CN1839876A - Heparin oral nanoemulsion composition and preparation method thereof - Google Patents
Heparin oral nanoemulsion composition and preparation method thereof Download PDFInfo
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- CN1839876A CN1839876A CN 200610023501 CN200610023501A CN1839876A CN 1839876 A CN1839876 A CN 1839876A CN 200610023501 CN200610023501 CN 200610023501 CN 200610023501 A CN200610023501 A CN 200610023501A CN 1839876 A CN1839876 A CN 1839876A
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- heparin
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960002897 heparin Drugs 0.000 title claims abstract description 63
- 229920000669 heparin Polymers 0.000 title claims abstract description 63
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000007908 nanoemulsion Substances 0.000 title description 8
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000004064 cosurfactant Substances 0.000 claims abstract description 11
- 239000012071 phase Substances 0.000 claims abstract description 9
- -1 fatty acid ester Chemical class 0.000 claims description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 235000009508 confectionery Nutrition 0.000 claims description 11
- 150000002148 esters Chemical group 0.000 claims description 11
- 239000003055 low molecular weight heparin Substances 0.000 claims description 8
- 229940127215 low-molecular weight heparin Drugs 0.000 claims description 8
- 239000003921 oil Substances 0.000 claims description 8
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000007903 gelatin capsule Substances 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- 229950007687 macrogol ester Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical group O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- IELOKBJPULMYRW-UHFFFAOYSA-N α-tocopherol succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-UHFFFAOYSA-N 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 229920001400 block copolymer Polymers 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 15
- 241000700159 Rattus Species 0.000 description 12
- 206010051055 Deep vein thrombosis Diseases 0.000 description 11
- 239000012153 distilled water Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 230000000968 intestinal effect Effects 0.000 description 5
- 210000004347 intestinal mucosa Anatomy 0.000 description 5
- 238000003305 oral gavage Methods 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 4
- 206010047249 Venous thrombosis Diseases 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 4
- 229960005080 warfarin Drugs 0.000 description 4
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001630 jejunum Anatomy 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 2
- 208000006193 Pulmonary infarction Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000000600 disaccharide group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000002356 laser light scattering Methods 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 230000007575 pulmonary infarction Effects 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010068676 Pneumoretroperitoneum Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000005727 Retropneumoperitoneum Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 201000002816 chronic venous insufficiency Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 210000003692 ilium Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000512 nanotoxicity Toxicity 0.000 description 1
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- 238000012856 packing Methods 0.000 description 1
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- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
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- 238000005728 strengthening Methods 0.000 description 1
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Abstract
The invention relates to a heparin oral nano composition and its preparation method, wherein the composition is clear transparent solution comprising oil phase, surface active agent, cosurfactant and/or water by right amount, the ratio of the oil phase and the surface active agent is 24:1-1:6, the ratio of the surface active agent and the cosurfactant is 5:1-1:5.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to heparin oral nano composition and preparation method thereof.
Background technology
Heparin (Standard Heparin SH) is a class glycosaminoglycans, by alduronic acid and glucamine with 1, the polysaccharide chain mixture that the repetition disaccharide unit that 4 keys connect is formed, contain 10～30 disaccharide unit and do not wait, molecular weight is 4000～20000Da, mean molecule quantity 12000Da.(Low Molecular WeightHeparin is the lower-molecular-weight component that heparin obtains by enzymatic degradation or chemical depolymerization LMWH) to low molecular weight heparin, and molecular weight ranges is generally 3000-8000Da.SH and LMWH are mainly used in prevention and treatment thrombotic disease such as deep venous thrombosis, pulmonary infarction etc. clinically.(Deep Venous Thrombosis, DVT) modal is lower limb and one venous thrombosis of postcava thrombosis, especially ilium to deep venous thrombosis.DVT can cause chronic venous insufficiency, lower extremity swelling and distension even ulcer etc., and more seriously the DVT patient of 22%-29% can concurrent fatefulue pulmonary infarction.DVT postoperative sickness rate is higher, particularly after the Replacement of Hip Joint incidence rate of DVT up to 40-70%.Acute DVT academic therapy is while in hospital intravenous injection heparin or subcutaneous injection low molecular weight heparin, and oral anticoagulant medicine warfarin (Warfarin) is 6 months after leaving hospital.Since the warfarin plasma protein binding rate up to 99%, with other drug interact many, side effect such as easy hemorrhage are arranged, so the patient often will experience time several weeks and carry out dose titration and monitoring before leaving hospital, also will make regular check on platelet and prothrombin time International standardization rate during oral this medicine, this causes great inconvenience for DVT patient's treatment.Therefore study heparin or low molecular weight heparin oral formulations to replace oral warfarin to help strengthening the safety and the compliance of DVT patient treatment.But heparin or low molecular weight heparin belong to macromolecular drug, and the characteristics that water solublity is extremely strong, molecular weight reaches the bear electric charge greatly make it be difficult to see through the gastrointestinal mucosa absorption.
Summary of the invention
The object of the invention is to provide a kind of heparin oral nano composition and preparation method thereof.
The present invention is intended to improve the absorption through intestinal mucosa of heparin or low molecular weight heparin by the nano-emulsion dosage form.The present invention can improve heparin through the penetrating ability of intestinal mucosa, increases the heparin oral administration biaavailability simultaneously.
The clear solution that heparin oral nano of the present invention is made up of by proper proportion oil phase, surfactant, cosurfactant and water.
Heparin of the present invention is selected from the mixture of heparin, low molecular weight heparin, heparitin sulfate or mentioned component.
Described heparin oral nano is characterized in that oil phase is medium chain triglyceride, medium chain two sweet esters or medium chain monoglyceride, and wherein medium chain is meant that carbochain is C
8-C
10
Described heparin oral nano, it is characterized in that surfactant is selected from polyoxyethylene sorbitan fatty acid ester (Tween), polyoxyethylene aliphatic alcohol ether class (Brij, Brij), polyoxyethylene fatty acid ester class (Myrij, Myrj), ethylene oxide-oxypropylene block copolymer (poloxamer, Poloxamer), polyoxyethylene glycol acidifying natural or castor oil hydrogenated (Cremophor or HCO, BASF), tocopherol acid succinate macrogol ester (TPGS, Eastman), Polyethylene Glycol-8-caprylic/decanoin (Labrasol, Gattefosse), lecithin, or fabaceous lecithin.In above-mentioned surfactant, preferred Cremophor, Tween, TPGS and Labrasol.
Described heparin oral nano is characterized in that cosurfactant adopts medium chain monoglyceride, medium chain two sweet esters, medium chain to mix list/two sweet esters, diethylene glycol monoethyl ether (Transcutol-P), propylene glycol, Polyethylene Glycol (PEG of molecular weight 200-600), ethanol or mentioned component mixture.In above-mentioned cosurfactant, preferred medium chain monoglyceride, medium chain two sweet esters and medium chain mix list/two sweet esters.
Medium chain monoglyceride trade name of the present invention is Imwitor
988 (Sasol Corp.) or Capmul
MCM C8 (Abitec Corp.); It is Imwitor that medium chain mixes list/two sweet ester trade names
742 (Sasol Corp.), CapMum
MCM (Abitec Corp.) or Capmul
MCM C10 (Abitec Corp.); Medium chain triglyceride trade name is Miglycol
812N (Sasol Corp.), Captex
355EP, Captex
350 or Captex
300 EP (Abitec Corp.) etc.
Heparin oral nano of the present invention, the ratio that it is characterized in that described oil phase and surfactant is 24: 1-1: 6, wherein preferred proportion is 6: 1-1: 1.
The ratio of described surfactant and cosurfactant is 5: 1-1: 5, and wherein preferred proportion is 3: 1-1: 3.
Heparin oral nano of the present invention can be directly oral, also can pack in hard gelatin capsule or Perle, enteric hard gelatin capsule or the enteric Perle, also can mix, then make solid tablet or the solid particle capsule preparations is oral with solid carrier such as silicon dioxide, calcium sulfate, alginic acid etc.
Heparin oral nano provided by the invention has and improves heparin through the penetrating ability of intestinal mucosa and increase the effect of heparin oral administration biaavailability.
Description of drawings
Fig. 1 be embodiment 1, embodiment 2, embodiment 3 and heparin solution agent through rat at the postactivated partial thromboplastin time of body original position administration (APTT)-time graph;
Fig. 2 is that embodiment 1, embodiment 4, embodiment 5 and heparin solution agent are through the postactivated partial thromboplastin time of rat oral gavage administration (APTT)-time graph;
Fig. 3 is the tissue slice figure that heparin is respectively organized preparation jejunum behind rat oral gavage.
Wherein, A: solution; B: embodiment 1; C: embodiment 4; D: embodiment 5; The E:0.1% TritonX
The specific embodiment:
Embodiment 1 preparation nano-emulsion
Group component (g)
Miglycol?812N 0.2
Tween?80 0.2
Imwitor?742 0.15
Distilled water 0.05
LMWH 0.05
Precision takes by weighing the LMWH of recipe quantity, behind the dissolved in distilled water, adds Tween 80, Imwitor742, and mix homogeneously adds the Miglyol812N of recipe quantity again, stir form clear solution promptly.Use Nicomp
TM(Santa Barbara USA) measures 380ZLS type granularity determination of laser light scattering instrument, and particle diameter is 27.1 ± 2.0nm.
Embodiment 2 preparation nano-emulsions
Group component (g)
Miglycol?812N 0.32
Cremophor?EL 0.08
Imwitor?988 0.15
Distilled water 0.05
Heparin 0.05
Precision takes by weighing the heparin of recipe quantity, behind the dissolved in distilled water, adds Cremophor EL, Imwitor 988, and mix homogeneously adds the Miglyol812N of recipe quantity again, stir form clear solution promptly.Use Nicomp
TM380ZLS type granularity determination of laser light scattering instrument is measured, and particle diameter is 29.2 ± 3.5nm.
Embodiment 3 preparation nano-emulsions
Group component (g)
Miglycol?812N 0.1
TPGS 0.2
Propylene glycol 0.25
Distilled water 0.05
LMWH 0.05
Precision takes by weighing the LMWH of recipe quantity, behind dissolved in distilled water, adds TPGS, propylene glycol, and mix homogeneously adds the Miglyol812N of recipe quantity again, stir form clear solution promptly.
Embodiment 4
Group component (g)
Miglycol?812N 0.3
Labrasol 0.15
Transcutol-P 0.1
Distilled water 0.05
Heparin 0.05
When nano-emulsion prepared, precision took by weighing the heparin of recipe quantity, behind dissolved in distilled water, added Labrasol, Transcutol-P, and mix homogeneously adds the Miglyol812N of recipe quantity again, stir form clear solution promptly.
Embodiment 5
Group component (g)
Miglycol?812N 0.25
Tween?80 0.1
Imwitor?742 0.2
LMWH 0.05
During preparation, Miglycol 812N, the Cremophor EL of recipe quantity and Imwitor742 mixed and stir making the solution that forms clear, add LMWH, stir and make the formation suspensoid, in the hard capsule of packing into promptly.
Embodiment 6
The present invention use activated partial thromboplastin time (APTT) reflection heparin nano-emulsion oral after in vivo pharmacodynamics effect, the result shows that heparin concentration is high more in the blood plasma, APTT is long more.
Heparin oral nano of the present invention carries out testing at body original position intestinal loop:
Get 24 of the SD rats of body weight 250g～280g, fasting overnight (can freely drink water), the pneumoretroperitoneum of weighing injection chloral hydrate (6.5%) solution 1ml/100g is fixed in its back of the body position on the operation platen after the anesthesia, makes the carotid artery intubate and uses for getting blood.Rat is divided into 4 groups at random, cuts off abdominal part along ventrimeson, jejunum injecting heparin dosage be 50mg/kg respectively organize preparation, be respectively heparin-saline solution (0.2ml) and embodiment of the invention 1-3.Different time is got blood 0.45ml above-mentioned each group all reaches administration before administration after, add in the centrifuge tube that contains 3.2% liquor sodii citratis 0.05ml, mixing, the centrifugal 10min of 6000rpm, get blood plasma and be stored in rapidly in-20 ℃ of refrigerators, use APTT kit measurement APTT, the APTT-time graph is seen Fig. 1.The result shows: blood plasma APTT shows that than the solution significant prolongation heparin nano-emulsion of the present invention can significantly increase the penetrating ability of heparin through intestinal mucosa after the heparin oral nano embodiment 1-3 jejunum of the present invention administration.
Heparin oral nano of the present invention carries out the gastric infusion experiment:
Get 24 of the SD rats of body weight 250g～280g, fasting overnight is freely drunk water, and rat is divided into 4 groups at random, 6 every group.Rat oral gavage give heparin dosage be 50mg/kg respectively organize preparation, be respectively the heparin-saline solution (0.2ml) and the embodiment of the invention 1, embodiment 4 and embodiment 5.Get blood 0.45ml respectively at different time eye socket after reaching administration before the administration, add in the centrifuge tube that contains 3.2% liquor sodii citratis 0.05ml mixing, the centrifugal 10min of 6000rpm, get blood plasma and be stored in rapidly in-20 ℃ of refrigerators, measure APTT, different time APTT curve is seen shown in Figure 2.The result shows that than solution, heparin oral nano embodiment 1 of the present invention and embodiment 4-5 be equal significant prolongation plasma A PTT behind rat oral gavage, shows that heparin oral nano of the present invention can significantly increase the heparin oral administration biaavailability.
Heparin oral nano toxicity of the present invention is investigated:
Get fasting overnight body weight 250g～280g the SD number of rats only, with heparin solution agent (0.2ml), the embodiment of the invention 1 and embodiment 4-5 1h behind rat oral gavage (heparin 50mg/kg), with the etherization rat till death, cut off abdominal part, take out jejunal segment, be placed in the paraformaldehyde solution with the pH6.8PBS flushing, make paraffin section,, under optical microscope, observe intestinal villi and change with hematoxylin and eosin dyeing, observe jejunal mucous membrane whether villous merge, the equivalent damage that comes off, the results are shown in Figure 3.Fine hair was kept perfectly after Fig. 3 A showed oral heparin solution agent; Fig. 3 B shows the oral embodiment of the invention 1 not damage of back intestinal villus; Fig. 3 C and 3D show that the oral embodiment of the invention 4 and embodiment 5 back intestinal villus slightly shorten and obscission, but keep fine hair than complete morphology generally; The positive contrast of Fig. 3 E shows behind oral 0.1% TritonX that intestinal villus seriously merges and comes off.More than experiment shows that heparin oral nano does not almost have toxicity to intestinal mucosa.
Claims (11)
1, a kind of heparin oral nano composition, it is characterized in that making clear solution by oil phase, surfactant, cosurfactant and/or water, the ratio of described oil phase and surfactant is 24: 1-1: 6, and the ratio of described surfactant and cosurfactant is 5: 1-1: 5.
2, heparin oral nano composition according to claim 1 is characterized in that described heparin is selected from the mixture of heparin, low molecular weight heparin, heparitin sulfate or mentioned component.
3, heparin oral nano composition according to claim 1 is characterized in that described oil phase is medium chain triglyceride, medium chain two sweet esters, medium chain monoglyceride or said mixture.
4, heparin oral nano composition according to claim 3, it is characterized in that described oil phase wherein medium chain be carbochain C
8-C
10
5, heparin oral nano composition according to claim 1, it is characterized in that described surfactant be selected from the acidifying natural or castor oil hydrogenated of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene aliphatic alcohol ether class, polyoxyethylene fatty acid ester class, ethylene oxide-oxypropylene block copolymer, polyoxyethylene glycol, tocopherol acid succinate macrogol ester, Polyethylene Glycol-8-glycerol sad/decanoin, lecithin or fabaceous lecithin.
6, heparin oral nano composition according to claim 5 is characterized in that described surfactant is acidifying natural or castor oil hydrogenated, polyoxyethylene sorbitan fatty acid ester, tocopherol acid succinate macrogol ester or the Polyethylene Glycol-8-caprylic/decanoin of polyoxyethylene glycol.
7, heparin oral nano composition according to claim 1 is characterized in that described cosurfactant is selected from medium chain monoglyceride, medium chain two sweet esters, medium chain mixing list/two sweet esters, diethylene glycol monoethyl ether (Transcutol P), propylene glycol, Polyethylene Glycol (PEG of molecular weight 200-600), ethanol or said mixture.
8, heparin oral nano composition according to claim 7 is characterized in that described cosurfactant is that medium chain monoglyceride, medium chain two sweet esters or medium chain mix list/two sweet esters.
9, the heparin oral nano composition of addressing according to claim 1, the ratio that it is characterized in that oil phase and surfactant is 6: 1-1: 1.
10, the heparin oral nano composition of addressing according to claim 1, the ratio that it is characterized in that surfactant and cosurfactant is 3: 1-1: 3.
11, the heparin oral nano composition of addressing according to claim 1 is characterized in that described heparin oral nano is directly oral, or pack into hard gelatin capsule or Perle or enteric hard gelatin capsule or enteric Perle; Or be mixed and made into solid tablet with solid carrier silicon dioxide, calcium sulfate or alginic acid or the solid particle capsule preparations is oral.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012113116A1 (en) * | 2011-02-24 | 2012-08-30 | 美迪思生物科技(北京)有限公司 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
| CN104207145A (en) * | 2014-09-18 | 2014-12-17 | 苏州经贸职业技术学院 | Vitamin E nano-microemulsion and preparation method thereof |
| CN107080734A (en) * | 2008-03-20 | 2017-08-22 | 维尔恩公司 | The emulsion of PEG derivatives comprising tocopherol |
-
2006
- 2006-01-18 CN CN 200610023501 patent/CN1839876A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107080734A (en) * | 2008-03-20 | 2017-08-22 | 维尔恩公司 | The emulsion of PEG derivatives comprising tocopherol |
| US10668029B2 (en) | 2008-03-20 | 2020-06-02 | Virun, Inc. | Compositions containing non-polar compounds |
| WO2012113116A1 (en) * | 2011-02-24 | 2012-08-30 | 美迪思生物科技(北京)有限公司 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
| CN104207145A (en) * | 2014-09-18 | 2014-12-17 | 苏州经贸职业技术学院 | Vitamin E nano-microemulsion and preparation method thereof |
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