperature not exceeding 100 C; adding koji into the heated material: brewing the mixture; then, powdering the mixture; and adding the t obtained powdered mixture Into an oil mixturc- romprislng j iS4an oil obtained from sesame heated at, a temperature not exceeding 100~C and an oil obtained from raw sesame, whertt.in a ratio of the oil. mixture to a total amount o f powder mn.:ture and the oil mixture. is 60 to 95 by weiht.

AS the raw Lma~erial abuidantly contatning the 3 1 '1 antloxidant substances, in addition to said rice germ, wheat germ and soybean, there may be listed plant species described in the Japanese Unexamined Patent Application Lald-open No. 63-79834, barley, adzuki bean, corn, hatomugi (pearl barley), pea and the like and the like, however, according to the study by the present inventors, the rice germ, wheat germ and soybean are the most preferable raw materials.

Next to rice germ, wheat germ and soybean, there can be listed rice bran, hatomugi (pearl barley) and wheat. Therefore, as a raw material, at least one of rice bran, hatomugt (pearl barley) and wheat may be included together with rice germ and/or wheat germ. In any case, the ratio of the germ (rice germ and/or wheat germ) in the cereal raw material is preferably at least more than or equal to 1 by weight.

The antioxidant substances in the cereal raw material described above form a complicated macromolecule polymer together with other substances, and therefore has no activity as it Is, so that It is necessary to cut macromolecule bonds by means of mildly heating or the like so as to release low molecular weight antioxidant substances. However, if heating temperature is too high, the low molecular weight antioxidant substances are deactivated, so that it is

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C. C C1 ~~cct C, C i C I S 7 necessary to select a heating condition taking into consideration this fact.

In order to satisfy such a condition, it is necessary to heat the cereal raw material at a temperature not exceeding 1001C slowly and in sufficient length of time, In detail, the cereal raw material is put in a vessel made of ceramic such as pottery or the like Irradiating far-infrared rays, preferably having wavelengths of 4 to 14 m, and heating is performed while slowly stirring and maintaining the temperature at about 90 to 960C.

The heating time varies depending on kinds of cereal species, so that it cannot be indiscriminately defined, however, it is preferably about 30 minutes to 3 hours. Incidentally, the heating method is not limited 11 to the above-mentioned method provided that the antioxidant substances in the cereal raw material are sufficiently released as low molecular substances while deactivation thereof is prevented.

It After heat treatment described above, koji (Aspergillus orizae) is added to the raw material to brew it. The brewing condition is preferably at 20 to S 36C for about 2 to 6 days. When brewing is performed S using a fermenter, about 2 to 3 hours are sufficient.

This brwing is performed in order to further promote 8 liberation and conversion into low molecular weight substances of the antioxidant substances in the cereal raw material, and, through this brewing step, the activity of the antloxidant substances are remarkably enhanced as compared with a raw material only subjected to heat treatment.

Next, the brewed material is ground to make it into fine powder. Grinding may be performed using a commercially available grinder. Some types of grinder, however, generate high temperature during the use, thus deactivating the antioxidant substances. Therefore, it is preferable to use those which generate no high temperature when used. For example, a stone mill may be used.

Next, the oil is prepared by mixing an oil obtained from heated sesame (hereinafter referred to as the sesame paste oil) with an oil obtained from raw sesame in an appropriate ratio, and the above-mentioned fine powder is added to the oil mixture. The sesame paste oil is an oil obtained by, after a raw sesame is heated at a temperature not exceeding 100C0 slowly in sufficient length of time, griding and squeezing it, however, the fine solid contents formed by grinding sesame remain as it Is, so that the appearance provides a paste state. This sesame paste oil abundantly

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t at I 1 c' 9 contains the low molecular weight antioxidant substances, and by using it, It is possible to obtain the oily preparation having a high activity of the antloxidant substance.

However, this sesame paste oil has a high viscosity, and the size of an oil droplet is also large, so that the preparation in which only the sesame paste oil is added with the above-described fine powder has a poor penetrating ability into the insides of cells in a disease portion. However, when the sesame oil obtained from raw sesame is added to the sesame paste oil, the size of the droplet can be small, and the penetrating ability into the Insides of the cells in a disease portion is improved.

The oil collected from raw sesame is an oil obtained by, after a raw sesame is ground as it is and squeezing it, removing solid contents, and a commercially available as an ordinary sesame )il. Since the mixing ratio of the sesame paste oil to the ordinary sesame oil is different also depending on the amount of the fine powder to be added, It cannot be indlscimlnately defined. It is preferably 1 to 3 parts by weight of the ordinary sesame oil with respect to 1 part by weight of the sesame paste oil.

The ratio of the oil mixture to the fine powder

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added thereto Is such one that the mixed oil comes to to 95 by weight of a total amount of the both. If the oil mixture is less than 60 by weight, the ability to pass through the cell membrane Is poor. On the other hand, if the oil mixture exceeds 95 by weight, the concentration of the antioxidant substances as the effective components is low, so that the effect of suppressing the production of the reactive oxygen and lipid peroxide also decreases.

The oily preparation of the present invention, which Is orally taken, can be prepared by adding the fine powder to the oil mixture by enclosing it In a gelatin capsule or the like as soon as the oil mixture is prepared. The material mixture, however, can be matured preferably at 20 to 350C for about 3 to 30 days, more preferably at 28 to 300C for about I week, before encapsulation.

By applying the maturing treatment, the liberation and low molecular weight conversion of the antioxidant substances are further progressed by the koji remaining in the fine powder, and the antioxidant SCt.

substances well attaches to the oil mixture, so that the activity and the osmotic ability into the inside of the cell of the reactive components are further improved.

The oily preparation of the present Invention E 1

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4fuY 5010 11 can also include a cereal raw material comprising rice germ or wheat germ and soybean, and optionally at least one of rice bran, hatomugi (pearl barley) or wheat, which is made Into fine powder as it is without heating and brewing, and added to the oil mixture together with the heated and brewed fine powder described above.

In the fine powder of the cereal raw material which is not heated and brewed, the antioxidant substance as the effective components are not liberated and converted into low molecular weight substances.

However, when it Is added to the oil mixture together with the heated and brewed fine powder, the liberation and low molecular weight conversion of the antioxidant substances gradually proceed even after encapsulation, owing to the koji remaining in the brewed fine powder, so that there is such an advantage that the effect of suppressing the production of the reactive oxygen and lipid peroxide is maintained for a long period.

On the contrary, in the oily preparation in which only the heated and brewed fine powder is used, due to enzyme reactions and the like which continuously proceed even after encapsulation, the antioxidant substances as the effective components are gradually decomposed, so that the effective period Is short as compared with one In which the non-treated fine powder S .U I j 6* .uCtt I Clr

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P:\WPDOCS\NEH\473870.002:NH 14 12 4 *4 a

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Itt4 Is I 1 4 4a K S *r 4* 4 r a.

However, in the case where the adding amount of the non-treated fine powder is too much, the activity of the effective component decreases. Therefore, it is preferable that the non-treated fine powder Is about to 1 part by weight based on 1 part by weight of the heated and brewed fine powder. Incidentally, also in this case of including two types of fine powders, the oil mixture is 60 to 95 4 by weight of the total amount.

In the thus-obtained oily preparation according to the present invention, both the activity of the antioxidant substances and the osmotic power into the inside of the cell are high, and as clarified also from results of clinical tests as described hereinafter, It exhibits remarkable effects against various inflammations and inveterate diseases for which the therapeutic effects have been insufficient by conventional anti-inflammatory agents.

The oily preparation of the present invention may be encapsulated with gelatin or the like, and orally taken as a medicine. In addition, in the case of abnormal pigmentation such as dermatitis, chloasma, freckles and the like, or wrinkles and the like, the oily preparation can be applied directly to an affected part. In addition to dermatitis and the like, the 13 present oily preparation can be applied also to adult diseases and inveterate diseases such as chronic arthrorheumatism, thrombophlebitis, progressive systemic sclerema, Buerger's disease, Raynaud's disease, intractable dermatoulcer and the like. The preparation of the invention also has effects on treatment and prevention of other various pollution-caused diseases, burns, external wounds, fatigue, hangover, constipation and the like.

In addition, the oily preparation of the present S invention has no side-effect because of the use of only cereal, koji and sesame as the raw materials, so that it is possible to take orally as a health food for maintaining and enhancing the health. It is needless to say that, when making a preparation, it is optional to add auxiliary medicines or components useful for health such as various vitamins, minerals and the like, and flavors, taste-adjusting agents, coloring agents and the '"like.

S. Embodiment *Each one part of rice germ, soybean, rice bran, hatomugi (pearl barley) and wheat was charged in a pot made of pottery emitting far-infrared rays of 4 to 14 I m, and heated at 90 to 96°C for 3 hours with slow stirring not to making scorch. Next, koji was added by 4

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i 14 3 of a total amount to brew at 36 to 40 0 C for 72 hours, and then the brewed material was made into fine powder using a stone mill. In addition, above-mentioned five kinds of cereal raw materials, which were not heated and brewed, were ground with a stone mill to obtain fine powders of the same amount. On the other hand, sesame was heated in the same manner as the above serial materials, and, after it was ground with a stone mill, squeezed to obtain a sesame paste oil.

Next, 28.1 parts by weight of the sesame paste oil was mixed with 48.9 parts by weight of a commercially available sesame oil: to which mixture were added 11.5 parts by weight of the heated and brewed fine powder and 11,5 parts by weight of the non-treated fine powder; and the obtained mixture was st. red homogeneously. The obtained mixture was matured at 28 0

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for 1 week, then encapsulated in gelatin to obtain an oily preparation.

Effect of the Invention In vitro test For an in vitro test of the ability of arriving and penetrating to oily site6, the oily preparation of the embodiment was added to a TBA (thiobarbituric acid) reaction system in which an oily unsaturated fatty acid (decosahexaenolc acid) was reacted with reactive oxygen

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r+ r r ~r r r r r I r r r generated by ultraviolet rays and produced lipid peroxide, and the degree of s ippression of the production of lipid peroxide was measured.

Namely, to 0.1 cc of decosahexaenoic acid diluted by 100 times, 1.8 mg/ml of the test sample of the oily preparation of the present invention was added, and the lipid peroxide produced was measured with the TBA reaction. In the TBA reaction, 0.2 ml of 7 sodium dodecyl sulfate, 2 ml of 0.1 N HC1, and 0.3 ml of phosphotungstic acid were mixed; 1.8 mg/ml of the test sample was added to the mixture; 1 ml of a reagent in which 0.67 TBA was mixed with acetic acid by 1:1 was added; and the measurement was performed with excitation at 515 nm and emission at 553 nm using a fluorescent spectrophotometer.

As comparative examples, used the votanlcal nutrient of Japanese Patent No. 1366268 (Comparative example 1) and the antloxidant composition described in Japanese Nonexamined Patent Application Lald-open No. 63- 79834 (Comparative example measurements being performed In the same manner. Results are shown in Table 1.

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16 Table I Average (6 niunutes value) Test sample 9*

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C S

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.5 Control 461 ±62

(UV+)

oily preparation of' the 121 ±13 present Invention (1.8 mg/mi) Comparative example 1 271 ±34 t (1.8 mg/mi) Comparative example 2 358 (1.8 mg/mi) UV+: ultraviolet Irradiation to;0.01 P 0.05 control) Po:<P0.01 control) oP -C 0.0001 control) Test result Although any of the test samples significantly 17 suppressed the generation of the lipid peroxide (TBA reactive substances) from the unsaturated fatty acid (docosahexaenoic acid) by Irradiation of ultraviolet ray especially the oily preparation of the present invention remarkably suppressed this generation (P 0.0001). This result supports the fact that the oily preparation of the present Invention has a higher activity of the antloxidant substance, and a higher penetrating ability into the inside of the cell In which a disease occurs than the conventional preparations (Comparative examples 1 and 2).

A [3,4-'Ha2]-antioxidant substance was prepared in which the low molecular weight antloxidant substance contained in the oily preparation of the present invention was labeled with an isotope It was added into a human tissue in a test tube; and the count (cpm) of 3 Ha] bound to its cell membrane was measured by a scintillation counter; thereby the ability to arrive at the cell membrane was tested (labeled tritiated S thymidlne was 2 Cl/mM).

The same tests were also performed for Comparative examples 1 and 2. Results are shown in Table 2. As clarified from Table 2, the oily preparation of the present invention had the highest jI

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18 affinity to cell membrane as compared with Comparative examples 1 and 2.

Table 2 Test sample cpm Incorporation Control Oily preparation of the present invention (1.8 mg/ml) 15643 cpm 103 cells 56372 cpm 103 cells Comparative example 1 (1.8 mg/ml) Comparative example 2 (1.8 mg/mi) 33451 cpm 10 3 cells 30567 cpm 103 cells

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C W I I The oily preparation of the present invention was subjected to ultrasonic treatment and added to a reactive oxygen generating system (neutrophile and xanthine-xanthlne oxidase) so that a converted living body concentration became 1.6 mg/ml; and three types of 19I .4.

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a 5*

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S. 4 S 54 reactive oxygens H202 and OH*) were measured to compare with the case of no addition (control). The converted living body concentratlon is an amount assumed to exist in blood when an ordinary taking amount per one day (9 g in the case of the oily preparation of the present invention) Is absorbed into a living body.

The measuring methods for the three types of reactive oxygens are as follows.

For 02", the method was used in which the amount of reduction of ferrl-cytochrome C by 02- was measured at a wavelength of 550 nm with a spectrophotometer of Beckman, and converted to the amount of Op-.

For R202, depending on the fact that H 2 0 2 decreases fluorescence generated by scopoletin under the presence of peroxidase, by using scopoletin and peroxidase, the degree of decrease in fluorescence of scopoletin was measured using a fluorescent spectrophotometer made by Hitachi Ltd. with excitation of 370 nm and emission of 460 nm.

For utilizing a principle that a -ketomethiol-butylic acid (KMB) reacts with OH' to generate ethylene gas, the method was used In which the ethylene gas was quantified with a gas chromatography made by Hitachi Ltd., so q to convert into OH". The same tests were also perforomd for Comparative examples 1 and 2.

Result6~ are shown In Table 3.

Ta bl I Reactive oxygen HpOP TPest sample Control 1.532 nmol 485 pinol 854 pmol Oily preparation 0.589 nmol 161 pmol 283 pmol of' the present Invcr 1ion (1.8 mg/mi) Comparative 1.285 nmol 403 prnol 707 pmol example I (1.8 mg/IL)0 Comparative 0.231 nmol 538 pmol 108 pmo] examplo 2 (1.8 mg/rn]j) 4* 4.

~4 44 4 44,4 44 4 4s 4 4 5 *4 44 4 i I S 4 *4 T1est, result 21 The antioxidant effect of the oily preparation of the present invention was slightly inferior to that of Comparative example 2, hdwever, there was exhibited the antioxidant effect which was stronger than that of Comparative example 1. However, as clarified from abovementioned Tables 1 and 2, Comparative example 2 has a smaller contents of oily substances, so that it has poor ability to arrive at the cell In which a disease occurs.

Therefore, when it Is judged as a total, the oily preparation of the present invention, In which the antioxidant effect is high and the penetrating ability S into the inside of the cell in a disease portion is hest, is most excellent as an antioxidant agent.

**ftft ft f ([11 Clinical test The therapeutic effect was investigated on 96 patients of autoimmune diseases, collagen diseases such as chronic arthro-rheumatism, hemasthenosis, nephritis, hepatocirrhosis, chloasma, freckles and the like, who have hitherto resisted or got worse against any one of non-steroldal antiphlogistic drugs, steroids and the 2 antioxidant composition of Comparative example 2. The results are shown in Table 4.

l 2 2 1 4 'rebt Oily preparation of the present invention (1.8 mg/nd) sample Cominpar ativ e example I (1.8 mg/mi) Comnparativye example 2 (1.8 mg/mI) Disaese 4 4 *4 49 44 4 4 44.4 4,4444 4 4 Chronic 13/18 0/7 4/14 (28%) arthro rhleuminat ismi Anglitis 3/5 0/3 1/4 (259.) Progressive 9/12 2/10 6/12 systemic scierema Derinato- 6/8 2/12 6/13 (46%) inyosytis Throinbo- 2/3 0/4 1/5 ph lebit is Buerger's 6/8 0/3 3/6 disease Raynaud's 10/12 3/8 7/12 (58%) disease 4 44 4 45 Crus var icos is 8/11 (72%) 3/5 (60%) 4/9 (44%) 1/5 (20%) 11/15 (73%) 2/6 (33%) Intractable dermatou Icer Chloasma, 11/14 4/12 17/25 (68%) freckl es

Claims (6)

1. An oily preparation obtained by: heating a cereal raw material comprising rice germ and/or wheat germ and soybean at a temperature not exceeding 100 C; making the heated material into fine powder; adding koji to the powdered material and brewing the powdered material; and adding thus-brewed material to an oil mixture comprising a paste oil obtained from sesame heated at a i temperature not exceeding 100°C and an oil obtained from raw sesame, wherein a ratio of said oil mixture to a total amount of the fine powder and the oil mixture is to 95 by weight.

2. The oily preparation according to claim 1, which further includes a cereal raw material comprising rice germ and/or wheat germ and soybean made into fine powder without heating and brewing.

3. The oily preparation according to claim 1 or 2 wherein said heated or non-heated cereal raw material Includes, in addition to rice germ and/or wheat germ and soybean, at least one of rice bran, hatomugi (pearl H 24 barley) or wheat.

4. The oily preparation' according to claim 1 or 2 which is encapsulated for taking orally as a medicine or a health food. h A method of producing an oily preparation wherein when the cereal raw material of claim 1, 2 or 3 is heated with far-infrared ray having a wavelength of 4 to 14 /1 i. G. A method of producing an oily preparation wherein the cereal raw material according to claim 1, 2 or 3 is brewed at 20 to 36"C for 2 to 6 days after treatment with heat. i

7. A method of producing an oily preparation wherein the fine powder according to claim 1, 2 or 3 Is added to the oil mixture, so as to mature at 20 to 35 0 C for 3 to 30 days. ct -I 4097M/PT 25

8. Oily preparations, methods for the anufacture, or methods of treatment involvi ntaining them, substantially as h efore described with reference to the Exam DATED this 21st day of June, 1993. EMIYO NIWA By His Patent Attorneys DAVIES COLLISON CAVE 00 0 to ?,ALI. 0 b/ ABSTRACT An oily preparation and its production method where the activity of antiox-ldant substances as effective components are high and the penetrating ability into the inside of the cell in a disease portion is high, and its production method. The oily preparation is prepared by heating a cereal raw material comprising rice germ and/or wheat germ and soybean at a temperature not exceeding 100°C; making it fine powder after koji Is added to the heated material to brew It; and adding thus brewed powder to an oil mixture comprising an oil obtained from sesame heated in the same manner and an oil obtained from raw sesame, wherein a ratio of oil mixture to a total amount of the fine powder and the oil mixture is 60 to 95 by weight. This oily preparation can be used to prevent and treat t i various inflammations and inveterate diseases resulting from or worsened by destruction of cellular organization by reactive oxygen and lipid peroxide produced in a human body. i 1 i