JP2023109691A - Pharmaceutical composition and application thereof in preparation of anti-osteoporosis agent - Google Patents
Pharmaceutical composition and application thereof in preparation of anti-osteoporosis agent Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 230000003262 anti-osteoporosis Effects 0.000 title claims abstract description 6
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 39
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229940093265 berberine Drugs 0.000 claims abstract description 20
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims abstract description 20
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims abstract description 17
- AEDDIBAIWPIIBD-ZJKJAXBQSA-N mangiferin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(OC=2C(=CC(O)=C(O)C=2)C2=O)C2=C1O AEDDIBAIWPIIBD-ZJKJAXBQSA-N 0.000 claims abstract description 6
- YLRXAIKMLINXQY-ZDUSSCGKSA-O (S)-magnoflorine Chemical compound C1=C(OC)C(O)=C2C3=C(O)C(OC)=CC=C3C[C@@H]3[N+](C)(C)CCC1=C23 YLRXAIKMLINXQY-ZDUSSCGKSA-O 0.000 claims abstract description 3
- KYEAXNAYHSCLMT-CVVGWEDFSA-N Magnoflorine Natural products C[C@H]1OC=C2[C@@H]3[C@@H]1CN4CCc5c([nH]c6ccccc56)[C@@H]4[C@@H]3OC2=O KYEAXNAYHSCLMT-CVVGWEDFSA-N 0.000 claims abstract description 3
- YWQSXCGKJDUYTL-UHFFFAOYSA-N Mangiferin Natural products CC(CCC=C(C)C)C1CC(C)C2C3CCC4C(C)(C)CCCC45CC35CCC12C YWQSXCGKJDUYTL-UHFFFAOYSA-N 0.000 claims abstract description 3
- PTPHDVKWAYIFRX-UHFFFAOYSA-N Palmatine Natural products C1C2=C(OC)C(OC)=CC=C2C=C2N1CCC1=C2C=C(OC)C(OC)=C1 PTPHDVKWAYIFRX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940043357 mangiferin Drugs 0.000 claims abstract description 3
- QUCQEUCGKKTEBI-UHFFFAOYSA-N palmatine Chemical compound COC1=CC=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C1OC QUCQEUCGKKTEBI-UHFFFAOYSA-N 0.000 claims abstract description 3
- UWEHVAXMSWXKRW-UHFFFAOYSA-N Sinactine Chemical compound C1C2=C3OCOC3=CC=C2CC2N1CCC1=C2C=C(OC)C(OC)=C1 UWEHVAXMSWXKRW-UHFFFAOYSA-N 0.000 claims abstract 4
- ALFVETOFBDLGLQ-MRXNPFEDSA-N (+)-Sinactine Natural products O(C)c1c(OC)cc2c([C@@H]3[N+](Cc4c5OCOc5ccc4C3)CC2)c1 ALFVETOFBDLGLQ-MRXNPFEDSA-N 0.000 claims abstract 2
- RBBVPNQTBKHOEQ-KKSFZXQISA-O Phellodendrine Chemical compound C1CC2=CC(OC)=C(O)C=C2[C@H]2[N@+]1(C)CC(C=C(C(=C1)O)OC)=C1C2 RBBVPNQTBKHOEQ-KKSFZXQISA-O 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 43
- 229940079593 drug Drugs 0.000 claims description 38
- 239000003472 antidiabetic agent Substances 0.000 claims description 28
- 230000003178 anti-diabetic effect Effects 0.000 claims description 22
- LYFPBWOBIJJASK-INIZCTEOSA-N (S)-(-)-Canadine Natural products O(C)c1c(OC)ccc2c1C[N+]1[C@H](c3c(cc4OCOc4c3)CC1)C2 LYFPBWOBIJJASK-INIZCTEOSA-N 0.000 claims description 17
- 241000218378 Magnolia Species 0.000 claims description 17
- PQECCKIOFCWGRJ-UHFFFAOYSA-N Tetrahydro-berberine Natural products C1=C2C3CC4=CC=C(OC)C(O)=C4CN3CCC2=CC2=C1OCO2 PQECCKIOFCWGRJ-UHFFFAOYSA-N 0.000 claims description 17
- VZTUIEROBZXUFA-UHFFFAOYSA-N canadine Chemical compound C1=C2C3CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 VZTUIEROBZXUFA-UHFFFAOYSA-N 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 208000002249 Diabetes Complications Diseases 0.000 claims description 5
- 206010012655 Diabetic complications Diseases 0.000 claims description 5
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 5
- 229940124605 anti-osteoporosis drug Drugs 0.000 claims description 4
- 150000002211 flavins Chemical class 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims 1
- 201000001119 neuropathy Diseases 0.000 claims 1
- 230000007823 neuropathy Effects 0.000 claims 1
- 208000033808 peripheral neuropathy Diseases 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 50
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 241000218377 Magnoliaceae Species 0.000 abstract 1
- 238000011282 treatment Methods 0.000 description 91
- 241000252212 Danio rerio Species 0.000 description 63
- 230000000694 effects Effects 0.000 description 36
- 230000014509 gene expression Effects 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 15
- 230000001009 osteoporotic effect Effects 0.000 description 14
- 230000011164 ossification Effects 0.000 description 11
- 208000006386 Bone Resorption Diseases 0.000 description 10
- 230000024279 bone resorption Effects 0.000 description 10
- 241000251468 Actinopterygii Species 0.000 description 8
- 210000000988 bone and bone Anatomy 0.000 description 8
- 230000003287 optical effect Effects 0.000 description 8
- 238000003359 percent control normalization Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 7
- 102000013563 Acid Phosphatase Human genes 0.000 description 7
- 108010051457 Acid Phosphatase Proteins 0.000 description 7
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 7
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 7
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 7
- 229960003105 metformin Drugs 0.000 description 7
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 101150098533 SOST gene Proteins 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 230000000366 juvenile effect Effects 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 101150074062 Tnfsf11 gene Proteins 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 2
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 2
- 239000002617 bone density conservation agent Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 208000008924 Femoral Fractures Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は糖尿病の治療技術分野に属し、具体的には医薬組成物及び抗骨粗鬆症薬物の製造
における応用に関する。
The present invention belongs to the technical field of treating diabetes, and specifically relates to its application in the preparation of pharmaceutical compositions and anti-osteoporosis drugs.
糖尿病骨粗鬆症は糖尿病合併骨量減少、骨微細構造変化、骨脆性増加など骨折が発生しや
すい全身性、代謝性骨格疾患である。糖尿病患者の中で発病率は60%に達し、長期にわた
って深刻な痛みと機能障害の主な原因となっている。
Diabetic osteoporosis is a systemic and metabolic skeletal disease associated with diabetes associated with bone loss, changes in bone microstructure, increased bone fragility, and other factors that lead to fractures. It has an incidence rate of up to 60% among diabetics and is a leading cause of severe long-term pain and disability.
現在の糖尿病骨粗鬆症の臨床治療において、骨吸収抑制剤（例えばビスリン酸塩、ホルモ
ン、カルシトニンなど）と骨形成促進剤（例えば甲状腺ホルモン類似ペプチドなど）が一
般的に用いられている。しかし、上述の治療薬は依然として多くの不足が存在し、主に：
（1）骨吸収抑制剤の長期服用後、下顎部壊死、非典型大腿骨骨折、心臓病と乳癌の多発
などの副作用が現れやすい、（2）骨形成促進剤は骨肉腫または他の骨腫瘍を引き起こす
リスクがある。
In current clinical treatments for diabetic osteoporosis, bone resorption inhibitors (eg, bisphosphates, hormones, calcitonin, etc.) and bone formation promoters (eg, thyroid hormone-like peptides, etc.) are commonly used. However, there are still many deficiencies in the above therapeutic agents, mainly:
(1) Side effects such as mandibular necrosis, atypical femoral fracture, heart disease and breast cancer are likely to occur after long-term use of bone resorption inhibitors. there is a risk of causing
糖尿病骨粗鬆症の発病機序は比較的に複雑であるため、骨粗鬆症を治療する薬物あるいは
糖尿病薬物だけで治療を行うだけでは糖尿病骨粗鬆症の肝心な病理段階を遮断することが
できず、治療効果が理想的ではない。そのため、糖尿病骨粗鬆症を効果的に治療するため
には、血糖降下機能と骨代謝機能を同時に備えた薬物が必要である。
Since the pathogenesis of diabetic osteoporosis is relatively complicated, only treatment with osteoporosis drugs or diabetic drugs alone cannot block the key pathological stage of diabetic osteoporosis, and the therapeutic effect is ideal. isn't it. Therefore, in order to effectively treat diabetic osteoporosis, a drug having both hypoglycemic function and bone metabolism function is required.
本発明の目的は、血糖降下および糖尿病性骨粗鬆症の予防および治療として機能する医薬
組成物および抗骨粗鬆症薬の調製におけるその応用を提供することである。
上記発明の目的を達成するために、本発明は以下の手段を提供する。
It is an object of the present invention to provide a pharmaceutical composition and its application in the preparation of an anti-osteoporotic drug that functions as a hypoglycemic and prophylactic and therapeutic treatment for diabetic osteoporosis.
In order to achieve the above object of the invention, the present invention provides the following means.
本発明は、７．６４～４０．９０重量％のマンゴシド（ｍａｎｇｉｆｅｒｉｎ）と、４．
２６～７．３９重量％のテトラヒドロベルベリン（ｔｅｔｒａｈｙｄｒｏｅｐｉｂｅｒｂ
ｅｒｉｎｅ）と、２４．３３～３５．３１重量％のフラビン（ｐｈｅｌｌｏｄｅｎｄｒｉ
ｎｅ）と、１０．１１～１４．６４重量％のモクレン塩基（ｍａｇｎｏｆｌｏｒｉｎｅ）
と、２．３０～４．２６重量％のヒドロキシオキシベルベリン（１３－ｈｙｄｒｏｘｙｏ
ｘｙｂｅｒｂｅｒｉｎｅ）と、０．１２～０．２９重量％のバマルティン（ｐａｌｍａｔ
ｉｎｅ）と、１７．９６～３０．７１重量％のベルベリン（ｂｅｒｂｅｒｉｎｅ）とを含
有する医薬組成物を提供する。
本発明の医薬組成物は、血糖値を著しく低下させるだけでなく、糖尿病性骨粗鬆症のゼブ
ラフィッシュの頭部骨格エリアを著しく向上（Ｐ＜０．０１）し、頭部骨格光学密度（Ｐ
＜０．０１）を著しく向上（Ｐ＜０．０１）することができ、そして、アルカリホスファ
ターゼ活性を向上（Ｐ＜０．０１）し、骨形成関連遺伝子（ａｌｐ、ｏｐｇ、ｒｕｎｘ２
）の発現を促進（Ｐ＜０．０１）することができ、そして、抗酒石酸酸性ホスファターゼ
活性を低下（Ｐ＜０．０１）し、骨吸収関連遺伝子（ａｃｐ５α、ｓｏｓｔ、ｒａｎｋｌ
）の発現を低減（Ｐ＜０．０１）することができ、さらに、該医薬組成物は、生体に毒性
や副作用がなく、安全性と信頼性が高く、血糖降下薬、抗糖尿病性骨粗鬆症薬、抗骨粗鬆
症薬の研究開発の見通しが良好である。
これに基づき、本発明はまた、血糖降下薬、抗糖尿病合併症薬および抗骨粗鬆症薬の調製
における上記の医薬組成物の応用を提供する。
該抗糖尿病合併症薬は、抗糖尿病性骨粗鬆症薬、抗糖尿病性腎症薬、抗糖尿病性神経障害
薬および抗糖尿病性血管合併症薬の少なくとも１種類を含む。
該抗糖尿病合併症薬には、抗糖尿病性骨粗鬆症薬が含まれる。
本発明はまた、血糖降下薬、抗糖尿病合併症薬および抗骨粗鬆症薬を提供し、上記の薬剤
らはすべて本発明の医薬組成物を含有する。
上記医薬組成物は、７．６４～４０．９０重量％のマンゴシドと、４．２６～７．３９重
量％のテトラヒドロベルベリンと、２４．３３～３５．３１重量％のフラビンと、１０．
１１～１４．６４重量％のモクレン塩基と、２．３０～４．２６重量％のヒドロキシオキ
シベルベリンと、０．１２～０．２９重量％のバマルティンと、１７．９６～３０．７１
重量％のベルベリンとを含有する。
上記医薬組成物は、１９．６９重量％のマンゴシドと、６．０１重量％のテトラヒドロベ
ルベリンと、３３．２６重量％のフラビンと、１２．９４重量％のモクレン塩基と、２．
９２重量％のヒドロキシオキシベルベリンと、０．２２重量％のバマルティンと、２４．
９６重量％のベルベリンとを含有する。
4. 7.64 to 40.90% by weight of mangiferin;
26-7.39% by weight of tetrahydroepiberine
erine) and 24.33-35.31% by weight of flavin (pellodendri
ne) and 10.11-14.64% by weight magnoflorine
and 2.30-4.26% by weight of hydroxyoxyberberine (13-hydroxyo
xyberberine) and 0.12-0.29% by weight of bamartine (palmat
ine) and 17.96-30.71% by weight of berberine.
The pharmaceutical composition of the present invention not only significantly lowered blood glucose levels, but also significantly improved (P<0.01) cranial skeletal area and cranial skeletal optical density (P
<0.01), and improved (P<0.01) alkaline phosphatase activity, osteogenesis-related genes (alp, opg, runx2).
) and decreased (P<0.01) antitartrate acid phosphatase activity, bone resorption-related genes (acp5α, sost, rankl
) can be reduced (P<0.01), and the pharmaceutical composition has no toxicity or side effects in vivo, is highly safe and reliable, and can be used as a hypoglycemic agent and antidiabetic osteoporosis agent. , anti-osteoporosis drug research and development prospects are good.
Based on this, the present invention also provides the application of the above pharmaceutical composition in the preparation of hypoglycemic agents, anti-diabetic complications agents and anti-osteoporotic agents.
The anti-diabetic complications drug includes at least one of an anti-diabetic osteoporosis drug, an anti-diabetic nephropathy drug, an anti-diabetic neuropathy drug and an anti-diabetic vascular complications drug.
The anti-diabetic complications drug includes an anti-diabetic osteoporosis drug.
The present invention also provides hypoglycemic agents, anti-diabetic complications agents and anti-osteoporosis agents, all of which contain the pharmaceutical compositions of the present invention.
The pharmaceutical composition contains 7.64-40.90% by weight mangoside, 4.26-7.39% by weight tetrahydroberberine, 24.33-35.31% by weight flavin,10.
11-14.64% by weight magnolia base, 2.30-4.26% by weight hydroxyoxyberberine, 0.12-0.29% by weight bamartine, 17.96-30.71%
% berberine by weight.
The pharmaceutical composition contains 19.69% by weight mangoside, 6.01% by weight tetrahydroberberine, 33.26% by weight flavin, 12.94% by weight magnolia base,2.
92% by weight of hydroxyoxyberberine and 0.22% by weight of bamartine;24.
Contains 96% by weight of berberine.
本発明の医薬組成物は、血糖値を著しく低下させるだけでなく、糖尿病性骨粗鬆症のゼブ
ラフィッシュの頭部骨格エリアを著しく向上（Ｐ＜０．０１）し、頭部骨格光学密度（Ｐ
＜０．０１）を著しく向上（Ｐ＜０．０１）することができ、そして、アルカリホスファ
ターゼ活性を向上（Ｐ＜０．０１）し、骨形成関連遺伝子（ａｌｐ、ｏｐｇ、ｒｕｎｘ２
）の発現を促進（Ｐ＜０．０１）することができ、そして、抗酒石酸酸性ホスファターゼ
活性を低下（Ｐ＜０．０１）し、骨吸収関連遺伝子（ａｃｐ５α、ｓｏｓｔ、ｒａｎｋｌ
）の発現を低減（Ｐ＜０．０１）することができ、さらに、該医薬組成物は、生体に毒性
や副作用がなく、安全性と信頼性が高く、血糖降下薬、抗糖尿病性骨粗鬆症薬、抗骨粗鬆
症薬の研究開発の見通しが良好である。
The pharmaceutical composition of the present invention not only significantly lowered blood glucose levels, but also significantly improved (P<0.01) cranial skeletal area and cranial skeletal optical density (P
<0.01), and improved (P<0.01) alkaline phosphatase activity, osteogenesis-related genes (alp, opg, runx2).
) and decreased (P<0.01) antitartrate acid phosphatase activity, bone resorption-related genes (acp5α, sost, rankl
) can be reduced (P<0.01), and the pharmaceutical composition has no toxicity or side effects in vivo, is highly safe and reliable, and can be used as a hypoglycemic agent and antidiabetic osteoporosis agent. , anti-osteoporosis drug research and development prospects are good.
以下、本発明の技術的態様について、図面及び具体的な実施形態に基づいてさらに詳細に
説明する。
Hereinafter, technical aspects of the present invention will be described in more detail based on the drawings and specific embodiments.
実施例１
１９．６９重量％のマンゴシドと、６．０１重量％のテトラヒドロベルベリンと、３３．
２６重量％のフラビンと、１２．９４重量％のモクレン塩基と、２．９２重量％のヒドロ
キシオキシベルベリンと、０．２２重量％のバマルティンと、２４．９６重量％のベルベ
リンとを含有する医薬組成物。
各原料を上記物質の量で混合することにより、本実施例の医薬組成物を得た。
本実施例の医薬組成物の抗糖尿病性骨粗鬆症機能を研究するために、Ａ、Ｂ組のゼブラフ
ィッシュを試験対象とし、それぞれ幼魚実験と成魚実験を行った。このうち、幼魚実験は
頭部骨格の骨量と光学密度に対する医薬組成物の影響を観察するために用いられ、成魚実
験は骨形成の促進と骨吸収の抑制における医薬組成物の役割を観察するために用いられる
。
Example 1
19.69% by weight mangoside; 6.01% by weight tetrahydroberberine;33.
A medicament containing 26% by weight flavin, 12.94% by weight magnolia base, 2.92% by weight hydroxyoxyberberine, 0.22% by weight bamartine and 24.96% by weight berberine Composition.
The pharmaceutical composition of this example was obtained by mixing each raw material in the amount of the above substances.
In order to study the anti-diabetic osteoporosis function of the pharmaceutical composition of this example, zebrafish in groups A and B were used as test subjects, and juvenile and adult fish experiments were performed. Of these, the juvenile fish experiment is used to observe the effects of the pharmaceutical composition on bone mass and optical density of the cranial skeleton, and the adult fish experiment observes the role of the pharmaceutical composition in promoting bone formation and inhibiting bone resorption. used for
（１）頭部骨格の骨量と光学密度
幼魚飼育水体にストレプトゾシン（０．３０ｍｍｏｌ／Ｌ）を添加することにより、糖尿
病性骨粗鬆症ゼブラフィッシュモデルを作製した。健康幼魚をブランク群とし、糖尿病性
骨粗鬆症ゼブラフィッシュをモデル群と治療群（医薬組成物１０ｍｇ／Ｌ投与）に分けた
。１週間の連続治療後、各群ゼブラフィッシュ（ｎ＝６）の徴候を測定した。結果を図１
と図２に示す。
図１と図２から明らかなように、ブランク群と比較して、モデル群のゼブラフィッシュの
頭部骨格骨量と頭部骨格光学密度がいずれも顕著に低下した（Ｐ＜０．０１）。一方、モ
デル群と比較して、治療群のゼブラフィッシュは１週間の投与治療後、頭部骨格エリアが
顕著に向上し（Ｐ＜０．０１）、頭部骨格光学密度が向上した（Ｐ＜０．０１）。
(1) Bone mass and optical density of head skeleton A diabetic osteoporosis zebrafish model was prepared by adding streptozocin (0.30 mmol/L) to juvenile fish cultured water bodies. A healthy juvenile fish was used as a blank group, and diabetic osteoporotic zebrafish were divided into a model group and a treatment group (10 mg/L administration of the pharmaceutical composition). After one week of continuous treatment, the signs of each group of zebrafish (n=6) were measured. Figure 1 shows the results
and FIG.
As is clear from FIGS. 1 and 2, both the cranial skeletal bone mass and cranial skeletal optical density of the zebrafish in the model group were significantly reduced compared to the blank group (P<0.01). On the other hand, compared with the model group, the zebrafish in the treatment group had significantly improved head skeleton area (P<0.01) and head skeleton optical density (P<0.01) after one week of administration treatment. 0.01).
（２）成魚試験
成体ゼブラフィッシュを採取し、ストレプトゾシン３５０ｍｇ／ｋｇを腹腔注射して糖尿
病性骨粗鬆症ゼブラフィッシュモデルを作製した。健康ゼブラフィッシュをブランク群と
し、糖尿病性骨粗鬆症ゼブラフィッシュをモデル群、低用量治療群（医薬組成物０．１ｍ
ｇ／ｋｇ投与）、中用量治療群（医薬組成物１ｍｇ／ｋｇ投与）、高用量治療群（医薬組
成物１０ｍｇ／ｋｇ投与）及び陽性対照群（メトホルミン３ｍｇ／ｋｇ投与）に分けた。
２週間の連続治療後、各群のゼブラフィッシュ（ｎ＝６）の徴候を測定した。
１）骨形成促進作用の研究
ＥＬＩＳＡ法を用いて各群のゼブラフィッシュ体内のアルカリホスファターゼの活性を測
定し、３回繰り返し測定し、平均値を取り、測定結果は図３に示す。同時に、ＲＴ-ＰＣ
Ｒ技術を用いて骨形成関連遺伝子（ａｌｐ、ｏｐｇ、ｒｕｎｘ２）の発現レベルを測定し
、３回繰り返し測定し、平均値を取り、測定結果を図４、図５及び図６に示す。
(2) Adult fish test Adult zebrafish were harvested and intraperitoneally injected with 350 mg/kg of streptozocin to prepare a diabetic osteoporosis zebrafish model. A healthy zebrafish was used as a blank group, a diabetic osteoporosis zebrafish was used as a model group, and a low-dose treatment group (pharmaceutical composition 0.1 m
administration of 1 mg/kg of the pharmaceutical composition), a medium dose treatment group (administration of 1 mg/kg of the pharmaceutical composition), a high dose treatment group (administration of 10 mg/kg of the pharmaceutical composition) and a positive control group (administration of 3 mg/kg of metformin).
After 2 weeks of continuous treatment, signs of zebrafish (n=6) in each group were measured.
1) Investigation of Osteogenesis-Promoting Effect The activity of alkaline phosphatase in the zebrafish of each group was measured using the ELISA method, the measurement was repeated three times, and the average value was taken. At the same time, the RT-PC
The expression levels of osteogenesis-related genes (alp, opg, runx2) were measured using the R technique, measured three times, and averaged. The results are shown in FIGS.
図３から、ブランク群と比較して、モデル群ゼブラフィッシュのアルカリホスファターゼ
活性が顕著に低下した（Ｐ＜０．０１）。一方、モデル群と比較して、高用量治療群ゼブ
ラフィッシュのアルカリホスファターゼ活性は顕著に上昇した（Ｐ＜０．０１）。
図４、図５及び図６から明らかなように、ブランク群と比較して、モデル群ゼブラフィッ
シュ中の骨形成関連遺伝子ａｌｐ（Ｐ＜０．０１）、ｏｐｇ（Ｐ＜０．０１）、ｒｕｎｘ
２（Ｐ＜０．０１）の発現レベルは全て著しく低下した。一方、モデル群と比較して、低
用量治療群、中用量治療群及び高用量治療群の骨形成関連遺伝子ａｌｐの発現レベルはい
ずれも顕著に上昇した（Ｐ＜０．０１）。中用量治療群と高用量治療群の骨形成関連遺伝
子ｏｐｇの発現レベルはいずれも顕著に上昇した（Ｐ＜０．０１）。低用量治療群、中用
量治療群及び高用量治療群の骨形成関連遺伝子ｒｕｎｘ２の発現レベルは顕著に上昇した
（Ｐ＜０．０１）。中用量群および高用量群のａｌｐ、ｏｐｇ、ｒｕｎｘ２の発現は、陽
性対照群に匹敵するか、または陽性対照群よりも高かった。
以上の研究結果により、本発明の医薬組成物は骨形成を促進する作用を果たすことができ
、糖尿病性骨粗鬆症の捻転に顕著な効果があることが明らかになった。
From FIG. 3, the alkaline phosphatase activity of the model group zebrafish was significantly reduced compared to the blank group (P<0.01). On the other hand, the alkaline phosphatase activity in the high-dose treatment group zebrafish was significantly elevated compared to the model group (P<0.01).
4, 5 and 6, compared with the blank group, the osteogenesis-related genes alp (P<0.01), opg (P<0.01), runx in the model group zebrafish
2 (P<0.01) were all significantly reduced. On the other hand, compared with the model group, the expression levels of the osteogenesis-related gene alp in the low-, medium-, and high-dose treatment groups were all significantly elevated (P<0.01). The expression level of the osteogenesis-related gene opg was significantly elevated in both the medium-dose treatment group and the high-dose treatment group (P<0.01). The expression level of the osteogenesis-related gene runx2 was significantly elevated in the low-, medium-, and high-dose treatment groups (P<0.01). The expressions of alp, opg, runx2 in the medium and high dose groups were comparable to or higher than the positive control group.
From the above research results, it has been clarified that the pharmaceutical composition of the present invention can promote osteogenesis and has a remarkable effect on torsion in diabetic osteoporosis.
２）骨吸収抑制作用の研究
ＥＬＩＳＡ法を用いて各群のゼブラフィッシュ体内の抗酒石酸酸性ホスファターゼの活性
を測定し、３回繰り返し測定し、平均値を取り、測定結果は図７に示す。同時に、ＲＴ-
ＰＣＲ技術を用いて骨吸収関連遺伝子（ａｃｐ５α、ｓｏｓｔ、ｒａｎｋｌ）の発現レベ
ルを測定し、３回繰り返し測定し、平均値を取り、測定結果を図８、図９及び図１０に示
す。
図７から、ブランク群と比較して、モデル群ゼブラフィッシュの抗酒石酸酸性ホスファタ
ーゼ活性が顕著に上昇した（Ｐ＜０．０１）。一方、モデル群と比較して、高用量治療群
ゼブラフィッシュの抗酒石酸酸性ホスファターゼ活性は顕著に低下し（Ｐ＜０．０１）、
ブランク群に匹敵した。
2) Investigation of Bone Resorption Inhibitory Activity The activity of anti-tartrate acid phosphatase in the zebrafish of each group was measured using ELISA method, the measurement was repeated three times, and the average value was taken. The measurement results are shown in FIG. At the same time, RT-
The expression levels of bone resorption-related genes (acp5α, sost, rankl) were measured using PCR technology, measured three times, and averaged. The results are shown in FIGS.
From FIG. 7, the anti-tartrate acid phosphatase activity of the model group zebrafish was significantly increased compared to the blank group (P<0.01). On the other hand, compared with the model group, the anti-tartrate acid phosphatase activity of the high-dose treatment group zebrafish was significantly reduced (P<0.01),
Comparable to the blank group.
図８、図９及び図１０から明らかなように、ブランク群と比較して、モデル群ゼブラフィ
ッシュ中の骨吸収関連遺伝子（ａｃｐ５α、ｓｏｓｔ、ｒａｎｋｌ）の発現レベルはいず
れも著しく上昇した（Ｐ＜０．０１）。一方、モデル群と比較して、低用量治療群、中用
量治療群及び高用量治療群の骨吸収関連遺伝子ａｃｐ５αの発現レベルはいずれも顕著に
低下した（Ｐ＜０．０１）。中用量治療群と高用量治療群の骨吸収関連遺伝子ｓｏｓｔの
発現レベルはいずれも顕著に低下し（Ｐ＜０．０１）且つ陽性対照群に匹敵するか、また
は陽性対照群よりも低かった。低用量治療群、中用量治療群及び高用量治療群の骨吸収関
連遺伝子ｒａｎｋｌの発現レベルはいずれも顕著に低下した（Ｐ＜０．０１）。
以上より、本医薬組成物は糖尿病による骨形成抑制を逆転するだけでなく、糖尿病による
骨吸収の向上を抑制することもでき、抗糖尿病性骨粗鬆症薬物の調製に用いることができ
る。
As is clear from FIGS. 8, 9 and 10, the expression levels of bone resorption-related genes (acp5α, sost, rankl) in the model group zebrafish were all significantly elevated compared to the blank group (P< 0.01). On the other hand, compared with the model group, the expression levels of the bone resorption-related gene acp5α in the low-, medium-, and high-dose groups all significantly decreased (P<0.01). The expression levels of the bone resorption-related gene sost in the medium-dose treatment group and the high-dose treatment group were both significantly decreased (P<0.01) and comparable to or lower than the positive control group. The expression levels of bone resorption-related gene rankl in the low-dose treatment group, medium-dose treatment group and high-dose treatment group were all significantly decreased (P<0.01).
As described above, the present pharmaceutical composition can not only reverse the suppression of bone formation caused by diabetes, but also suppress the improvement of bone resorption caused by diabetes, and can be used for the preparation of an anti-diabetic osteoporosis drug.
３）血糖降下作用の研究
ＥＬＩＳＡ法を用いて各群のゼブラフィッシュ体内のブドウ糖レベルを測定し、３回繰り
返し測定し、平均値を取り、測定結果は図１１に示す。
図１１から、ブランク群と比較して、モデル群ゼブラフィッシュのブドウ糖レベルが顕著
に上昇した（Ｐ＜０．０１）。一方、モデル群と比較して、高用量治療群ゼブラフィッシ
ュのブドウ糖は顕著に低下した（Ｐ＜０．０１）。
3) Investigation of hypoglycemic effect Using the ELISA method, the glucose level in the zebrafish of each group was measured, the measurement was repeated three times, and the average value was taken. The measurement results are shown in FIG.
From FIG. 11, compared with the blank group, the glucose level of the model group zebrafish was significantly elevated (P<0.01). On the other hand, compared with the model group, the glucose in the high-dose treatment group zebrafish decreased significantly (P<0.01).
４）薬物単用と併用の違い
幼魚飼育水体にストレプトゾバクチンを加えることにより、糖尿病性骨粗鬆症ゼブラフィ
ッシュモデルを作製した。健康幼魚をブランク群とし、糖尿病性骨粗鬆症ゼブラフィッシ
ュをモデル群と治療群（医薬組成物と単用医薬のそれぞれの投与量は１０ｍｇ／Ｌ）に分
けた。１週間の連続治療後、各群ゼブラフィッシュ（ｎ＝６）の徴候を測定し、結果を図
１２に示す。
図１２から明らかなように、モデル群と比較して、マンゴシド治療群、テトラヒドロベル
ベリン治療群（Ｐ＜０．０５）、モクレン塩基治療群（Ｐ＜０．０１）、ヒドロキシオキ
シベルベリン治療群（Ｐ＜０．０５）、ベルベリン治療群（Ｐ＜０．０１）および医薬組
成物治療群のゼブラフィッシュは、１週間の投与治療後、いずれも頭部骨格エリアが顕著
に増加し（Ｐ＜０．０１）、医薬組成物治療群の治療効果はさらに良かった。一方、バマ
ルティン治療群とフラビン治療群は糖尿病性骨粗鬆症ゼブラフィッシュの頭部骨格エリア
が増加できなかった。
4) Difference between drug monotherapy and drug combination A diabetic osteoporosis zebrafish model was prepared by adding streptozobactin to juvenile fish breeding water bodies. A healthy juvenile fish was used as a blank group, and diabetic osteoporotic zebrafish were divided into a model group and a treatment group (the dosage of the pharmaceutical composition and the single-use drug was 10 mg/L, respectively). After one week of continuous treatment, the signs of each group of zebrafish (n=6) were measured and the results are shown in FIG.
As is clear from FIG. 12, compared with the model group, mangoside treatment group, tetrahydroberberine treatment group (P < 0.05), magnolia base treatment group (P < 0.01), hydroxyoxyberberine treatment group (P <0.05), the berberine-treated group (P<0.01) and the pharmaceutical composition-treated zebrafish both showed a significant increase in the head skeleton area after one week of administration treatment (P<0.05). 01), the therapeutic effect of the pharmaceutical composition treatment group was even better. On the other hand, the bamartin-treated group and the flavin-treated group could not increase the cranial skeletal area of diabetic osteoporotic zebrafish.
実施例２
７．６４重量％のマンゴシドと、７．３９重量％のテトラヒドロベルベリンと、３５．０
６重量％のフラビンと、１４．６４重量％のモクレン塩基と、４．２６重量％のヒドロキ
シオキシベルベリンと、０．２９重量％のバマルティンと、３０．７１重量％のベルベリ
ンとを含有する医薬組成物。
各原料を上記物質の量で混合することにより、本実施例の医薬組成物を得た。
実施例３
１０．４０重量％のマンゴシドと、７．０６重量％のテトラヒドロベルベリンと、３５．
３１重量％のフラビンと、１３．８６重量％のモクレン塩基と、３．６３重量％のヒドロ
キシオキシベルベリンと、４．２６重量％のバマルティンと、２９．４７重量％のベルベ
リンとを含有する医薬組成物。
各原料を上記物質の量で混合することにより、本実施例の医薬組成物を得た。
実施例４
３４．３９重量％のマンゴシドと、４．３２重量％のテトラヒドロベルベリンと、２８．
０６重量％のフラビンと、１０．２２重量％のモクレン塩基と、２．４２重量％のヒドロ
キシオキシベルベリンと、０．１５重量％のバマルティンと、２０．４４重量％のベルベ
リンとを含有する医薬組成物。
各原料を上記物質の量で混合することにより、本実施例の医薬組成物を得た。
実施例５
４０．９０重量％のマンゴシドと、４．２６重量％のテトラヒドロベルベリンと、２４．
３３重量％のフラビンと、１０．１１重量％のモクレン塩基と、２．３０重量％のヒドロ
キシオキシベルベリンと、０．１２重量％のバマルティンと、１７．９６重量％のベルベ
リンとを含有する医薬組成物。
各原料を上記物質の量で混合することにより、本実施例の医薬組成物を得た。
Example 2
7.64% by weight mangoside, 7.39% by weight tetrahydroberberine, 35.0%
A medicament containing 6% by weight flavin, 14.64% by weight magnolia base, 4.26% by weight hydroxyoxyberberine, 0.29% by weight bamartine and 30.71% by weight berberine Composition.
The pharmaceutical composition of this example was obtained by mixing each raw material in the amount of the above substances.
Example 3
10.40% by weight mangoside; 7.06% by weight tetrahydroberberine;35.
A medicament containing 31% by weight flavin, 13.86% by weight magnolia base, 3.63% by weight hydroxyoxyberberine, 4.26% by weight bamartine and 29.47% by weight berberine Composition.
The pharmaceutical composition of this example was obtained by mixing each raw material in the amount of the above substances.
Example 4
34.39% by weight mangoside; 4.32% by weight tetrahydroberberine;28.
06% by weight of flavin, 10.22% by weight of magnolia base, 2.42% by weight of hydroxyoxyberberine, 0.15% by weight of bamartine, and 20.44% by weight of berberine Composition.
The pharmaceutical composition of this example was obtained by mixing each raw material in the amount of the above substances.
Example 5
40.90% by weight mangoside; 4.26% by weight tetrahydroberberine;24.
A medicament containing 33% by weight of flavin, 10.11% by weight of magnolia base, 2.30% by weight of hydroxyoxyberberine, 0.12% by weight of bamartine and 17.96% by weight of berberine Composition.
The pharmaceutical composition of this example was obtained by mixing each raw material in the amount of the above substances.
実施例２～５で調製した医薬組成物をそれぞれ採取し、糖尿病性骨粗鬆症ゼブラフィッシ
ュに対して治療（投与量１０ｍｇ／Ｌ）を行い、１週間の連続治療後、各ゼブラフィッシ
ュ（ｎ＝６）の徴候を測定した。結果を図１３に示す。
図１３から明らかなように、ブランク群と比較して、モデル群ゼブラフィッシュの頭部骨
格骨量は顕著に低下し（Ｐ＜０．０１）、一方、モデル群と比較して、各医薬組成物治療
群のゼブラフィッシュは１週間の投与治療後、頭部骨格エリアが顕著に向上し（Ｐ＜０．
０１）、その中で実施例１の併用医薬群は更に顕著で、ブランク群に匹敵した。
Each of the pharmaceutical compositions prepared in Examples 2 to 5 was collected and treated (dose 10 mg/L) against diabetic osteoporosis zebrafish. After one week of continuous treatment, each zebrafish (n=6) were measured. The results are shown in FIG.
As is clear from FIG. 13, compared to the blank group, the head skeletal bone mass of the model group zebrafish was significantly reduced (P<0.01), while compared to the model group, each pharmaceutical composition The zebrafish in the animal treatment group showed a significant improvement in the head skeleton area after one week of administration treatment (P<0.
01), among them, the concomitant drug group of Example 1 was more remarkable and comparable to the blank group.
対比例１
７．４８重量％のテトラヒドロベルベリンと、４１．４２重量％のフラビンと、１６．１
２重量％のモクレン塩基と、３．６３重量％のヒドロキシオキシベルベリンと、０．２８
重量％のバマルティンと、３１．０８重量％のベルベリンとを含有する医薬組成物。
対比例２
２０．９５重量％のマンゴシドと、３５．３９重量％のフラビンと、１３．７７重量％の
モクレン塩基と、３．１０重量％のヒドロキシオキシベルベリンと、０．２４重量％のバ
マルティンと、２６．５５重量％のベルベリンとを含有する医薬組成物。
対比例３
２９．５０重量％のマンゴシドと、９．００重量％のテトラヒドロベルベリンと、１９．
３９重量％のモクレン塩基と、４．３７重量％のヒドロキシオキシベルベリンと、０．３
３重量％のバマルティンと、３７．４０重量％のベルベリンとを含有する医薬組成物。
対比例４
２２．６２重量％のマンゴシドと、６．９０重量％のテトラヒドロベルベリンと、３８．
２１重量％のフラビンと、３．３５重量％のヒドロキシオキシベルベリンと、０．２６重
量％のバマルティンと、２８．６７重量％のベルベリンとを含有する医薬組成物。
対比例５
２０．２８重量％のマンゴシドと、６．１９重量％のテトラヒドロベルベリンと、３４．
２６重量％のフラビンと、１３．３３重量％のモクレン塩基と、０．２３重量％のバマル
ティンと、２５．７１重量％のベルベリンとを含有する医薬組成物。
対比例６
１９．７３重量％のマンゴシドと、６．０２重量％のテトラヒドロベルベリンと、３３．
３４重量％のフラビンと、１２．９７重量％のモクレン塩基と、２．９２重量％のヒドロ
キシオキシベルベリンと、２４．９６重量％のベルベリンと、を含有する医薬組成物。
対比例７
２４重量％のマンゴシドと、８．０１重量％のテトラヒドロベルベリンと、４４．３２重
量％のフラビンと、１７．２５重量％のモクレン塩基と、３．８９重量％のヒドロキシオ
キシベルベリンと、０．３０重量％のバマルティンと、を含有する医薬組成物。
Contrast 1
7.48 wt% tetrahydroberberine, 41.42 wt% flavins, 16.1 wt%
2 wt% magnolia base, 3.63 wt% hydroxyoxyberberine, 0.28
A pharmaceutical composition containing weight percent bamartine and 31.08 weight percent berberine.
Contrast 2
20.95% by weight mangoside, 35.39% by weight flavin, 13.77% by weight magnolia base, 3.10% by weight hydroxyoxyberberine, 0.24% by weight bamartine, 26 A pharmaceutical composition containing .55% by weight of berberine.
Contrast 3
29.50% by weight mangoside, 9.00% by weight tetrahydroberberine;19.
39 wt% magnolia base, 4.37 wt% hydroxyoxyberberine, 0.3
A pharmaceutical composition containing 3% by weight of bamartine and 37.40% by weight of berberine.
Contrast 4
22.62% by weight mangoside; 6.90% by weight tetrahydroberberine;38.
A pharmaceutical composition containing 21% by weight flavin, 3.35% by weight hydroxyoxyberberine, 0.26% by weight bamartine and 28.67% by weight berberine.
Contrast 5
20.28% by weight mangoside; 6.19% by weight tetrahydroberberine;34.
A pharmaceutical composition containing 26% by weight flavin, 13.33% by weight magnolia base, 0.23% by weight bamartine and 25.71% by weight berberine.
contrast 6
19.73% by weight mangoside; 6.02% by weight tetrahydroberberine;33.
A pharmaceutical composition containing 34% by weight flavin, 12.97% by weight magnolia base, 2.92% by weight hydroxyoxyberberine, and 24.96% by weight berberine.
contrast 7
24% by weight mangoside, 8.01% by weight tetrahydroberberine, 44.32% by weight flavin, 17.25% by weight magnolia base, 3.89% by weight hydroxyoxyberberine, 0.30 % by weight of bamartine.
対比例１～７で調製した医薬組成物をそれぞれ採取し、糖尿病性骨粗鬆症ゼブラフィッシ
ュに対して治療（投与量１０ｍｇ／Ｌ）を行い、１週間の連続治療後、各ゼブラフィッシ
ュ（ｎ＝６）の徴候を測定した。結果を図１３に示す。
The pharmaceutical compositions prepared in Comparative Examples 1 to 7 were collected and treated (dose 10 mg/L) against diabetic osteoporotic zebrafish, and after one week of continuous treatment, each zebrafish (n=6). were measured. The results are shown in FIG.
図１４から明らかなように、ブランク群と比較して、モデル群ゼブラフィッシュの頭部骨
格骨量は顕著に低下し（Ｐ＜０．０１）、一方、モデル群と比較して、対比例１～７の各
医薬組成物治療群のゼブラフィッシュは１週間の投与治療後、頭部骨格エリアが顕著に向
上した（Ｐ＜０．０１）。しかし、治療効果はいずれも実施例１ほど顕著ではなかった。
As is clear from FIG. 14, compared to the blank group, the cranial skeletal bone mass of the model group zebrafish was significantly reduced (P<0.01), while compared to the model group, the contrast ratio of 1 The zebrafish in each pharmaceutical composition treatment group of ~7 had significantly improved cranial bone area after 1 week of administration treatment (P<0.01). However, none of the therapeutic effects were as pronounced as in Example 1.
Claims (10)
７．６４～４０．９０重量％のマンゴシド（ｍａｎｇｉｆｅｒｉｎ）と、４．２６～７．
３９重量％のテトラヒドロベルベリン（ｔｅｔｒａｈｙｄｒｏｅｐｉｂｅｒｂｅｒｉｎｅ
）と、２４．３３～３５．３１重量％のフラビン（ｐｈｅｌｌｏｄｅｎｄｒｉｎｅ）と、
１０．１１～１４．６４重量％のモクレン塩基（ｍａｇｎｏｆｌｏｒｉｎｅ）と、２．３
０～４．２６重量％のヒドロキシオキシベルベリン（１３－ｈｙｄｒｏｘｙｏｘｙｂｅｒ
ｂｅｒｉｎｅ）と、０．１２～０．２９重量％のバマルティン（ｐａｌｍａｔｉｎｅ）と
、１７．９６～３０．７１重量％のベルベリン（ｂｅｒｂｅｒｉｎｅ）と、
を含有することを特徴とする医薬組成物。 A pharmaceutical composition comprising
7.64-40.90% by weight of mangiferin and 4.26-7.
39% by weight of tetrahydroepiberberine
), 24.33-35.31% by weight of phellodendrine,
10.11 to 14.64% by weight magnoflorine, and 2.3
0-4.26% by weight of hydroxyoxyberberine (13-hydroxyoxyber
berine), 0.12-0.29% by weight of palmatine, and 17.96-30.71% by weight of berberine,
A pharmaceutical composition comprising:
ベルベリンと、２４．３３～３５．３１重量％のフラビンと、１０．１１～１４．６４重
量％のモクレン塩基と、２．３０～４．２６重量％のヒドロキシオキシベルベリンと、０
．１２～０．２９重量％のバマルティンと、１７．９６～３０．７１重量％のベルベリン
と、
を含有することを特徴とする請求項１に記載の医薬組成物。 7.64-40.90% by weight mangoside, 4.26-7.39% by weight tetrahydroberberine, 24.33-35.31% by weight flavin, 10.11-14.64% by weight Magnolia base, 2.30-4.26% by weight of hydroxyoxyberberine, 0
. 12-0.29% by weight of bamartine and 17.96-30.71% by weight of berberine;
The pharmaceutical composition according to claim 1, characterized in that it contains
２６重量％のフラビンと、１２．９４重量％のモクレン塩基と、２．９２重量％のヒドロ
キシオキシベルベリンと、０．２２重量％のバマルティンと、２４．９６重量％のベルベ
リンと、
を含有することを特徴とする請求項１に記載の医薬組成物。 19.69% by weight mangoside; 6.01% by weight tetrahydroberberine;33.
26% by weight flavins, 12.94% by weight magnolia base, 2.92% by weight hydroxyoxyberberine, 0.22% by weight bamartine, 24.96% by weight berberine;
The pharmaceutical composition according to claim 1, characterized in that it contains
用。 Application of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of antidiabetic complications drug.
用であって、
前記抗糖尿病合併症薬は、抗糖尿病性骨粗鬆症薬、抗糖尿病性腎症薬、抗糖尿病性神経障
害薬および抗糖尿病性血管合併症薬の少なくとも１種類を含む、
抗糖尿病合併症薬の調製における医薬組成物の応用。 Application of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of an anti-diabetic complications drug,
The antidiabetic complications drug includes at least one of an antidiabetic osteoporosis drug, an antidiabetic nephropathy drug, an antidiabetic neuropathy drug, and an antidiabetic vascular complications drug.
Application of the pharmaceutical composition in the preparation of antidiabetic complications drug.
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