专

一种魔方出水装置和水龙头

KR2800514A1

发明人

林孝发, 林孝山, 洪志怀

受让人

九牧厨卫股份有限公司

申请人

Maik Szarszewski

申请号

119497

申请日

2020-03-01

公开(公告)号

KR2800514A1

公开(公告)日

1978-07-27

IPC分类号

F16B002/08F16L021/08F16L033/02F16L033/035

CPC分类号

优先权号

10-2009-0134354

优先权日

2009-12-29

摘要

The gasket, e.g. for sealing a high-pressure pipe flange joint in power engineering, chemicals and other industries, consists of alternating layers of spiral-wound metal strip (1) and a filling material. The metal strip is folded into S-shaped layers with surfaces touching in the middle, and adjacent sections of the strip are situated in a mirror-image formation.

The metal strip can be of steel or other alloy with springy properties, while the filler can be of asbestos paper or fibre, fluoroplast, ceramic or graphite fibres, or other materials.

ADVANTAGE -Improved sealing capacity through greater axial flexibility. Bul.18/15.5.90 @(2pp Dwg.No. 1/2)@

权利要求

(SEQ ID NO: 3) 5′-CCAAGAGCACCAAGAACUZ A -3′; (SEQ ID NO: 4) 5′-Z′ B AGUUCUUGGUGCUCUUGG-3′, wherein, Z A is selected from A, U, G, or C, and TB is the first nucleotide at the 5′ terminal of the antisense strand and complementary to Z A ; and the sense strand and antisense strand have the same or different length, wherein the sense strand has a length of 19 to 23 nucleotides, and the antisense strand has a length of 20 to 26 nucleotides.

2 . The siRNA conjugate according to claim 1 , wherein the nucleotide sequence I further comprises nucleotide sequence III, the nucleotide sequence II further comprises nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1 to 4 nucleotides; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO:3, the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence represented by SEQ ID NO:4, and the nucleotide sequence III and the nucleotide sequence IV have the same length and are reverse complementary.

3 . The siRNA conjugate according to claim 2 , wherein the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide, and the nucleotide sequence III has a base of G; or the nucleotide sequence III and the nucleotide sequence IV both have a length of 2 nucleotides, and in the direction from 5′ terminal to 3′ terminal, the nucleotide sequence III has a base composition of AG; or, the nucleotide sequence III and the nucleotide sequence IV both have a length of 3 nucleotides, and in the direction from 5′ terminal to 3′ terminal, the nucleotide sequence III has a base composition of AAG; or, the nucleotide sequence III and the nucleotide sequence IV both have a length of 4 nucleotides, and in the direction from 5′ terminal to 3′ terminal, the nucleotide sequence III has a base composition of CAAG.

4 . The siRNA conjugate according to claim 1 , wherein the nucleotide sequence II further comprises a nucleotide sequence V; the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked to the 3′terminal of the antisense strand, thereby forming a 3′ overhang terminal of the antisense strand.

5 . The siRNA conjugate according to claim 4 , wherein, the nucleotide sequence V has a length 2 nucleotides; moreover the nucleotide sequence V is 2 continuous thymine deoxyribonucleotides or 2 continuous uridine ribonucleotides, or the nucleotide sequence V is complementary to the nucleotides at the corresponding positions of the target mRNA.

wherein, Z′ B is the first nucleotide at the 5′terminal of the antisense strand, Z A is selected from A, U, G or C, and Z′ B is a nucleotide complementary to Z A .

siAN1 Sense strand: (SEQ ID NO: 8) 5′- CCAAGAGCACCAAGAACUA-3′ Antisense strand: (SEQ ID NO: 9) 5′- UAGUUCUUGGUGCUCUUGGCU-3′ siAN2 Sense strand: (SEQ ID NO: 10) 5′- AGCCAAGAGCACCAAGAACUA-3′ Antisense strand: (SEQ ID NO: 11) 5′- UAGUUCUUGGUGCUCUUGGCUUG-3′.

8 . The siRNA conjugate according to claim 1 , wherein each nucleotide in the sense strand and the antisense strand is independently a fluoro modified nucleotide or a non-fluoro modified nucleotide; wherein the fluoro modified nucleotide is present in the nucleotide sequence represented by SEQ ID NO:3 and the nucleotide sequence represented by SEQ ID NO:4; and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8, 9 of the nucleotide sequence represented by SEQ ID NO:3 are fluoro modified nucleotides; and in the direction from 5′terminal to 3′terminal, the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence represented by SEQ ID NO:4 are fluoro modified nucleotides.

9 . The siRNA conjugate according to claim 8 , wherein each non-fluoro modified nucleotide is a methoxy modified nucleotide, and the methoxy modified nucleotide refers to a nucleotide formed by replacing 2′-hydroxy of the ribose group with a methoxy group.

10 . The siRNA conjugate according to claim 9 , wherein in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 5, 7, 8 and 9 of the nucleotide sequence represented by SEQ ID NO:3 in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the sense strand of the siRNA are methoxy modified nucleotides; and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 8, 9, 14 and 16 of the nucleotide sequence represented by SEQ ID NO:4 in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the sense strand of siRNA are methoxy modified nucleotides; or, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 5, 7, 8 and 9 of the nucleotide sequence represented by SEQ ID NO:3 in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the sense strand of the siRNA are methoxy modified nucleotides; and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 14 and 16 in the nucleotide sequence represented by SEQ ID NO:4 in the antisense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the antisense strand of the siRNA are methoxy modified nucleotides; or, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 of the nucleotide sequence represented by SEQ ID NO:3 in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the sense strand of the siRNA are methoxy modified nucleotides; and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence represented by SEQ ID NO:4 in the antisense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the other positions in the antisense strand of the siRNA are methoxy modified nucleotides.

siAN1-M1 sense strand: (SEQ ID NO: 12) 5′-CmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 13) 5′-UmAfGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmUm-3′ siAN2-M1 sense strand: (SEQ ID NO: 14) 5′-AmGmCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 15) 5′-UmAfGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmUmUmGm- 3′ siAN1-M2 sense strand: (SEQ ID NO: 12) 5′-CmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 16) 5′-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUm-3′ siAN2-M2 sense strand: (SEQ ID NO: 14) 5′-AmGmCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 17) 5′-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUmUmGm- 3′ siAN1-M3 sense strand: (SEQ ID NO: 18) 5′-CmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 16) 5′-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUm-3′ siAN2-M3 sense strand: (SEQ ID NO: 19) 5′-AmGmCmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 17) 5′-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUmUmGm- 3′, wherein C, G, U, and A represent the base composition of the nucleotides; m represents that the nucleotide adjacent to the left side of the letter m is a methoxy modified nucleotide; and f represents that the nucleotide adjacent to the left side of the letter f is a fluoro modified nucleotide.

12 . The siRNA conjugate according to claim 1 , wherein in the siRNA, at least one phosphate group is a phosphorothioate group, and the phosphorothioate linkage is present at at least one of the following positions: the position between the first and second nucleotides at 5′ terminal of the sense strand; the position between the second and third nucleotides at 5′ terminal of the sense strand; the position between the first and second nucleotides at 3′ terminal of the sense strand; the position between the second and third nucleotides at 3′ terminal of the sense strand; the position between the first and second nucleotides at 5′ terminal of the antisense strand; the position between the second and third nucleotides at 5′ terminal of the antisense strand; the position between the first and second nucleotides at 3′ terminal of the antisense strand; and the position between the second and third nucleotides at 3′ terminal of the antisense strand.

siAN1-MiS sense strand: (SEQ ID NO: 20) 5′-CmsCmsAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 21) 5′-UmsAfsGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmsCmsUm- 3′ siAN2-M1S sense strand: (SEQ ID NO: 22) 5′-AmsGmsCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 23) 5′-UmsAfsGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmUmsU msGm-3′ siAN1-M25 sense strand: (SEQ ID NO: 20) 5′-CmsCmsAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 24) 5′-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmsCmsUm- 3′ siAN2-M2S sense strand: (SEQ ID NO: 22) 5′-AmsGmsCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 25) 5′-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUmsU msGm-3′ siAN1-M3S sense strand: (SEQ ID NO: 26) 5′-CmsCmsAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 24) 5′-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmsCmsUm- 3′ siAN2-M3S sense strand: (SEQ ID NO: 27) 5′-AmsGmsCmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 25) 5′-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUmsU msGm-3′, wherein C, G, U, and A represent the base composition of the nucleotides; m represents that the nucleotide adjacent to the left side of the letter m is a methoxy modified nucleotide; f represents that the nucleotide adjacent to the left side of the letter f is a fluoro modified nucleotide; and s represents that a phosphorothioate linkage is present between the two nucleotides adjacent to both sides of the letter s.

wherein R is selected from H, OH, methoxy, or F; “Base” represents a base selected from A, U, C, G, or T.

siAN1-M1P1 sense strand: (SEQ ID NO: 12) 5′-CmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 28) 5′-P1-UmAfGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmUm- 3′ siAN2-M1P1 sense strand: (SEQ ID NO: 14) 5′-AmGmCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 29) 5′-P1-UmAfGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmUmU mGm-3′ siAN1-M2P1 sense strand: (SEQ ID NO: 12) 5′-CmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 30) 5′-P1-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUm- 3′ siAN2-M2P1 sense strand: (SEQ ID NO: 14) 5′-AmGmCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 31) 5′-P1-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUmU mGm-3′ siAN1-M3P1 sense strand: (SEQ ID NO: 18) 5′-CmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 30) 5′-P1-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmUm- 3′ siAN2-M3P1 sense strand: (SEQ ID NO: 19) 5′-AmGmCmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 31) 5′-P1-UmAfGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmU mUmGm-3′ siAN1-M1SP1 sense strand: (SEQ ID NO: 20) 5′-CmsCmsAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 32) 5′-P1-UmsAfsGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmsC msUm-3′ siAN2-M1SP1 sense strand: (SEQ ID NO: 22) 5′-AmsGmsCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 33) 5′-P1-UmsAfsGmUmUmCfUmUfGfGmUmGmCmUfCmUfUmGmGmCmU msUmsGm-3′ siAN1-M2SP1 sense strand: (SEQ ID NO: 20) 5′-CmsCmsAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 34) 5′-P1-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmsC msUm-3′ siAN2-M2SP1 sense strand: (SEQ ID NO: 22) 5′-AmsGmsCmCmAmAmGfAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 35) 5′-P1-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmU msUmsGm-3′ siAN1-M3SP1 sense strand: (SEQ ID NO: 26) 5′-CmsCmsAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 34) 5′-P1-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmsCms Um-3′ siAN2-M3SP1 sense strand: (SEQ ID NO: 27) 5′-AmsGmsCmCmAmAmGmAmGfCfAfCmCmAmAmGmAmAmCmUmAm-3′ antisense strand: (SEQ ID NO: 35) 5′-P1-UmsAfsGmUmUmCfUmUmGmGmUmGmCmUfCmUfUmGmGmCmU msUmsGm-3′ wherein C, G, U, and A represent the base composition of the nucleotides; m represents that the nucleotide adjacent to the left side of the letter m is a methoxy modified nucleotide; f represents that the nucleotide adjacent to the left side of the letter f is a fluoro modified nucleotide; s represents that a phosphorothioate linkage is present between the two nucleotides adjacent to both sides of the letter s; and P1 represents that the nucleotide adjacent to the right side of P1 is a 5′-phosphate nucleotide or a 5′-phosphate analogue modified nucleotide.

wherein E 1 is OH, SH or BH 2 , and Nu is siRNA; R 2 is a linear alkylene of 1 to 20 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with one or more groups selected from the group consisting of: C(O), NH, O, S, CH═N, S(O) 2 , C 2 -C 10 alkylene, C 2 -C 10 alkynylene, C 6 -C 10 arylene, C 3 -C 18 heterocyclylene, and C 5 -C 10 heteroarylene, and wherein R 2 is optionally substituted by any one or more groups selected from the group consisting of: C 1 -C 10 alkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 haloalkyl, —OC 1 -C 10 alkyl, —OC 1 -C 10 alkylphenyl, —C 1 -C 10 alkyl-OH, —OC 1 -C 10 haloalkyl, —SC 1 -C 10 alkyl, —SC 1 -C 10 alkylphenyl, —C 1 -C 10 alkyl-SH, —SC 1 -C 10 haloalkyl, halo, —OH, —SH, —NH 2 , —C 1 -C 10 alkyl-NH 2 , —N(C 1 -C 10 alkyl)(C 1 -C 10 alkyl), —NH(C 1 -C 10 alkyl), cyano, nitro, —CO 2 H, —C(O)O(C 1 -C 10 alkyl), —CON(C 1 -C 10 alkyl)(C 1 -C 10 alkyl), —CONH(C 1 -C 10 alkyl), —CONH 2 , —NHC(O)(C 1 -C 10 alkyl), —NHC(O)(phenyl), —N(C 1 -C 10 alkyl)C(O)(C 1 -C 10 alkyl), —N(C 1 -C 10 alkyl)C(O)(phenyl), —C(O)C 1 -C 10 alkyl, —C(O)C 1 -C 10 alkylphenyl, —C(O)C 1 -C 10 haloalkyl, —OC(O)C 1 -C 10 alkyl, —SO 2 (C 1 -C 10 alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 10 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 10 alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 10 alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 10 haloalkyl); each L 1 is a linear alkylene of 1 to 70 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with one or more groups selected from the group consisting of: C(O), NH, O, S, CH═N, S(O) 2 , C 2 -C 10 alkylene, C 2 -C 10 alkynylene, C 6 -C 10 arylene, C 3 -C 18 heterocyclylene, and C 5 -C 10 heteroarylene; and wherein L 1 is optionally substituted by any one or more groups selected from the group consisting of: C 1 -C 10 alkyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 1 -C 10 haloalkyl, —OC 1 -C 10 alkyl, —OC 1 -C 10 alkylphenyl, —C 1 -C 10 alkyl-OH, —OC 1 -C 10 haloalkyl, —SC 1 -C 10 alkyl, —SC 1 -C 10 alkylphenyl, —C 1 -C 10 alkyl-SH, —SC 1 -C 10 haloalkyl, halo, —OH, —SH, —NH 2 , —C 1 -C 10 alkyl-NH 2 , —N(C 1 -C 10 alkyl)(C 1 -C 10 alkyl), —NH(C 1 -C 10 alkyl), cyano, nitro, —CO 2 H, —C(O)O(C 1 -C 10 alkyl), —CON(C 1 -C 10 alkyl)(C 1 -C 10 alkyl), —CONH(C 1 -C 10 alkyl), —CONH 2 , —NHC(O)(C 1 -C 10 alkyl), —NHC(O)(phenyl), —N(C 1 -C 10 alkyl)C(O)(C 1 -C 10 alkyl), —N(C 1 -C 10 alkyl)C(O)(phenyl), —C(O)C 1 -C 10 alkyl, —C(O)C 1 -C 10 alkylphenyl, —C(O)C 1 -C 10 haloalkyl, —OC(O)C 1 -C 10 alkyl, —SO 2 (C 1 -C 10 alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 10 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 10 alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 10 alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 10 haloalkyl); represents a site where a group is attached to the rest of the molecule; and M1 represents a targeting group.

Rb is a C 1 -C 10 alkyl.

18 . The siRNA conjugate according to claim 17 , wherein L 1 is selected from connection combinations of one or more of A1, A4, A5, A6, A8, A10, A11, A13; or L 1 is selected from connection combinations of at least two of A1, A4, A8, A10, and A11.

19 . The siRNA conjugate according to claim 16 , wherein L 1 is 3 to 25 atoms in length; or L 1 is further 4 to 15 atoms in length.

20 . The siRNA conjugate according to claim 16 , wherein m1, m2 and m3 are each independently an integer of 2-5; or wherein m1=m2=m3.

21 . The siRNA conjugate according to claim 16 , wherein each of the targeting groups is independently a ligand having affinity to asialoglycoprotein receptors on the surface of mammalian hepatocytes; or each of the targeting group is independently selected from the group consisting of D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-O— [(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

wherein represents the site where a group is covalently linked, and q2 is an integer of 1-10.

24 . The siRNA conjugate according to claim 16 , wherein the P atom in the Formula A59 is linked to 3′ terminal of the sense strand of the siRNA.

25 . A method for treating dyslipidemia, wherein the method comprises administering an effective amount of the siRNA conjugate according to claim 1 to a subject suffering from dyslipidemia.

26 . A method for inhibiting the expression of ANGPTL3 gene in hepatocytes, comprising contacting an effective amount of the siRNA conjugate according to claim 1 with the hepatocytes.

27 . The method of claim 25 , wherein the dyslipidemia is hypercholesteremia, hypertriglyceridemia or atherosclerosis.

28 . A kit comprising the siRNA conjugate according to claim 1 .

说明书

[0001]技术领域

[0002]本实用新型涉及药物投放装置技术领域，具体为一种用于鳗鲡养殖的药物投放装置。

[0003]背景技术

[0004]鳗鲡是鳗鲡目鳗鲡科鳗鲡属鱼类，鳗鲡分布于中国渤海、黄海、东海、南海及其各通海的淡水河流，鳗鲡是目前市场较为常见的经济型鱼种，在对鳗鲡进行饲养的过程中需要对养殖池的内部进行投药杀菌，但是现有技术中的药物投放装置在对药物进行投放的过程中不便于对投放速度进行控制，并且投放的过程中药物需要再水中自行扩散，扩散效率较低。因此，需要对现有技术进行改进。

[0005]实用新型内容

[0006]本实用新型的目的在于提供一种用于鳗鲡养殖的药物投放装置，解决了药物的投放速度不便于控制和投药时药物扩散较慢的问题。

[0007]为实现上述目的，本实用新型提供如下技术方案：一种用于鳗鲡养殖的药物投放装置，包括储药罐，所述储药罐的下端内部固定连接有调节管，所述调节管的下端内部固定连接有连接嘴，所述连接嘴的下端固定连接有输送管，所述输送管远离所述储药罐的一端固定连接有固定架，所述调节管上设置有流量调节机构，所述固定架的内部滑动连接有两个对称分布的导杆，两个所述导杆远离所述输送管的一端固定连接有装夹架，所述导杆的设置有弹簧一，所述储药罐的外侧固定连接有安装架。

[0008]优选的，所述装夹架与所述固定架接触，所述装夹架的外侧固定连接有拉手，拉手可以带动装夹架进行移动。

[0009]优选的，所述弹簧一的一端与所述导杆固定连接，所述弹簧一的另一端与所述固定架固定连接，弹簧一可以通过弹力对导杆进行支撑。

[0010]优选的，所述流量调节机构包括阀板，所述调节管的内部通过轴承安装有阀板，所述调节管的内部固定连接有密封环，所述阀板的连接轴外侧固定连接有齿轮，所述阀板的连接轴左端垂直面上固定连接有手柄，所述手柄的内部铰接有翻转架，所述翻转架靠近所述齿轮的一端固定连接有限位齿，所述翻转架的上端固定连接有限位板，所述手柄的内部设置有弹簧二，限位板可以对翻转架进行限位。

[0011]优选的，所述密封环与所述阀板活动连接，所述限位板与所述手柄接触，所述限位齿与所述齿轮的齿槽滑动连接，限位齿可以通过齿轮对手柄进行限位。

[0012]优选的，所述弹簧二的一端与所述翻转架固定连接，所述弹簧二的另一端与所述手柄固定连接，弹簧二可以通过弹力带动翻转架自动复位。

[0013]与现有技术相比，本实用新型的有益效果如下：

[0014]1、本实用新型通过在储药罐上加设调节管、阀板和齿轮等结构，在使用的过程中可以通过手柄带动阀板进行转动，对调节管的流通管径进行调节，可以通过管径的大小对流速进行调节，从而可以使得装置药物的流速更加便于控制。

[0015]2、本实用新型通过在输送管上加设固定架、装夹架和导杆等结构，在使用的过程中可以通过弹簧一的弹力带动固定架和装夹架将输送管的出口装夹在制氧机的上方，然后向制氧机的制氧范围内进行投药，从而可以通过制氧机对水流的搅动将药物快速的扩散到水体的内部，可以有效的提升药物的扩散效率。

[0016]附图说明

[0017]图1为本实用新型整体结构立体图一；

[0018]图2为本实用新型整体结构立体图二；

[0019]图3为本实用新型的图1的立体剖视图；

[0020]图4为本实用新型的图1的A部结构放大图；

[0021]图5为本实用新型的图2的B部结构放大图。

[0022]图中：1、储药罐；2、调节管；3、连接嘴；4、输送管；5、固定架；6、流量调节机构；7、导杆；8、装夹架；9、拉手；10、弹簧一；11、安装架；61、阀板；62、密封环；63、齿轮；64、手柄；65、翻转架；66、限位齿；67、限位板；68、弹簧二。

[0023]具体实施方式

[0024]下面将结合本实用新型实施例中的附图，对本实用新型实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本实用新型一部分实施例，而不是全部的实施例。基于本实用新型中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本实用新型保护的范围。

[0025]请参阅图1、图2、图3、图4，一种用于鳗鲡养殖的药物投放装置，包括储药罐1，储药罐1的下端内部固定连接有调节管2，调节管2的下端内部固定连接有连接嘴3，连接嘴3的下端固定连接有输送管4，输送管4远离储药罐1的一端固定连接有固定架5，调节管2上设置有流量调节机构6，固定架5的内部滑动连接有两个对称分布的导杆7，两个导杆7远离输送管4的一端固定连接有装夹架8，导杆7的设置有弹簧一10，储药罐1的外侧固定连接有安装架11。

[0026]请参阅图1、图2、图3、图4，装夹架8与固定架5接触，装夹架8的外侧固定连接有拉手9，拉手9可以带动装夹架8进行移动，弹簧一10的一端与导杆7固定连接，弹簧一10的另一端与固定架5固定连接，弹簧一10可以通过弹力对导杆7进行支撑。

[0027]请参阅图1、图3、图5，流量调节机构6包括阀板61，调节管2的内部通过轴承安装有阀板61，调节管2的内部固定连接有密封环62，阀板61的连接轴外侧固定连接有齿轮63，阀板61的连接轴左端垂直面上固定连接有手柄64，手柄64的内部铰接有翻转架65，翻转架65靠近齿轮63的一端固定连接有限位齿66，翻转架65的上端固定连接有限位板67，手柄64的内部设置有弹簧二68，限位板67可以对翻转架65进行限位，密封环62与阀板61活动连接，限位板67与手柄64接触，限位齿66与齿轮63的齿槽滑动连接，限位齿66可以通过齿轮63对手柄64进行限位，弹簧二68的一端与翻转架65固定连接，弹簧二68的另一端与手柄64固定连接，弹簧二68可以通过弹力带动翻转架65自动复位。

[0028]本实用新型具体实施过程如下：在使用时，加工药物放入到储药罐1的内部，拉动拉手9，拉手9带动装夹架8进行移动，并对弹簧一10进行挤压，然后将制氧机的杆件放置在装夹架8和固定架5之间，同时松开拉手9，弹簧一10复位，弹簧一10可以通过弹力将装夹架8装夹在制氧机的外侧。

[0029]然后手握手柄64，并按压翻转架65，翻转架65对弹簧二68进行移动压缩，翻转架65带动限位齿66进行移动，当限位齿66脱离齿轮63的齿槽时，便可通过手柄64带动阀板61进行偏转，当阀板61偏转一定角度后，便可控制调节管2内部的流量速度，调节完成后，松开翻转架65，弹簧二68复位，弹簧二68可以通过弹力带动限位齿66滑入到调节后的齿槽内部，便可对阀板61的使用角度进行限位，储药罐1内部的药物通过输送管4流出后落在制氧机的制氧范围内部，便可通过制氧机对药物进行扩散。

[0030]尽管已经示出和描述了本实用新型的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本实用新型的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本实用新型的范围由所附权利要求及其等同物限定。

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