JPH0625057B2 - Bone formation promoter - Google Patents
Bone formation promoterInfo
- Publication number
- JPH0625057B2 JPH0625057B2 JP31397587A JP31397587A JPH0625057B2 JP H0625057 B2 JPH0625057 B2 JP H0625057B2 JP 31397587 A JP31397587 A JP 31397587A JP 31397587 A JP31397587 A JP 31397587A JP H0625057 B2 JPH0625057 B2 JP H0625057B2
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- JP
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- Prior art keywords
- calcium
- calcification
- epa
- bone
- bone formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は細胞膜微量構成成分として存在する脂肪酸の一
種を有効成分とする骨形成促進剤に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an osteogenesis promoter containing as an active ingredient one of fatty acids present as a minor constituent of cell membranes.
（従来の技術） 魚を食べると骨が丈夫になるという俗説があるが、その
根拠としては魚の骨に含まれるカルシウムによると考え
られていた。しかし最近の研究では、骨のカルシウムは
吸収され難いことが示唆されている。骨を丈夫にするに
は、骨の石灰化が重要である。骨の石灰化は、骨芽細胞
により形成された骨基質へのヒドロキシアパタイト結晶
の沈着によりもたらされる。(Prior Art) There is a myth that eating bones will make bones stronger, but it was thought that calcium was contained in the bones of the fish. However, recent studies suggest that bone calcium is difficult to absorb. Bone mineralization is important for making a bone strong. Bone mineralization results from the deposition of hydroxyapatite crystals on the bone matrix formed by osteoblasts.
従来、骨形成にはカルシウム製剤や骨代謝調節ホルモン
の活性型ビタミンＤ３、副甲状腺ホルモン、カルシトニ
ンなどの関与が知られている（折茂肇ら、医報フジNO．
60，特集各種骨病変と薬物療法、1986。松本俊夫、実験
医学 ５(8) 53，1987。須田立雄ら、癌細胞の分化誘導
と制癌、穂積・高久編、ソフトサイエンス社239頁、198
6「ビタミンＤ誘導体による癌細胞の分化誘導」）。Conventionally, it has been known that calcium preparations, active vitamin D 3 of bone metabolism regulating hormone, parathyroid hormone, calcitonin, and the like are involved in bone formation (Orimo Hajime et al., Ibid. Fuji.
60, Special issue: Various bone lesions and drug therapy, 1986. Toshio Matsumoto, Experimental Medicine 5 (8) 53, 1987. Tadao Suda et al., Induction of cancer cell differentiation and cancer control, Hozumi and Takahisa, 239, 198, Soft Science.
6 "Induction of cancer cell differentiation by vitamin D derivatives").
（発明が解決しようとする問題点） 最近の研究では骨形成に関してカルシウム製剤や魚のカ
ルシウムは吸収され難く、むしろ牛乳等からの摂取が有
効だと考えられる。しかし一方、このようなカルシウム
の直接摂取は動脈硬化に対し悪影響を与えることが知ら
れている。事実、カルシウム拮抗剤は循環器系の疾病の
治療に用いられているのが現状である。そこで単にカル
シウム量を増加させるだけでなく、骨形成の促進を司る
骨芽細胞（オステオブラスト）を活性化させ、石灰化を
促進する因子の探究が必要である。(Problems to be Solved by the Invention) In recent research, it is considered that calcium preparations and calcium of fish are difficult to be absorbed in bone formation, and rather intake from milk or the like is effective. On the other hand, however, such direct intake of calcium is known to adversely affect arteriosclerosis. In fact, calcium antagonists are currently being used to treat cardiovascular diseases. Therefore, it is necessary to search for factors that not only increase the amount of calcium but also activate osteoblasts (osteoblasts) that control bone formation and promote calcification.
従って、本発明の目的は、この因子として細胞膜微量構
成成分として存在する脂肪酸の一種を有効成分とする骨
形成促進剤を提供することである。Therefore, an object of the present invention is to provide an osteogenesis promoter containing as an active ingredient one of the fatty acids present as a minor constituent of cell membranes as this factor.
（問題点を解決するための手段） 本発明は、全−シス−５，８，11，14，17−エイコサペ
ンタエン酸を有効成分とする骨形成促進剤を特徴とす
る。(Means for Solving Problems) The present invention is characterized by an osteogenesis promoter containing all-cis-5,8,11,14,17-eicosapentaenoic acid as an active ingredient.
以下、本発明につき詳細に説明する。Hereinafter, the present invention will be described in detail.
本発明者らは、従来の魚を食べると骨が丈夫になるとい
う俗説に鑑み、魚の中に骨形成促進効果をもつものが存
在すると仮定して各種の物質を実験して魚油に多く含ま
れる全−シス−５，８，11，14，17−エイコサペンタエ
ン酸が骨形成を促進することを見出した。In view of the conventional myth that eating bones makes bones stronger, the present inventors have experimented with various substances assuming that some fish have bone formation-promoting effects, and contained a large amount in fish oil. We have found that all-cis-5,8,11,14,17-eicosapentaenoic acid promotes bone formation.
マウス頭蓋冠由来の骨芽細胞を培地中で培養すると、融
合状態になった後も細胞は増殖を続け、重層化する。し
かし、培養14日目以降から増殖は抑制され、これとほぼ
同時期からカルシウムの細胞の骨基質層への蓄積が急速
に増加する。細胞の骨基質層に蓄積されるカルシウムの
うちには、基質の石灰化により蓄積されたもののほか、
細胞内に取り込まれたもの、細胞膜質と結合したもの等
も含まれていると考えられた。前述の松本の研究によれ
ば長期間培養により急速に増加したカルシウムの細胞の
骨基質層への蓄積は、主に石灰化に基づくものと判断さ
れている。この石灰化は、コラーゲン上にリン酸カルシ
ウムが沈着した形であることも知られた。以上の結果か
ら骨芽細胞を用い、細胞の骨基質層へのカルシウムの蓄
積を測定することにより石灰化をイン・ヴィトロで定量
的に骨形成を評価することが可能であることが明らかで
ある。カルシウムの蓄積は石灰の染色とカルシウムのア
イソトープ（45Ca）の測定で判定される。When osteoblasts derived from mouse calvaria are cultured in a medium, the cells continue to proliferate and become stratified even after the fused state. However, from the 14th day of culture onward, the proliferation was suppressed, and from about the same time, the accumulation of calcium in the bone matrix layer of cells rapidly increased. Among the calcium accumulated in the bone matrix layer of cells, in addition to those accumulated by calcification of the matrix,
It was considered that the substances incorporated into cells, those bound to the cell membrane, etc. were also included. According to the above-mentioned study by Matsumoto, the accumulation of calcium in the bone matrix layer of cells, which was rapidly increased by long-term culture, was judged to be mainly due to calcification. It was also known that this calcification was in the form of calcium phosphate deposited on collagen. From the above results, it is clear that it is possible to quantitatively evaluate bone formation in vitro by measuring the accumulation of calcium in the bone matrix layer of cells using osteoblasts. . Calcium accumulation is determined by lime staining and measurement of calcium isotope ( 45 Ca).
以上の実験系を用いて骨芽細胞の石灰化に対する高度不
飽和脂肪酸の影響を調べたところ、全−シス−５，８，
11，14，17−エイコサペンタエン酸が骨形成促進剤とし
て有効であることを見出した。When the effect of polyunsaturated fatty acids on the calcification of osteoblasts was investigated using the above experimental system, all-cis-5,8,
We have found that 11,14,17-eicosapentaenoic acid is effective as an osteogenesis promoter.
（発明の効果） 本発明は直接骨芽細胞に作用してカルシウムの石灰化を
促進するのに効果がある。そのため、加齢に伴って腎か
らカルシウムイオンの排泄が亢進して骨が折れ易い骨粗
鬆症や寝たきりの不動化によって骨萎縮を発生する不動
性骨粗鬆症に対する治療や、骨の保護および骨の強化に
用いられる。本発明の有効成分は、錠剤、カプセル剤、
脂肪乳剤等の飲み薬や点滴剤や経管栄養剤等の静注薬と
することができる。投与量は１日当たり１〜1000mg／k
g、好ましくは10〜300mg／kgである。また歯列矯正時の
骨代謝促進には、貼り薬とすることができる。(Effect of the Invention) The present invention is effective in directly acting on osteoblasts and promoting calcification of calcium. Therefore, it is used for the treatment of osteoporosis in which excretion of calcium ions from the kidneys increases with age and bones are easily broken, and immobility osteoporosis in which bone atrophy occurs due to immobilization of bedridden, as well as for bone protection and bone strengthening. . The active ingredient of the present invention includes tablets, capsules,
It can be taken as a drug such as fat emulsion or an intravenous drug such as drip or tube feeding. Dosage is 1 to 1000 mg / k per day
g, preferably 10-300 mg / kg. Moreover, it can be used as a patch to promote bone metabolism during orthodontics.
なお、ＥＰＡのラットに対する急性毒性はＬＤ50値20ｇ
／kg以上であり、またラット10匹に３ｇ／kg／日の割合
で45日間経口投与した結果、全数が異状なく生存してい
たことから、本発明の薬剤は安全性が非常に高いことが
認められる。The acute toxicity of EPA to rats has LD50 value of 20g.
/ Kg or more, and as a result of oral administration to 10 rats at a rate of 3 g / kg / day for 45 days, all of them survived without any abnormality. Therefore, the drug of the present invention is very safe. Is recognized.
（実施例） 以下の実施例に使用した全−シス−５，８，11，14，17
−エイコサペンタエン酸（以下、ＥＰＡという）、ドコ
サヘキサエン酸およびアラキドン酸は精製魚油を加水分
解して得た脂肪酸を、尿素付加処理して高度不飽和脂肪
酸を分別した後、逆相分配カラムを装着した高性能液体
クロマトグラフィーで精密分取して得たものである。(Example) All-cis-5,8,11,14,17 used in the following examples
-Eicosapentaenoic acid (hereinafter referred to as EPA), docosahexaenoic acid, and arachidonic acid were subjected to urea addition treatment of fatty acids obtained by hydrolyzing purified fish oil to separate highly unsaturated fatty acids, and then a reverse phase partition column was installed. It was obtained by precision fractionation by high performance liquid chromatography.
マウス頭蓋冠由来の骨芽細胞であるＭＣ３Ｔ３−Ｅ１細
胞を用い、本細胞の石灰化に対する高度不飽和脂肪酸の
影響を調べた。本骨芽細胞をα−グリセロリン酸カルシ
ウムの存在下で、10％胎児牛血清を含むα−ＭＥＭ（最
少必須培養液：ヘーズルトン社）で培養した。正常培養
条件下で、37℃にて上記培養液１ml中（直径30mmのペト
リ皿）に本細胞および本細胞と試験試料を添加して培養
した。試験試料はアラキドン酸（ＡＡ）、ＥＰＡ、ドコ
サヘキサエン酸（ＤＨＡ）を各々１μｇ／ml、５μｇ／
mlとなるように骨芽細胞の培養液中に加え石灰化が認め
られるまで約14日以上培養した。Using MC3T3-E1 cells, which are mouse calvaria-derived osteoblasts, the effect of highly unsaturated fatty acids on the calcification of these cells was examined. The osteoblasts were cultured in α-MEM (minimum essential culture medium: Hazleton) containing 10% fetal bovine serum in the presence of α-glycerophosphate. Under normal culture conditions, the present cells and the present cells and a test sample were added and cultured in 1 ml of the above culture solution (Petri dish with a diameter of 30 mm) at 37 ° C. Test samples were arachidonic acid (AA), EPA, and docosahexaenoic acid (DHA) at 1 μg / ml and 5 μg / ml, respectively.
It was added to the osteoblast culture solution so that the amount became ml, and the cells were cultured for about 14 days or longer until calcification was observed.
この石灰化は、コラーゲン上にリン酸カルシウムが沈着
した形であった。This calcification was in the form of calcium phosphate deposited on collagen.
石灰化を開始して４日目に塩化カルシウムを添加し、そ
の後２日ごとに上記培養液を交換し、そのたびに塩化カ
ルシウムを添加し、10日目の石灰化の程度をコッサ法で
染色して定量した。本細胞の石灰を構成するリン酸カル
シウムを銀で置換して証明した。ペトリ皿から培養液を
除去した後蒸留水で洗い、５％硝酸銀溶液に入れ、間接
日光で１時間暴露した。その後蒸留水で２回洗浄し、５
％チオ硫酸ナトリウム液に２分浸し、水洗を５分行い、
ケルン・エヒテロール液に５分浸し脱水、透徹、封入を
行った。リン酸カルシウムは黒褐色に染め上がった。Calcium chloride was added on the 4th day after the start of calcification, the above culture medium was exchanged every 2 days thereafter, calcium chloride was added each time, and the degree of calcification on the 10th day was stained with the Kossa method. And quantified. It was proved by substituting silver for calcium phosphate constituting lime of this cell. After removing the culture solution from the petri dish, it was washed with distilled water, placed in a 5% silver nitrate solution, and exposed to indirect sunlight for 1 hour. Then, wash twice with distilled water and
% Sodium thiosulfate solution for 2 minutes, rinse with water for 5 minutes,
It was immersed in a Cologne-Echterol solution for 5 minutes, dehydrated, clarified, and sealed. The calcium phosphate was dyed blackish brown.
その結果、ドコサヘキサエン酸投与率では１μｇ／ml、
５μｇ／mlの投与においても非投与群と石灰化量は変動
がなかった。一方、アラキドン酸投与群では濃度依存的
に石灰化の抑制が認められた。しかし幸運なことにＥＰ
Ａ添加群では濃度依存的に石灰化の促進が認められた
（第１図）。この結果は、骨芽細胞ではアラキドン酸を
シクロオキシゲナーゼの基質としてプロスタランジン類
を産生し石灰化を抑制するが、ＥＰＡではシクロオキシ
ゲナーゼの基質となり難くプロスタランジン類の産生を
抑制するために石灰化を促進していることが考えられ
る。As a result, the dose of docosahexaenoic acid was 1 μg / ml,
There was no change in the amount of calcification from the non-administration group even at the administration of 5 μg / ml. On the other hand, in the arachidonic acid administration group, suppression of calcification was observed in a concentration-dependent manner. But luckily the EP
In the A-added group, promotion of calcification was observed in a concentration-dependent manner (Fig. 1). This result shows that in osteoblasts, arachidonic acid is used as a substrate for cyclooxygenase to produce prostalandins, which suppresses calcification, but in EPA, it is difficult to become a substrate for cyclooxygenase, and calcification is suppressed in order to suppress production of prostalandins. It is thought that they are promoting it.
そこでＥＰＡの石灰化、即ち骨形成の促進度合いを定量
するため放射性カルシウム45Caを用いた。前述の培養条
件と同様に処理した細胞をコントロールとし、試験試料
はＥＰＡ、アラキドン酸（ＡＡ）、ドコサヘキサエン酸
（ＤＨＡ）を各々５μｇ／ml投与した。石灰化を開始し
て４日目に45Caでラベルした塩化カルシウム１μCi／ml
を各々添加し、その後２日ごとに上記培養液を交換し、
その度に45Caでラベル化した塩化カルシウムを１μCi／
mlを各々添加した。10日目の石灰化の程度を定量化する
ためペトリ皿をα−ＭＥＭ培養液で洗浄し、骨基質層を
ラバーポリスマンで掻き取り均一水溶液としてからシン
チレーションカウンター（ベックマン社）で計測した。Therefore, radioactive calcium 45 Ca was used to quantify the degree of calcification of EPA, that is, the degree of promotion of bone formation. Cells treated in the same manner as the above-mentioned culture conditions were used as controls, and EPA, arachidonic acid (AA), and docosahexaenoic acid (DHA) were administered at 5 μg / ml each as a test sample. Calcium chloride labeled with 45 Ca on the 4th day after the start of calcification 1 μCi / ml
, And then the above culture medium was replaced every 2 days,
Each time, 1 μCi / of calcium chloride labeled with 45 Ca was added.
ml was added each. In order to quantify the degree of calcification on the 10th day, the Petri dish was washed with an α-MEM culture solution, the bone matrix layer was scraped with a rubber policeman to obtain a uniform aqueous solution, and then measured with a scintillation counter (Beckman).
その結果、ＥＰＡ投与群ではコントロールに比べて、デ
ィッシュ当たりの45Caの蓄積量に相当するカウンター数
が2.2 倍であった。（第２図）。As a result, the number of counters corresponding to the accumulated amount of 45 Ca per dish in the EPA-administered group was 2.2 times that in the control. (Fig. 2).
上記の結果より、ＥＰＡは骨芽細胞を活性化し、骨形成
能を促進することが明らかとなった。ＥＰＡは魚油に多
量に含まれる高度不飽和脂肪酸であり、ＥＰＡにこのよ
うな骨形成促進効果が認られたことは、従来の魚を食べ
ると骨が丈夫になるという俗説は、単にカルシウムの摂
取ばかりでなく、魚油中のＥＰＡによっても正当化され
た。From the above results, it was revealed that EPA activates osteoblasts and promotes osteogenic ability. EPA is a polyunsaturated fatty acid contained in fish oil in a large amount, and the fact that EPA has been found to have such a bone formation-promoting effect is based on the popular theory that bones become stronger when conventional fish are eaten. Not only was it justified by EPA in fish oil.
齧歯類用固形飼料（ラボＭＲ−Ａ−１、日本農産工業株
式会社；粗脂肪６％、カルシウム1.35％、リン0.92％、
ビタミンＤ３３IU/g含有）で飼育された15週令の雌のＳ
Ｄ系ラットを30匹三協ラボサービス株式会社から購入し
た。このラットを10匹ずつ３群に分け表１に示す試験飼
料（精製低カルシウム・低脂肪飼料、株式会社船橋農
場；粗脂肪0.2 ％、カルシウム0.01％、リン0.51％、ビ
タミンＤ３２IU/g含有を基本組成として調整）を１匹に
１日当り12ｇを与えた。Solid feed for rodents (Lab MR-A-1, Nippon Agricultural Industry Co., Ltd .; crude fat 6%, calcium 1.35%, phosphorus 0.92%,
15-week-old female S bred with vitamin D 3 3 IU / g)
30 D strain rats were purchased from Sankyo Lab Service Co., Ltd. The rats test feed shown in divided Table 1 into three groups by 10 mice (purified low calcium, low fat diet, Ltd. Funabashi Farms; crude fat 0.2%, calcium 0.01%, phosphorus 0.51%, Vitamin D 3 2 IU / g containing 12 g per day was given to one animal.
コントロール群とカルシウム無添加群の試験資料は脂肪
含量が6.2 ％になるようコーン油を添加した。カルシウ
ム無添加ＥＰＡ群の試験飼料はコーン油5.58％とＥＰＡ
（ガスクロマトグラフィー純度91％）0.62％を添加し
た。またコントロール群の試験飼料はカルシウム含量が
1.25％になるよう乳酸カルシウム五水塩を添加した。試
験飼料は少量づつ真空パックし冷凍保存して使用した。Corn oil was added to the test materials of the control group and the calcium-free group so that the fat content was 6.2%. The test feed for the calcium-free EPA group was 5.58% corn oil and EPA.
(Gas chromatography purity 91%) 0.62% was added. The control group's test feed has a high calcium content.
Calcium lactate pentahydrate was added to 1.25%. The test feed was vacuum-packed little by little and stored frozen before use.
ラットは投与実験開始前に卵巣摘出処置をした。Rats were ovariectomized before the start of the administration experiment.
ラットは各試験飼料で６週間飼育した後、体重を測定し
たから屠殺し大腿骨を採取した。大腿骨は湿重量と破断
力（三点曲げによる破壊強度）を測定した。測定は破壊
特製測定装置（飯尾電機製ＤＹＮ−1255）を用いた。フ
ルスケール50kgでチャートスピード1200mm/minで記録し
ながら、試料をプランジャースピード100mm/min で破断
した。その結果をコンピューター（日本電気製：ＰＣ−
9801）により解析した。After the rats were fed with each test feed for 6 weeks, their weights were measured, and then they were slaughtered and femurs were collected. The femur was measured for wet weight and breaking force (breaking strength by three-point bending). For the measurement, a breakage special measuring device (DYN-1255 manufactured by Iio Denki) was used. The sample was broken at a plunger speed of 100 mm / min while recording at a chart speed of 1200 mm / min with a full scale of 50 kg. The result is computer (NEC: PC-
9801).
結果 大腿骨を採取する前の各群のラットの平均体重に有意な
差は無く、体重差による骨重量への影響のないことを確
認した。大腿骨の平均湿重量と破壊強度で、カルシウム
無添加群はコントロール群に対し、有意に低下した。こ
れに対し、カルシウム無添加のＥＰＡ群は、カルシウム
無添加群の平均湿重量と破壊強度（第３図参照）の低下
を有意に回復した。Results There was no significant difference in the average body weight of the rats in each group before collecting the femur, and it was confirmed that the difference in body weight had no effect on the bone weight. The mean wet weight and fracture strength of the femur were significantly lower in the calcium-free group than in the control group. On the other hand, the calcium-free EPA group significantly recovered the decrease in average wet weight and fracture strength (see FIG. 3) of the calcium-free group.
以上の結果より、生体内においてＥＰＡが骨形成促進作
用を有することが確認された。From the above results, it was confirmed that EPA has a bone formation promoting action in vivo.
第１図は、アラキドン酸（ＡＡ）と全−シス−５，８，
11，14，17−エイコサペンタエン酸（ＥＰＡ）の石灰化
に及ぼす影響（コッサ法染色、培養後11日目に染色）を
示す図、 第２図は、ＥＰＡ、ドコサヘキサエン酸（ＤＨＡ）およ
びＡＡの45Caの蓄積への影響を示す図である。 第３図は、卵巣摘出したラットの大腿骨の破壊強度に及
ぼすカルシウムとＥＰＡの影響を示す図である。 ＊＊：コントロールと比較して有意（ｐ＜0.01） ＃＃：Ca(-)/ＥＰＡと比較して有意（ｐ＜0.01）FIG. 1 shows arachidonic acid (AA) and all-cis-5,8,
FIG. 2 is a diagram showing the effects of 11,14,17-eicosapentaenoic acid (EPA) on calcification (Kossa method staining, staining on day 11 after culturing). FIG. 2 shows EPA, docosahexaenoic acid (DHA) and AA. FIG. 3 is a diagram showing the effect of 45 Ca on the accumulation. FIG. 3 is a diagram showing the effects of calcium and EPA on the fracture strength of the femur of an ovariectomized rat. **: Significant compared to control (p <0.01) ##: Significant compared to Ca (-) / EPA (p <0.01)
Claims (1)
ペンタエン酸を有効成分とする骨形成促進剤。1. An osteogenesis promoter containing all-cis-5,8,11,14,17-eicosapentaenoic acid as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31397587A JPH0625057B2 (en) | 1987-12-14 | 1987-12-14 | Bone formation promoter |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31397587A JPH0625057B2 (en) | 1987-12-14 | 1987-12-14 | Bone formation promoter |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01157912A JPH01157912A (en) | 1989-06-21 |
| JPH0625057B2 true JPH0625057B2 (en) | 1994-04-06 |
Family
ID=18047734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31397587A Expired - Fee Related JPH0625057B2 (en) | 1987-12-14 | 1987-12-14 | Bone formation promoter |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0625057B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9112052D0 (en) * | 1991-06-05 | 1991-07-24 | Efamol Holdings | Fatty acid treatment |
| GB9217780D0 (en) * | 1992-08-21 | 1992-10-07 | Efamol Holdings | Fatty acid treatment |
| EG22407A (en) | 2000-02-17 | 2003-01-29 | Iams Company | Method for improving bone modeling and chondrocyte functioning in growing canines |
| RU2435435C2 (en) * | 2007-02-22 | 2011-12-10 | Хилл'c Пет Ньютришн, Инк. | Composition and methods for improvement of growing animals development |
-
1987
- 1987-12-14 JP JP31397587A patent/JPH0625057B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01157912A (en) | 1989-06-21 |
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