JP2005306785A - New cyclooxygenase inhibitor - Google Patents
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Abstract
Description
本発明は、食品、医薬品、医薬部外品及び化粧品等の分野において好適に使用できるダンマラン系化合物からなるシクロオキシゲナーゼ阻害剤に関するものである。 The present invention relates to a cyclooxygenase inhibitor comprising a dammarane compound that can be suitably used in the fields of foods, pharmaceuticals, quasi drugs and cosmetics.
生体内の様々な組織に存在し、細胞膜を構成する不飽和脂肪酸のアラキドン酸は、シクロオキシゲナーゼ(以下、COXと略記する)又はリポキシゲナーゼが関与する代謝によって、ケミカルメディエーターであるプロスタグランジン(以下、PGと略記する)やロイコトリエンなどを生成する。 Arachidonic acid, an unsaturated fatty acid that exists in various tissues in the body and constitutes the cell membrane, is a chemical mediator, prostaglandin (hereinafter referred to as PG), by metabolism involving cyclooxygenase (hereinafter abbreviated as COX) or lipoxygenase. Abbreviated) and leukotrienes.
COXは2種類のアイソザイム(COX−1とCOX−2)から構成されることが知られており(非特許文献1)、そのうちCOX−1は胃や腸等の消化管、腎臓、卵巣、精嚢及び血小板等に存在する構成酵素であり、胃液分泌、利尿、および血小板凝集等の生理的な役割を担っている。一方、COX−2はサイトカインや発癌プロモーター及びホルモン等の刺激により新たに産生される誘導酵素であり、炎症反応、血管新生、アポトーシス、発癌、排卵、分娩及び骨吸収等に関与している(例えば、非特許文献2など)。
COXと疾患との関係では、例えば、リューマチや関節炎を起す一因子として、COXの関与する代謝で生成するケミカルメディエーターが原因であるとの報告から、COXを阻害する薬剤の研究・開発が行われている。さらに、上記のような疾患とCOXとの関係の中で、特にCOX−2の関与が有力であることが判明している。また、近年の研究では、癌やアルツハイマー病においてもCOX−2の関与が報告されている(例えば、非特許文献3など)。
これまでのCOX阻害剤は、COX−1と同時にCOX−2も阻害してしまうため、COX−1の阻害は生理機能に必要なPGの合成も阻害してしまうこととなり、消化管障害等の種々の副作用を引き起こす危険を有していた。例えば、解熱鎮痛剤であるアスピリンは、COX−1及びCOX−2を共に阻害するため胃腸障害を起すことが知られている。
It is known that COX is composed of two types of isozymes (COX-1 and COX-2) (Non-Patent Document 1), of which COX-1 is a gastrointestinal tract such as stomach and intestine, kidney, ovary, and seminal fluid. It is a constitutive enzyme present in sac and platelets and plays a physiological role such as gastric juice secretion, diuresis and platelet aggregation. On the other hand, COX-2 is an inductive enzyme that is newly produced by stimulation of cytokines, tumor promoters and hormones, and is involved in inflammatory reactions, angiogenesis, apoptosis, carcinogenesis, ovulation, labor, bone resorption, etc. (for example, Non-patent document 2).
Regarding the relationship between COX and diseases, for example, as a factor causing rheumatism and arthritis, chemical mediators produced by metabolism involving COX are the cause, and research and development of drugs that inhibit COX have been conducted. ing. Furthermore, it has been found that the involvement of COX-2 is particularly effective in the relationship between the above-mentioned diseases and COX. In recent studies, the involvement of COX-2 has also been reported in cancer and Alzheimer's disease (for example, Non-Patent Document 3).
Since conventional COX inhibitors inhibit COX-2 simultaneously with COX-1, inhibition of COX-1 also inhibits the synthesis of PG necessary for physiological functions, such as gastrointestinal disorders. Had the risk of causing various side effects. For example, aspirin, an antipyretic analgesic, is known to cause gastrointestinal disorders because it inhibits both COX-1 and COX-2.
そこで上記の問題を解決するための手段として、COX−1を阻害せずにCOX−2のみを選択的に阻害する薬剤が注目されている。即ち、COX−2の選択的阻害剤であれば、癌の増殖や転移および炎症等を少ない副作用で抑制する効果が期待できる。この代表的なものがCelecoxib、Rofecoxib等であり、更にその他のものも精力的に開発が行われている(例えば特許文献1、特許文献2参照。)。 Therefore, as a means for solving the above problems, an agent that selectively inhibits only COX-2 without inhibiting COX-1 has attracted attention. That is, a selective inhibitor of COX-2 can be expected to suppress cancer growth, metastasis, inflammation and the like with few side effects. Typical examples of this are Celecoxib, Rofecoxib, and the like, and others have been vigorously developed (see, for example, Patent Document 1 and Patent Document 2).
一方、種々の植物やキノコ類に含まれる生理活性成分として、様々なトリテルペン骨格を有する化合物が抗腫瘍剤、血管新生抑制剤、抗アレルギー剤、養毛料やニキビ治療などの医薬品、医薬部外品や化粧品等の分野において報告されている(例えば、特許文献3〜5など)。さらに、トリテルペン骨格を有する化合物のうち、特にダンマラン系化合物が抗腫瘍効果を有することも知られている(特許文献6及び7)。しかしながら、ダンマラン系化合物(1)及び(2)について、COX阻害作用又はCOX−2選択的阻害作用に関する報告はない。 On the other hand, as a physiologically active ingredient contained in various plants and mushrooms, compounds having various triterpene skeletons are antitumor agents, angiogenesis inhibitors, antiallergic agents, pharmaceuticals such as hair restorers and acne treatments, and quasi-drugs. And in the field of cosmetics and the like (for example, Patent Documents 3 to 5). Furthermore, it is also known that among compounds having a triterpene skeleton, danmaran compounds have an antitumor effect (Patent Documents 6 and 7). However, there is no report regarding the COX inhibitory action or the COX-2 selective inhibitory action of dammarane compounds (1) and (2).
本発明の目的は、上述のような状況をふまえ、医薬品の分野で有用なシクロオキシゲナーゼ阻害剤を提供することにある。 An object of the present invention is to provide a cyclooxygenase inhibitor useful in the field of pharmaceuticals in view of the above situation.
本発明者等は、上記課題を解決するため鋭意研究を行った結果、これまでに発明者らがウリ科植物のアマチャズル(Gynostemma pentaphyllum MAKINO(Cucurbitaceae))より分離・同定したダンマラン系化合物が、優れたシクロオキシゲナーゼ阻害作用を有していることを見出し、本発明を完成したのである。
すなわち、本発明は下記一般式で表されるダンマラン系化合物(1)または(2)の少なくともいずれか1つを含有することを特徴とするシクロオキシゲナーゼ阻害剤である。
As a result of diligent research to solve the above-mentioned problems, the inventors of the present invention are excellent in dammamaran compounds that have been isolated and identified by the inventors from Guriostemma pentaphyllum MAKINO (Cucurbitaceae). The present invention was completed by finding that it has a cyclooxygenase inhibitory action.
That is, the present invention is a cyclooxygenase inhibitor characterized by containing at least one of the dammarane compounds (1) and (2) represented by the following general formula.
本発明のダンマラン系化合物は優れたシクロオキシゲナーゼ阻害効果、特に選択的なシクロオキシゲナーゼ−2阻害効果を有しており、食品、医薬品、医薬部外品及び化粧品等の分野に利用することができる。 The dammaran compound of the present invention has an excellent cyclooxygenase inhibitory effect, particularly a selective cyclooxygenase-2 inhibitory effect, and can be used in the fields of foods, pharmaceuticals, quasi drugs and cosmetics.
以下、本発明について詳細に説明する。
本発明のダンマラン系化合物は、化学合成によって得てもよいが、例えば、ウリ科植物のアマチャズル(Gynostemma pentaphyllum MAKINO(Cucurbitaceae))から抽出することができる。このアマチャズルは、アジア地域に広く分布する多年生つる性草本である。
Hereinafter, the present invention will be described in detail.
The dammaran compound of the present invention may be obtained by chemical synthesis, but can be extracted, for example, from the cucurbitaceae plant Gynostemma pentaphyllum MAKINO (Cucurbitaceae). This amachazul is a perennial vine herb widely distributed in the Asian region.
アマチャズルから上記ダンマラン系化合物を抽出するには、乾燥させたアマチャズルを、抽出効率を向上させる観点から適当な大きさに細かく裁断して、例えば、水、親水性有機溶媒又はこれらの混合溶媒を使用して室温(20〜25℃)程度の温度で浸漬し抽出処理するか、溶媒の沸点程度の温度で抽出処理する。親水性有機溶媒としては、例えばメタノール、エタノール、プロピルアルコール、イソプロピルアルコール等の炭素数1〜5の低級アルコールなどが挙げられ、これら親水性有機溶媒と水との混合溶媒などを用いることができる。なお、水と親水性有機溶媒との混合系溶媒を使用する場合には、親水性有機溶媒の含有率が50〜80%(容積%)となるように調製することが好ましい。これをアンバーライトカラムに付し、吸着部を水などで洗浄した後メタノールで溶出し減圧濃縮する。 In order to extract the above dammaran compound from amachazul, the dried amachazul is finely cut into an appropriate size from the viewpoint of improving the extraction efficiency and, for example, water, a hydrophilic organic solvent or a mixed solvent thereof is used. Then, it is immersed and extracted at a temperature of about room temperature (20 to 25 ° C.) or extracted at a temperature of about the boiling point of the solvent. Examples of the hydrophilic organic solvent include lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propyl alcohol, and isopropyl alcohol, and a mixed solvent of these hydrophilic organic solvent and water can be used. In addition, when using the mixed solvent of water and a hydrophilic organic solvent, it is preferable to prepare so that the content rate of a hydrophilic organic solvent may be 50 to 80% (volume%). This is applied to an amberlite column, and the adsorbing part is washed with water and then eluted with methanol and concentrated under reduced pressure.
さらに、上記の操作で得られた抽出エキスを減圧濃縮し、適量のメタノールを加えて、例えばアルミナカラムに通導し、吸着部を水などで洗浄した後メタノールで溶出する。得られた溶液を減圧乾燥し粗精製物とする。これを、通常の分離に用いられるシリカゲルカラムクロマトグラフィーや分取高速液体クロマトグラフィー等を組み合わせて分画することにより、本発明のダンマラン系化合物(1)及び(2)を単離・精製することができる。これらの単離・精製・同定については、発明者らの報告に詳述している。(在原重信ら,薬学雑誌,1983年,103巻,p173−185、在原重信ら,薬学雑誌,1984年,104巻,p1043−1049) Further, the extract obtained by the above operation is concentrated under reduced pressure, an appropriate amount of methanol is added, and the mixture is led to, for example, an alumina column, and the adsorption part is washed with water and then eluted with methanol. The obtained solution is dried under reduced pressure to obtain a crude product. Isolating and purifying the dammarane-based compounds (1) and (2) of the present invention by fractionating them in combination with silica gel column chromatography, preparative high-performance liquid chromatography, etc., which are usually used for separation. Can do. These isolation, purification and identification are described in detail in the report of the inventors. (Shigenobu Aihara et al., Pharmaceutical Journal, 1983, 103, p173-185, Shigenobu Aihara, Pharmaceutical Journal, 1984, 104, p1043-1049)
上記のダンマラン系化合物(1)及び/又は(2)を、食品、医薬品、医薬部外品及び化粧品等として用いる場合、前記の如くしてアマチャズルから単離したものでも良いが、精製前の抽出物として用いても良い。抽出物としては、これらの化合物のうち少なくとも1種を含有する粗抽出物を用いても良いが、特に医薬品に用いる場合は純度の高い精製物を用いることが好ましい。
かくして得られるダンマラン系化合物(1)及び(2)は、後述の如くシクロオキシゲナーゼ阻害作用、特に選択的なシクロオキシゲナーゼ−2阻害作用を有するため、食品、医薬品、医薬部外品や化粧品等の処方に配合して使用することができる。
When the above dammarane compound (1) and / or (2) is used as food, pharmaceuticals, quasi-drugs, cosmetics, etc., it may be isolated from amachazul as described above. You may use as a thing. As the extract, a crude extract containing at least one of these compounds may be used, but it is preferable to use a purified product having a high purity, particularly when used for a pharmaceutical product.
Since the dammaran compounds (1) and (2) thus obtained have a cyclooxygenase inhibitory action, particularly a selective cyclooxygenase-2 inhibitory action as described later, they are incorporated in prescriptions such as foods, pharmaceuticals, quasi drugs and cosmetics. Can be used.
以下、実施例により本発明を詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
(化合物の抽出・単離)
アマチャズルを出発原料として文献(在原重信ら,薬学雑誌,1983年,103巻,p173−185、在原重信ら,薬学雑誌,1984年,104巻,p1043−1049)に従い、化合物(1)及び(2)を抽出、単離した。単離した化合物は、核磁気共鳴スペクトル測定を主体とする各種スペクトルデータ、酸加水分解による糖の同定を行い、化合物(1)及び(2)の構造を確認した。
(Extraction and isolation of compounds)
Compounds (1) and (2) according to the literature (Shigenobu Aihara et al., Pharmaceutical Journal, 1983, 103, p173-185, Shigenobu Aihara, Pharmaceutical Journal, 1984, 104, p1043-1049) starting from amachazul. ) Was extracted and isolated. The isolated compound was subjected to various spectral data mainly based on nuclear magnetic resonance spectrum measurement and sugar identification by acid hydrolysis to confirm the structures of the compounds (1) and (2).
より詳細には、融点、旋光度、赤外吸収(以下、IRと略記)スペクトル、核磁気共鳴(以下、NMRと略記)スペクトルを測定した。
融点は、柳本製微量融点測定装置により測定し、すべて未補正である。旋光度は、日本分光製DIP−180型を用いてメタノール溶液で測定した。IRスペクトルは、日立製EPI−G3型を用いKBr法で測定した。NMRスペクトルは、Varian製XL−100A型を用い、重ピリジン(以下、C5D5Nと略記)を測定溶媒に、テトラメチルシランを内部標準として測定した。また、NMRスペクトル解析では、化学シフト(δ値)をppm単位で、結合定数をHz単位で示し、略号を使用し、各々 s; singlet, d; doublet, t; triplet, m; multiplet, br; broad, dd; double doublet, dt; double tripletで表した。さらに、ピークの帰属は、トリテルペン骨格や糖鎖の炭素番号をもとに表記した。
More specifically, melting point, optical rotation, infrared absorption (hereinafter abbreviated as IR) spectrum, and nuclear magnetic resonance (hereinafter abbreviated as NMR) spectrum were measured.
Melting points were measured with a Yanagimoto micro melting point measuring device and all are uncorrected. The optical rotation was measured with a methanol solution using a DIP-180 model manufactured by JASCO Corporation. The IR spectrum was measured by KBr method using Hitachi EPI-G3 type. The NMR spectrum was measured by using Varian XL-100A, using heavy pyridine (hereinafter abbreviated as C 5 D 5 N) as a measurement solvent and tetramethylsilane as an internal standard. In NMR spectrum analysis, chemical shift (δ value) is expressed in ppm, coupling constant is expressed in Hz, abbreviations are used, and s; singlet, d; doublet, t; triplet, m; multiplet, br; It was expressed as broad, dd; double doublet, dt; double triplet. Furthermore, the peak assignment was expressed based on the carbon number of the triterpene skeleton or sugar chain.
上記の操作及び構造解析から、アマチャズルから単離した化合物(1)及び(2)の構造式、並びに理化学的性質は以下の通りである。 From the above operation and structural analysis, the structural formulas and physicochemical properties of the compounds (1) and (2) isolated from the amachazul are as follows.
化合物(1)の構造式Structural formula of compound (1)
化合物(1)の理化学的性質
○融点:187 − 189 ℃
○旋光度:[α]25 D +13.4 °(c 1.8,メタノール)
○IRスペクトル:FT-IR (dry film) νmax 3375, 1635, 1165, 1070,1045,1020,990cm-1
○NMRスペクトル:
1)1H-NMR (C5D5N);δ 0.81s, 0.92s, 0.95s, 0.95s, 1.28s,1.57s,1.60d(J=5Hz),1.62s,1.62s,4.83d(J=7.5Hz),5.10d(J=7.5Hz),5.22m,5.42s
2)13C-NMR(C5D5N);解析結果は表1〜3に示した。
Physicochemical properties of Compound (1) Melting point: 187-189 ° C
○ Optical rotation: [α] 25 D +13.4 ° (c 1.8, methanol)
○ IR spectrum: FT-IR (dry film) ν max 3375, 1635, 1165, 1070, 1045, 1020, 990cm -1
○ NMR spectrum:
1) 1 H-NMR (C 5 D 5 N); δ 0.81s, 0.92s, 0.95s, 0.95s, 1.28s, 1.57s, 1.60d (J = 5Hz), 1.62s, 1.62s, 4.83d ( J = 7.5Hz), 5.10d (J = 7.5Hz), 5.22m, 5.42s
2) 13 C-NMR (C 5 D 5 N); analysis results are shown in Tables 1 to 3.
化合物(2)の構造式Structural formula of compound (2)
化合物(2)の理化学的性質
○融点:202 − 204 ℃
○旋光度:[α]22 D +6.6 °(c 2.1, メタノール)
○IRスペクトル:FT-IR (dry film)νmax 3375, 1640, 1150, 1075, 1040, 1015, 980 cm-1
○NMRスペクトル:
1)1H-NMR (C5D5N);δ 0.90s,0.92s,0.96s,1.05s, 1.27s, 1.57s, 1.63s, 1.68s, 1.65d(J=6Hz), 3.15(J=9.5Hz), 4.94(J=6.5Hz), 5.06(J=6.5Hz), 5.47(J=7Hz), 5.37s
2)13C-NMR (C5D5N);解析結果は表1〜3に示した。
Physicochemical properties of compound (2) Melting point: 202-204 ℃
○ Optical rotation: [α] 22 D +6.6 ° (c 2.1, methanol)
○ IR spectrum: FT-IR (dry film) ν max 3375, 1640, 1150, 1075, 1040, 1015, 980 cm -1
○ NMR spectrum:
1) 1 H-NMR (C 5 D 5 N); δ 0.90s, 0.92s, 0.96s, 1.05s, 1.27s, 1.57s, 1.63s, 1.68s, 1.65d (J = 6Hz), 3.15 (J = 9.5Hz), 4.94 (J = 6.5Hz), 5.06 (J = 6.5Hz), 5.47 (J = 7Hz), 5.37s
2) 13 C-NMR (C 5 D 5 N); analysis results are shown in Tables 1 to 3.
(COX−1及びCOX−2阻害活性評価試験)
実施例1で取得したダンマラン系化合物(1)及び(2)の各々について、COX−1阻害活性及びCOX−2阻害活性を測定した。
酵素には、COX−1としてヒツジ精嚢ミクロソーム(カイマンケミカル社製)、COX−2としてヒツジ胎盤由来COX−2精製品(カイマンケミカル社製)を使用し、各酵素によるアラキドン酸からPGE2への転換率を酵素活性とした。この酵素反応系で、化合物の各々を被検試料として添加し、以下の通り操作してCOX−1阻害活性及びCOX−2阻害活性を算出した。
(COX-1 and COX-2 inhibitory activity evaluation test)
For each of the dammarane compounds (1) and (2) obtained in Example 1, the COX-1 inhibitory activity and the COX-2 inhibitory activity were measured.
For the enzyme, sheep seminal vesicle microsomes (manufactured by Caiman Chemical) are used as COX-1, and sheep placenta-derived COX-2 purified product (manufactured by Caiman Chemical) is used as COX-2, and arachidonic acid from each enzyme is converted to PGE 2 . The conversion rate was defined as the enzyme activity. In this enzyme reaction system, each of the compounds was added as a test sample and operated as follows to calculate COX-1 inhibitory activity and COX-2 inhibitory activity.
すなわち、2.9mMフェノール及び1.4mMのヘマチンを含む143mMトリス緩衝液(pH7.5)70μLに、10%ジメチルスルホキシド水溶液に溶解させた被検試料(1×10-3M、10μL)を加えた後、COX−1あるいはCOX−2溶液(2IU、10μL)を添加して混和した。これを37℃で2分間プレインキュべートを行った。次いで、100mMトリス緩衝液で濃度を25.5μMに調整した放射性標識[1-14C]アラキドン酸(アマシャム・ファルマシア・バイオテク社製)を、10μL(0.14μCi)加えて混和した。これを37℃で2分間反応させた後、すぐに氷冷した。 That is, a test sample (1 × 10 −3 M, 10 μL) dissolved in 10% dimethyl sulfoxide aqueous solution was added to 70 μL of 143 mM Tris buffer (pH 7.5) containing 2.9 mM phenol and 1.4 mM hematin. After that, COX-1 or COX-2 solution (2 IU, 10 μL) was added and mixed. This was preincubated at 37 ° C. for 2 minutes. Subsequently, 10 μL (0.14 μCi) of radiolabeled [1- 14 C] arachidonic acid (Amersham Pharmacia Biotech) adjusted to a concentration of 25.5 μM with 100 mM Tris buffer was added and mixed. This was reacted at 37 ° C. for 2 minutes and immediately cooled on ice.
COX活性の算出は、柳と小松の方法(Biochem. Pharmacol.,25,937-941,1976)を参考に行った。すなわち、反応液にn−ヘキサン:酢酸エチル(2:1)混合液を0.4mL加えて30秒間撹拌した後、遠心分離して未反応のアラキドン酸を含む有機層を除去した。同様の抽出操作を2回繰り返した後、水層に50μLのエタノールを加えて30秒間攪拌した。その後、2,000×gで1分間遠心し、水層0.1mLを液体シンチレーションカウンター用バイアルに移した。これにシンチレーターとしてクリアゾル1(ナカライテスク社製)を2mL加え、PGE2分画カクテルとした。放射活性を液体シンチレ−ションカウンター(ALOKA社製LSC−1000)で測定し、放射活性の割合を算出してPGE2転換率とした。 COX activity was calculated with reference to the method of Yanagi and Komatsu (Biochem. Pharmacol., 25, 937-941, 1976). That is, 0.4 mL of n-hexane: ethyl acetate (2: 1) mixed solution was added to the reaction solution and stirred for 30 seconds, followed by centrifugation to remove the organic layer containing unreacted arachidonic acid. After the same extraction operation was repeated twice, 50 μL of ethanol was added to the aqueous layer and stirred for 30 seconds. Thereafter, the mixture was centrifuged at 2,000 × g for 1 minute, and 0.1 mL of the aqueous layer was transferred to a liquid scintillation counter vial. To this was added 2 mL of clear sol 1 (manufactured by Nacalai Tesque) as a scintillator to prepare a PGE 2 fraction cocktail. Radioactivity was measured with a liquid scintillation counter (ALSCA LSC-1000), and the ratio of radioactivity was calculated as the PGE 2 conversion rate.
比較対照として、アスピリン(1×10-2M、10μL)を、被検試料の代わりに用いて同様に操作した。
被検試料を添加しなかった時のPGE2転換率を100%とし、各被検試料を添加した時のPGE2転換率との差[100(%)−PGE2転換率(%)]をCOX阻害率(%)とした。その結果を表4に示す。
As a comparative control, aspirin (1 × 10 −2 M, 10 μL) was used instead of the test sample, and the same operation was performed.
The PGE 2 conversion rate when no test sample was added was defined as 100%, and the difference from the PGE 2 conversion rate when each test sample was added [100 (%) − PGE 2 conversion rate (%)] The COX inhibition rate (%) was used. The results are shown in Table 4.
本発明のダンマラン系化合物は優れたシクロオキシゲナーゼ阻害効果、特に選択的なシクロオキシゲナーゼ−2阻害効果を有しており、食品、医薬品、医薬部外品および化粧品等の分野に利用することができる。
The dammarane compound of the present invention has an excellent cyclooxygenase inhibitory effect, particularly a selective cyclooxygenase-2 inhibitory effect, and can be used in the fields of foods, pharmaceuticals, quasi drugs and cosmetics.
Claims (2)
A cyclooxygenase-2 selective inhibitor comprising a dammarane compound represented by formula (1) or (2).
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CN104367592A (en) * | 2014-11-19 | 2015-02-25 | 杨公明 | New application of sheep placenta extract in treatment of skin burn and trauma |
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CN104367623A (en) * | 2014-11-19 | 2015-02-25 | 杨公明 | Biological agent with function of treating skin burn wounds |
CN104367592A (en) * | 2014-11-19 | 2015-02-25 | 杨公明 | New application of sheep placenta extract in treatment of skin burn and trauma |
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