CN101426477A - 纳米颗粒卡维地洛制剂 - Google Patents
纳米颗粒卡维地洛制剂 Download PDFInfo
- Publication number
- CN101426477A CN101426477A CNA2007800139366A CN200780013936A CN101426477A CN 101426477 A CN101426477 A CN 101426477A CN A2007800139366 A CNA2007800139366 A CN A2007800139366A CN 200780013936 A CN200780013936 A CN 200780013936A CN 101426477 A CN101426477 A CN 101426477A
- Authority
- CN
- China
- Prior art keywords
- less
- carvedilol
- compositions
- dimethyl
- ammonium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 229960004195 carvedilol Drugs 0.000 title claims abstract description 330
- 239000000203 mixture Substances 0.000 title claims abstract description 287
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 title claims abstract 30
- 238000009472 formulation Methods 0.000 title claims description 46
- 239000002245 particle Substances 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims description 98
- 239000003381 stabilizer Substances 0.000 claims description 91
- 239000002105 nanoparticle Substances 0.000 claims description 77
- -1 oral suspension Substances 0.000 claims description 77
- 238000002360 preparation method Methods 0.000 claims description 65
- 239000006185 dispersion Substances 0.000 claims description 41
- 239000008187 granular material Substances 0.000 claims description 38
- 229920000642 polymer Polymers 0.000 claims description 38
- 239000003795 chemical substances by application Substances 0.000 claims description 36
- 239000012530 fluid Substances 0.000 claims description 25
- 239000007788 liquid Substances 0.000 claims description 25
- 206010019280 Heart failures Diseases 0.000 claims description 24
- 238000013270 controlled release Methods 0.000 claims description 24
- 239000002552 dosage form Substances 0.000 claims description 23
- 238000000227 grinding Methods 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 230000003213 activating effect Effects 0.000 claims description 19
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 206010020772 Hypertension Diseases 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 238000005516 engineering process Methods 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000000443 aerosol Substances 0.000 claims description 10
- 239000002876 beta blocker Substances 0.000 claims description 10
- 229920002678 cellulose Polymers 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 235000010980 cellulose Nutrition 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 239000007909 solid dosage form Substances 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229940097320 beta blocking agent Drugs 0.000 claims description 8
- 125000002091 cationic group Chemical group 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 8
- 239000000839 emulsion Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000003904 phospholipids Chemical class 0.000 claims description 7
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
- 210000000214 mouth Anatomy 0.000 claims description 6
- 210000002381 plasma Anatomy 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 5
- 230000031709 bromination Effects 0.000 claims description 5
- 238000005893 bromination reaction Methods 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 229940107161 cholesterol Drugs 0.000 claims description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 239000002934 diuretic Substances 0.000 claims description 5
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- YJHSJERLYWNLQL-UHFFFAOYSA-N 2-hydroxyethyl(dimethyl)azanium;chloride Chemical compound Cl.CN(C)CCO YJHSJERLYWNLQL-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 claims description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims description 4
- 210000004556 brain Anatomy 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 4
- 229960005156 digoxin Drugs 0.000 claims description 4
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 4
- 230000001882 diuretic effect Effects 0.000 claims description 4
- 238000007046 ethoxylation reaction Methods 0.000 claims description 4
- 210000001508 eye Anatomy 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 4
- 238000007912 intraperitoneal administration Methods 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 229920005604 random copolymer Polymers 0.000 claims description 4
- 210000000664 rectum Anatomy 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 4
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 claims description 4
- 238000001238 wet grinding Methods 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 102000016943 Muramidase Human genes 0.000 claims description 3
- 108010014251 Muramidase Proteins 0.000 claims description 3
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 229940078456 calcium stearate Drugs 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 3
- 235000012000 cholesterol Nutrition 0.000 claims description 3
- 210000001072 colon Anatomy 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 3
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 3
- 239000004325 lysozyme Substances 0.000 claims description 3
- 235000010335 lysozyme Nutrition 0.000 claims description 3
- 229960000274 lysozyme Drugs 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 229960002900 methylcellulose Drugs 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
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- 230000002265 prevention Effects 0.000 claims description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 3
- 229960004274 stearic acid Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- MOKBFXZQXUZAMV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO MOKBFXZQXUZAMV-UHFFFAOYSA-N 0.000 claims description 2
- UIRLNVFJXWEFHI-UHFFFAOYSA-N 2-chloroethyl(ethyl)azanium;bromide Chemical compound [Br-].CC[NH2+]CCCl UIRLNVFJXWEFHI-UHFFFAOYSA-N 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 102000009027 Albumins Human genes 0.000 claims description 2
- 241001044369 Amphion Species 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 2
- VFSNVROTSXGPDS-UHFFFAOYSA-N CCCCCCCCCCCCCCCCN.CCl Chemical compound CCCCCCCCCCCCCCCCN.CCl VFSNVROTSXGPDS-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- RUPBZQFQVRMKDG-UHFFFAOYSA-M Didecyldimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC RUPBZQFQVRMKDG-UHFFFAOYSA-M 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 2
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- FOLJTMYCYXSPFQ-CJKAUBRRSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-(octadecanoyloxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl octadecanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCCCCCCCCCC)O[C@@H]1O[C@@]1(COC(=O)CCCCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@H](CO)O1 FOLJTMYCYXSPFQ-CJKAUBRRSA-N 0.000 claims description 2
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 claims description 2
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000006177 alkyl benzyl group Chemical group 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 239000002160 alpha blocker Substances 0.000 claims description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 2
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 2
- WMLFGKCFDKMAKB-UHFFFAOYSA-M benzyl-diethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](CC)(CC)CC1=CC=CC=C1 WMLFGKCFDKMAKB-UHFFFAOYSA-M 0.000 claims description 2
- 229920001222 biopolymer Polymers 0.000 claims description 2
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- 239000005018 casein Substances 0.000 claims description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 2
- 235000021240 caseins Nutrition 0.000 claims description 2
- 239000004359 castor oil Chemical class 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- CDJGWBCMWHSUHR-UHFFFAOYSA-M decyl(triethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](CC)(CC)CC CDJGWBCMWHSUHR-UHFFFAOYSA-M 0.000 claims description 2
- RLGGVUPWOJOQHP-UHFFFAOYSA-M decyl-(2-hydroxyethyl)-dimethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCC[N+](C)(C)CCO RLGGVUPWOJOQHP-UHFFFAOYSA-M 0.000 claims description 2
- PLMFYJJFUUUCRZ-UHFFFAOYSA-M decyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)C PLMFYJJFUUUCRZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 229960004670 didecyldimethylammonium chloride Drugs 0.000 claims description 2
- GQOKIYDTHHZSCJ-UHFFFAOYSA-M dimethyl-bis(prop-2-enyl)azanium;chloride Chemical compound [Cl-].C=CC[N+](C)(C)CC=C GQOKIYDTHHZSCJ-UHFFFAOYSA-M 0.000 claims description 2
- 229960000878 docusate sodium Drugs 0.000 claims description 2
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical group O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 claims description 2
- VVNBOKHXEBSBQJ-UHFFFAOYSA-M dodecyl(triethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](CC)(CC)CC VVNBOKHXEBSBQJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000008387 emulsifying waxe Substances 0.000 claims description 2
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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Abstract
本发明指向具有改进的药代动学曲线、改进的生物利用度、溶解速率和效率的纳米颗粒卡维地洛组合物。在一种实施方式中,该纳米颗粒卡维地洛组合物的有效平均粒度小于约2000nm。
Description
发明领域
本发明涉及纳米颗粒卡维地洛制剂以及制备和使用该制剂的方法。本发明制剂在治疗高血压(血压过高)、充血性心力衰竭、癌症、病毒感染、精神病相关情况以及类似情形。
发明背景
关于卡维地洛的背景
高血压增加了心脏和动脉的工作量。如果它持续长时间,则心脏和动脉也许会不能适当地起作用。这能够损害脑血管、心脏和肾,导致中风、心力衰竭或肾衰竭。高血压也可增加心脏疾病发作的风险。如果血压受到控制,那么发生这些问题的可能性较小。
心力衰竭可被定义为心脏功能异常造成心脏泵送血液的速度达不到组织代谢的要求的情形。症状通常是非特异性的,并且包括疲劳、呼吸困难、踝肿以及运动障碍。慢性心力衰竭(CHF)总患病率估计为每1000人有10-20人,全年发病率为每1000人1-5人。随着年龄增长,患病率和发病率两者都上升。McDonagh等人的“Epidemiology andPathophysiology of Heart Failure,”Medicine,26:111-5(1998)。心力衰竭是发病和死亡的主要原因。Id.CHF被认为比其它慢性内科病症更损害生活质量。患CHF病人的Id.预后取决于严重性(如症状和运动能力所示)、年龄和性别,男性病人的预后较差。Id.心力衰竭病人需要终身治疗。药物治疗的目的是改善病人的生活和生存质量两方面。利尿剂和血管紧张素转换酶(ACE)抑制剂与非药物计量相结合形成了初期治疗的基础。Davies等人的“ABC of Heart Failure:Management:Diuretics,ACE Inhibitors,and Nitrates,”BMJ,320:428-31(2000)。在所选择病人中可加入地高辛。
现今有大量临床数据证明患CHF病人使用β-阻断剂的效力是由于左心室收缩功能不全导致的。Sharpe N.,“Benefits of Beta-Blockers forHeart Failure:Proven in 1999,”Lancet,353:1988-9(1999);Califf等人的“Beta-Blocker Therapy for Heart Failure,”JAMA,283:1335-7(2000)。
卡维地洛属于被称为β-肾上腺素抑制剂、β-抑制剂或更通常的β-阻断剂的一类药。β-阻断剂通过影响对身体某些部分中一些神经冲动的响应起作用,结果它们通过减少心脏的工作量而减少了心脏对对血和氧的需要。它们还有助于心脏更有规律地跳动。β-抑制剂还可使心脏心律不齐减轻一些。
卡维地洛被用于治疗高血压(血压过高)。卡维地洛也用于防止充血性心力衰竭进一步恶化,并结合其它治疗例如利尿剂、地高辛和ACE抑制剂。卡维地洛通过减弱交感神经系统的作用可能在心力衰竭中起作用。卡维地洛增大了左心室射血分数,降低心肺血管压力、降低心搏率并且防止左心室由于连续使用而逐步增大。卡维地洛被用于治疗心脏病发作后左心室功能紊乱。当左心室(心脏供血的主要腔室)变硬和增大时出现左心室功能紊乱并且可引起肺充血。β-阻断剂由美国食品药品管理局核准用于心力衰竭,其包括美托洛尔(Toprol-XL)和卡维地洛(COREG)。美托洛尔阻断β-1受体,卡维地洛阻断β-1、β-2和α-受体,两种药对于心力衰竭都是有益的,虽然卡维地洛将血压降低得更多。
卡维地洛也可用于治疗其它情形。例如最近已经报道卡维地洛具有抗癌活性。见美国专利号6,632,832“卡维地洛及其异构体的抗癌活性”,描述了利用卡维地洛及其异构体来抑制癌细胞的表皮生长因子和血小板衍生生长因子的依赖性增殖。所治疗的癌症示例包括结肠癌、卵巢癌、乳癌、前列腺癌、胰腺癌、肺癌、黑素瘤、恶性胶质瘤、口腔癌以及白血病。另外,WO 98/38986描述了使用卡维地洛治疗和防止病毒感染,以及美国专利号6,365,618“利用精神病药、卡维地洛治疗或预防迟发性运动障碍、迟发性肌张力不全、迟发性静坐不能的新方法”描述了卡维地洛治疗精神病的用途。该参考资料还教导了卡维地洛可用于改善其中使用了多巴胺阻断药物的精神病治疗,例如躁狂性发作、严重抑郁发作以及精神病特别是精神分裂症和情感分裂性精神障碍。
一些美国专利描述了非纳米颗粒卡维地洛包括(但不限于)美国专利号4,503,067“咔唑基-(4)-氧基丙醇胺化合物及治疗组合物”,美国专利号5,760,069“用于降低由于充血性心力衰竭导致的死亡率的治疗方法”,以及美国专利号5,902,821“咔唑化合物治疗充血性心力衰竭的用途”。
关于在临床试验中卡维地洛治疗,报道的不利情况包括头昏眼花(关于卡维地洛,约3个病人中有一个)、心博徐缓、血压过低、水肿、上呼吸道感染、疲劳、头晕、呼吸浅促、胸痛(关于卡维地洛,约7个病人中有一个)、低心博率和低血压、腹泻(关于卡维地洛,约7个病人中有一个)、高血糖(导致重量增加)、阳痿(在临床试验中,每50个男人有1-2人出现阳痿);现实数量可能高至15%(Am.J.Hypertens.,14:27-31,70-73(2001)),抑郁症、恶心、呕吐、背痛、失眠或头痛。
在美国,市售卡维地洛的商品名为(GlaxoSmithKline)(在其它国家市售卡维地洛为其它商品名,例如DilitrendTM、DimitoneTM、EucardicTM和KredexTM)。是含有3.125mg、6.25mg、12.5mg或25mg卡维地洛的白色椭圆形薄膜包衣片。6.25mg、12.5mg或25mg片剂是片剂。非活性成分由胶态二氧化硅、交聚维酮、羟丙基甲基纤维素、乳糖、硬脂酸镁、聚乙二醇、聚山梨醇酯80、聚维酮、蔗糖和二氧化钛。
对于不同的病人,卡维地洛的剂量将是不同的。以下信息仅包括卡维地洛的平均剂量。对于口服剂型(片剂):(a)充血性心力衰竭:成人—3.125mg一日两次,与食物一起服用;(b)心脏病发作后高血压或左心室功能紊乱:成人—6.25mg一日两次与食物一起服用。对于充血性心力衰竭,<85kg病人的最大推荐剂量是25mg每日两次,而>85kg病人是50mg每日两次。对于高血压,推荐卡维地洛初始剂量为6.25mg每日两次,每日最大剂量为50mg。
药物动力学:在口服之后,(卡维地洛)被迅速广泛地吸收,由于首过代谢程度很大,绝对生物利用度约为25%-35%。口服之后,卡维地洛的表观平均完全清除半衰期通常在7-10小时范围内。所达到的血浆浓度与口服剂量成比例。当与食物一起服用时,吸收速度减缓,如达到血浆水平峰值时间延迟所证明的,生物利用度的程度没有显著性差异。建议病人与食物一起服用(卡维地洛)以使起立性低血压的风险减至最小。
卡维地洛经历立体选择性首过代谢,健康受治疗者在口服之后,R(+)-卡维地洛血浆水平高于S(-)-卡维地洛约2-3倍。R(+)-卡维地洛的平均表观完全清除半衰期在5-9小时范围内,与之相比,S(-)-对映异构体为7-11小时。
B.有关纳米颗粒活性剂组合物的背景
纳米颗粒活性剂组合物,其首先被描述在美国专利号5,145,684(“′684专利”)中,是由可溶性差的治疗或诊断剂构成的颗粒,其表面上吸附或结合了非交联表面稳定剂。′684专利没有描述卡维地洛的纳米颗粒组合物。
制备纳米颗粒活性剂组合物的方法被描述在例如美国专利号5,518,187和5,862,999中,两者都是“药物研磨方法”;美国专利号5,718,388,“药物研磨连续法”;以及美国专利号5,510,118“含纳米颗粒的治疗组合物的制备方法”。
纳米颗粒活性剂组合物也被描述在例如美国专利号5,298,262“离子型浊点改性剂防止消毒期间颗粒聚集的用途”;5,302,401“减小冷冻干燥期间粒度增长的方法”;5,318,767“可用于医疗图像的X射线对比组合物”;.5,326,552“采用高分子量非离子型表面活性剂的纳米颗粒X射线血池对比剂的新制剂”;5,328,404“采用碘化芳族丙二酸酯的X射线成像方法”;5,336,507“采用带电磷脂减少纳米颗粒聚集的用途”;5,340,564“防止颗粒聚集和增加稳定性的含Olin10-G制剂”;5,346,702“采用非离子型浊点改性剂使消毒期间纳米颗粒聚集减至最小的用途”;5,349,957“非常小磁性右旋糖酐颗粒的制备和磁性”;5,352,459“采用净化表面改性剂防止消毒期间颗粒聚集的用途”;5,399,363和5,494,683,两者都是“表面改性的抗癌纳米颗粒”;5,401,492“作为磁共振增强剂的水不溶性非磁性锰粒”;5,429,824“泰洛沙泊作为纳米颗粒稳定剂的用途”;5,447,710“采用高分子量非离子型表面活性剂制备纳米颗粒X射线血池对比剂的方法”;5,451,393“可用于医疗图像的X射线对比组合物”;5,466,440“口服胃肠诊断X射线对比剂与可药用粘土组合的制剂”;5,470,583“含有带电磷脂以减少聚集的纳米颗粒组合物的制备方法”;5,472,683“混合有氨基甲酸酐作为纳米颗粒X射线对比剂用于血池和淋巴系统成像的纳米颗粒诊断”;5,500,204“作为X射线对比剂用于血池和淋巴系统成像的纳米颗粒诊断二聚物”;5,518,738“纳米颗粒NSAID制剂”;5,521,218“用作X射线对比剂的纳米颗粒碘二帕胺(Iododipamide)衍生物”;5,525,328“用于血库和淋巴系统成像的纳米颗粒诊断用的Diatrizoxy酯X射线对比剂”;5,543,133“含有纳米颗粒的X射线对比组合物的制备方法”;5,552,160“表面改性的NSAID纳米颗粒”;5,560,931“作为可消化油或脂肪酸中纳米颗粒分散体的混合物制剂”;5,565,188“作为纳米颗粒表面改性剂的聚亚烷基嵌段共聚物”;5,569,448“作为纳米颗粒组合物的稳定剂涂层的硫酸化非离子嵌段共聚物表面活性剂”;5,571,536“作为可消化油或脂肪酸中纳米颗粒分散体的混合物制剂”;5,573,749“混合有羧酸酐作为X射线对比剂用于血库和淋巴系统成像的纳米颗粒诊断”;5,573,750“诊断成像X射线对比剂”;5,573,783“具有保护性外包衣的可再分散纳米颗粒薄膜基体”;5,580,579“采用通过高分子量线性聚(氧化乙烯)聚合物稳定的纳米颗粒在胃肠道内特定位置粘合”;5,585,108“口服胃肠治疗剂与可药用粘土组合的制剂”;5,587,143“作为纳米颗粒组合物稳定剂涂层的环氧丁烷-氧化乙烯嵌段共聚物表面活性剂”;5,591,456“作为分散体稳定剂的具有羟丙基纤维素的磨制萘普生”;5,593,657“通过非离子和阴离子型稳定剂稳定的新钡盐制剂”;5,622,938“用于纳米晶体的糖基表面活性剂”;5,628,981“口服胃肠诊断X射线对比剂和口服胃肠治疗剂的改进制剂”;5,643,552“混合有碳酸酐作为用于血库和淋巴系统成像的X射线对比剂的纳米颗粒诊断”;5,718,388“药物研磨连续法”;5,718,919“含有布洛芬的R(-)对映体的纳米颗粒”;5,747,001“含有倍氯米松纳米颗粒分散体的气雾剂”;5,834,025“减少静脉注射给药纳米颗粒制剂引起有害的生理反应”6,045,829“采用纤维素类表面稳定剂的艾滋病病毒(HIV)蛋白酶抑制剂的纳米结晶制剂”;6,068,858“采用纤维素类表面稳定剂的艾滋病病毒(HIV)蛋白酶抑制剂的纳米结晶制剂的制备方法”;6,153,225“纳米颗粒萘普生的注射用制剂”;6,165,506“纳米颗粒萘普生的新固态剂型”;6,221,400“采用艾滋病病毒(HIV)蛋白酶抑制剂的纳米结晶制剂的哺乳动物治疗方法”;6,264,922“含纳米颗粒分散体的雾状喷雾剂”;6,267,989“防止纳米颗粒组合物中晶体生长和颗粒聚集的方法”;6,270,806“使用PEG衍生脂质作为纳米颗粒组合物的表面稳定剂的用途”;6,316,029“迅速分解固态口服剂型”;6,375,986“含有聚合物表面稳定剂与磺琥辛酯钠的增效组合的固体剂量纳米颗粒组合物”;6,428,814“具有阳离子表面稳定剂的生物粘附纳米颗粒组合物”;6,431,478“小型磨机”和6,432,381“靶向给药到上和/或下胃肠道的方法”;6,592,903“含有聚合物表面稳定剂与磺基琥珀酸辛基酯钠盐的增效组合的纳米颗粒分散体”;6,582,285“卫生湿磨装置”;6,656,504“含有无定形环孢霉素的纳米颗粒组合物”;6,742,734“用于磨制原料的系统和方法”;6,745,962“小型磨机及其方法”;6,811,767“纳米颗粒药物的液滴气雾剂”;6,908,626“具有立即释放和控释特征组合的组合物”;6,969,529“含有乙烯基吡咯烷酮和醋酸乙烯酯的共聚物作为表面稳定剂的纳米颗粒组合物”;6,976,647“用于磨制原料的系统和方法”;6,991,191“小型磨机的使用方法”以及7,101,576“纳米颗粒甲地孕酮制剂”,将其全部特别引入作为参考。
另外,美国专利公开号20070015719“纳米颗粒克拉霉素制剂”;美国专利公开号20070003628“纳米颗粒氯吡格雷格制剂”;美国专利公开号20070003615“纳米颗粒氯吡格雷和阿司匹林组合制剂”;美国专利公开号20060292214“纳米颗粒扑热息痛制剂”;美国专利公开号20060275372“纳米颗粒格列卫制剂”;美国专利公开号20060246142“纳米颗粒喹唑啉衍生物制剂”;美国专利公开号20060246141“纳米颗粒脂肪酶抑制剂制剂”;美国专利公开号20060216353“纳米颗粒皮质类固醇及抗组胺剂制剂”美国专利公开号20060210639“纳米颗粒二膦酸盐组合物”;美国专利公开号20060210638“纳米颗粒免疫抑制化合物的注射用组合物”;美国专利公开号20060204588“纳米颗粒非那甾胺、度他雄胺或盐酸坦索罗辛及其混合物的制剂”;美国专利公开号20060198896“纳米颗粒苯并二氮杂类的气雾剂和注射用制剂”;美国专利公开号20060193920“有丝分裂原激活(MAP)激酶抑制剂的纳米颗粒组合物”;美国专利公开号20060188566“多西他赛及其类似物的纳米颗粒制剂;美国专利公开号20060165806“纳米颗粒坎地沙坦制剂”;美国专利公开号20060159767“纳米颗粒比卡鲁胺制剂”;美国专利公开号20060159766“纳米颗粒他克莫司制剂”;美国专利公开号20060159628“纳米颗粒苯并噻吩制剂”;美国专利公开号20060154918“注射用纳米颗粒奥氮平制剂”;美国专利公开号20060121112“托吡酯药用组合物”;美国专利公开No.20020012675A1“控释纳米颗粒组合物”;美国专利公开号20040195413A1“用于磨制原料的组合物及方法”;美国专利公开号20040173696A1“磨制微量纳米颗粒候选化合物”;美国专利公开号20050276974“纳米颗粒费伯利特制剂”;美国专利公开号20050238725“具有缩氨酸作为表面稳定剂的纳米颗粒组合物”;美国专利公开号20050233001“纳米颗粒甲地孕酮制剂”;美国专利公开号20050147664“含有抗体的组合物以及利用其靶向给药纳米颗粒活性剂的方法”;美国专利公开号20050063913“新美他沙酮组合物”;美国专利公开号20050042177“西地那非游离碱的新组合物”;美国专利公开号20050031691“凝胶稳定纳米颗粒活性剂组合物”;美国专利公开号20050019412“新格列吡嗪组合物”;美国专利公开号20050004049“新灰黄霉素组合物”;美国专利公开号20040258758“纳米颗粒托吡酯制剂”;美国专利公开号20040258757“稳定纳米颗粒活性剂的液体剂量组合物”;美国专利公开号20040229038“纳米颗粒美洛昔康制剂”;美国专利公开号20040208833“新氟替卡松制剂”;美国专利公开号20040156895“含有普鲁兰多糖的固体剂型”;美国专利公开号20040156872“新尼美舒利组合物”;美国专利公开号20040141925“新去炎松组合物”;美国专利公开号20040115134“新硝苯地平组合物”;美国专利公开号20040105889“低粘度液体剂型”;美国专利公开号20040105778“固体纳米颗粒活性剂的γ辐射”;美国专利公开号20040101566“新过氧化苯甲酰组合物”;美国专利公开号20040057905“纳米颗粒丙酸倍氯米松组合物”;美国专利公开号20040033267“血管生成抑制剂的纳米颗粒组合物”;美国专利公开号20040033202“纳米颗粒固醇制剂及新固醇组合”;美国专利公开号20040018242“纳米颗粒制霉菌素制剂”;美国专利公开号20040015134“药物传递系统及方法”;美国专利公开号20030232796“纳米颗粒普利醇制剂和新普利醇组合”;美国专利公开号20030215502“易碎性减小的速溶剂型”;美国专利公开号20030185869“具有溶菌酶作为表面稳定剂的纳米颗粒组合物”;美国专利公开号20030181411“有丝分裂原激活蛋白(MAP)激酶抑制剂的纳米颗粒组合物”;美国专利公开号20030137067“具有立即释放和控释特征结合的组合物”;美国专利公开号20030108616“含有乙烯基吡咯烷酮和醋酸乙烯基酯的共聚物作为表面稳定剂的纳米颗粒组合物”;美国专利公开号20030095928“纳米颗粒胰岛素”;美国专利公开号20030087308“利用小型磨机或微射流技术的高通量筛选方法”;美国专利公开号20030023203“药物传递系统和方法”;美国专利公开号20020179758“磨制原料的系统及方法”;以及美国专利公开号20010053664“卫生湿磨装置”,描述了纳米颗粒活性剂组合物并且特别引入作为参考。
非晶微粒组合物被描述在例如美国专利号4,783,484“颗粒组合物及其用作抗菌剂”;4,826,689“由水不溶解有机化合物制备尺寸均匀颗粒的方法”;4,997,454“由不溶解化合物制备尺寸均匀颗粒的方法”;5,741,522“用于夹气泡在其内的超微、不聚集的尺寸均匀多孔颗粒及方法”;以及5,776,496“增强超声背向散射的超微多孔颗粒”。
本领域需要具有生物利用度大、发生率减少、频率降低或有害情况严重性降低、剂量减少及其它改进剂量特征的卡维地洛组合物。本发明满足这些需要。
发明概述
本发明涉及含有卡维地洛的纳米颗粒组合物。该组合物包括卡维地洛和吸附在或缔合在卡维地洛颗粒表面上的至少一种表面稳定剂。该纳米颗粒卡维地洛的有效平均粒度小于约2000nm。本发明的优选剂型是固体剂型,虽然可利用任何可药用剂型。
本发明另一方面涉及包括本发明纳米颗粒卡维地洛制剂的药物组合物,该药物组合物包括卡维地洛、至少一种表面稳定剂和可药用载体以及任何所需赋形剂。
本发明另一方面涉及一种纳米颗粒卡维地洛组合物,较之传统微晶或可溶性卡维地洛制剂,其具有改进的药物代谢分布。
在又一实施方式中,本发明包括这样的卡维地洛组合物,其中将该组合物给药到处于禁食状态的受治疗者与将该组合物给药到处于进食状态的受治疗者相比产生相似或生物等效吸收速率,这是通过测量AUC、Cmax、Tmax或其组合而得到的。
本发明的另一实施方式涉及的纳米颗粒卡维地洛组合物另外还包括可用于治疗高血压、充血性心力衰竭或有关情形的一种或多种化合物。
本发明进一步公开了一种制备本发明纳米颗粒卡维地洛组合物的方法。该方法包括使卡维地洛与至少一种表面稳定剂接触一定时间并且在足以形成纳米颗粒卡维地洛组合物的条件下进行。该一种或多种表面稳定剂可与卡维地洛在卡维地洛尺寸缩减之前、期间或之后进行接触。
本发明还涉及使用本发明的纳米颗粒卡维地洛组合物治疗或预防例如高血压、充血性心力衰竭、癌、病毒介入的情形,精神病有关情形例如迟发性运动障碍、迟发性肌张力不全和迟发性静坐不能以及相关情形。
前述概要说明和以下详细说明两者都是示范性的并且意在提供如权利要求所要求的本发明的进一步说明。对于本领域技术人员来说,从以下本发明的详细说明中将显而易见本发明的其它目的、优点和新特征。
本发明的详细描述
A.介绍
本发明涉及包括卡维地洛的纳米颗粒组合物。该组合物包括卡维地洛并优选包括至少一种吸附在或与该药物表面缔合的表面稳定剂。该纳米颗粒卡维地洛的有效平均粒度小于约2000nm。
与传统的卡维地洛非纳米颗粒或可溶性剂型相比,本发明的纳米颗粒卡维地洛制剂的优点包括(但不限于):(1)更小片剂或其它固体剂型尺寸,或制剂的给药频率更小;(2)与传统的卡维地洛微晶或可溶性剂型相比,为了得到相同的药理学效果所需的药剂量更小;(3)生物利用度增加;(4)药代动力学曲线例如Tmax,Cmax,和/或AUC得到改进;(5)当进食给药与对禁食给药相比较时,纳米颗粒卡维地洛组合物有大体上相似或生物等效的药代动力学曲线;(6)与传统的卡维地洛微晶或可溶性型相比,纳米颗粒卡维地洛组合物的分解速率增大;(7)与传统的卡维地洛微晶或可溶性型相比,不利事件的发生率、频率、或严重度减小;以及(8)纳米颗粒卡维地洛组合物与可用于治疗高血压、充血性心力衰竭及有关情形的其它活性剂联合使用。
本发明还包括纳米颗粒卡维地洛组合物和一种或多种无毒性生理可接受载体、助剂或赋形剂,其共同被称为载体。该组合物可被配制成用于口服的固体、液体或气雾剂形式、用于非肠道注射(例如静脉内、肌肉或皮下)、阴道、鼻、直肠、眼、局部(粉剂、药膏或药水)、口腔、脑池内、腹膜内、或局部给药等。本发明的一种优选剂型是用于口服的固体剂型,虽然任何可药用剂型都可被采用。可例举的固体剂型包括(但不限于)片剂、胶囊、小药囊、锭剂、粉剂、丸剂或粒剂。
本发明的剂型,包括固体剂型,可以是例如速溶剂型、控释剂型、冻干剂型、缓释剂型、持续释放剂型、脉冲式释放剂型、立即释放和控释混合剂型,或其组合。优选固体剂量片剂制剂。
B.定义
在此使用几个定义来描述本发明,如以下及整个本申请中所述。
在此使用的术语“有效平均粒度”是指当例如通过沉降场流动分离法、质子关联能谱法、光散射、碟式离心分离法或本领域技术人员已知的其它方法,以重量或其它适当的测量技术(即以体积、数量等)计,至少50%的纳米颗粒卡维地洛粒子的粒度为小于约2000nm。
在此使用的术语“约”,本领域普通技术人员应理解并且在上下文中使用其之处多少有一点变化。对于本领域普通技术人员来说,如果该术语在上下文中使用其之处给出的使用不清楚,则“约”是指等于加上或减去该特定范围的10%。
关于在此使用的“稳定”卡维地洛颗粒,该术语意味着(但不限于)一种或多种以下参数:(1)由于颗粒中间吸引力或相反粒度随时间显著增长,卡维地洛颗粒不会略微絮凝或聚结;(2)卡维地洛颗粒的物理结构不会随时间改变,例如由非晶相转化为结晶相;(3)卡维地洛颗粒是化学稳定的;和/或(4)本发明纳米颗粒的制备中卡维地洛没有在熔点或之上进行了加热步骤。
术语“传统的”或“非纳米颗粒活性剂”是指可溶性或有效平均粒度大于约2000nm的活性剂。在此定义的纳米颗粒活性剂的有效平均粒度小于约2000nm。
在此使用的词组“水溶性差药物”是指那些药物在水中溶解度小于约30mg/ml,优选为小于约20mg/ml,优选为小于约10mg/ml,或优选为小于约1mg/ml。
在此使用的词组“治疗有效量”是指该药剂量对于给药到需要这种治疗的有效数量受治疗者提供特定的药理学反应。要强调的是,在特定情形下将治疗有效量药物给药到特定受治疗者并不总是对治疗此处所述的情形/病症有效,即使该剂量被那些本领域技术人员认为是治疗有效量。
C.纳米颗粒卡维地洛组合物的优选特征
本发明纳米颗粒卡维地洛组合物有许多药理学特征被提高了。
1.生物利用度提高
2.药物代谢分布改进
本发明还提供了当给药到哺乳动物受治疗者时具有理想的药物代谢分布的卡维地洛组合物。卡维地洛组合物的理想药物代谢分布优选包括(但不限于):(1)在给药相同剂量下,当化验给药之后的哺乳动物受治疗者血浆时,优选的是其卡维地洛Cmax大于非纳米颗粒卡维地洛制剂(例如)Cmax;和/或(2)在给药相同剂量下,当化验给药之后的哺乳动物受治疗者血浆时,优选的是其卡维地洛AUC大于非纳米颗粒卡维地洛制剂(例如)AUC;和/或(3)在给药相同剂量下,当化验给药之后的哺乳动物受治疗者血浆时,优选的是其卡维地洛Tmax小于非纳米颗粒卡维地洛制剂(例如)Tmax。在此使用的理想的药物代谢分布是初始剂量卡维地洛之后测量的药物代谢分布。
在一种实施方式中,在给药相同剂量下,纳米颗粒卡维地洛组合物在与非纳米颗粒卡维地洛制剂(例如)的比较药代动力学试验中表现出Tmax不大于非纳米颗粒卡维地洛制剂所表现出的Tmax的约90%,不大于约80%,不大于约70%,不大于约60%,不大于约50%,不大于约30%,不大于约25%,不大于约20%,不大于约15%,不大于约10%,或不大于约5%。
在另一实施方式中,在给药相同剂量下,纳米颗粒卡维地洛组合物在与非纳米颗粒卡维地洛制剂(例如)的比较药代动力学试验中表现出Cmax大于非纳米颗粒卡维地洛制剂所表现出的Cmax至少为约50%,至少为约100%,至少为约200%,至少为约300%,至少为约400%,至少为约500%,至少为约600%,至少为约700%,至少为约800%,至少为约900%,至少为约1000%,至少为约1100%,至少为约1200%,至少为约1300%,至少为约1400%,至少为约1500%,至少为约1600%,至少为约1700%,至少为约1800%,或至少为约1900%。
在又一实施方式中,在给药相同剂量下,纳米颗粒卡维地洛组合物在与非纳米颗粒卡维地洛制剂(例如)的比较药代动力学试验中表现出AUC大于非纳米颗粒卡维地洛制剂(例如)所表现出的AUC至少为约25%,至少为约50%,至少为约75%,至少为约100%,至少为约125%,至少为约150%,至少为约175%,至少为约200%,至少为约225%,至少为约250%,至少为约275%,至少为约300%,至少为约350%,至少为约400%,至少为约450%,至少为约500%,至少为约550%,至少为约600%,至少为约750%,至少为约700%,至少为约750%,至少为约800%,至少为约850%,至少为约900%,至少为约950%,至少为约1000%,至少为约1050%,至少为约1100%,至少为约1150%,或至少为约1200%。
3.本发明卡维地洛组合物的药物代谢分布不受到受治疗者摄取该组合物时进食或禁食的影响
在另一本发明实施方式中,纳米颗粒卡维地洛组合物中的卡维地洛药物代谢分布没有受到受治疗者摄取该组合物时进食或禁食的显著影响。这意味着当纳米颗粒卡维地洛组合物在进食与禁食给药相比较时,吸收的药量(如AUC测得)或药物吸收速率(如Tmax和/或Cmax测得)差异很小或无可评估性差异。当进食-禁食给药比较时,含纳米颗粒卡维地洛组合物的AUC、Cmax和/或Tmax(或其任意组合)差异优选为小于约100%,小于约90%,小于约80%,小于约70%,小于约60%,小于约50%,小于约45%,小于约40%,小于约35%,小于约30%,小于约25%,小于约20%,小于约15%,小于约10%,小于约5%,或小于约3%。
大体上消除了食物影响的剂型的好处包括受治疗者方便度增加,因此增大了受治疗者的遵从度,因为受治疗者不需要确保他们服药时是与食物一起或不与食物一起。这是重要的,因为在受治疗者遵从度差下,可观察到处方药的医疗状况更坏。
在一种本发明实施方式中,本发明包括含纳米颗粒卡维地洛的组合物,其中将该组合物给药到处于禁食状态的受治疗者与将该组合物给药到处于进食状态的受治疗者是生物等效的,特别是如由美国食品药品管理局以及相应的欧洲管理机构(EMEA)所给出的Cmax和AUC准则所规定。在U.S.FDA和当前的European EMEA准则下,两种产品或方法是生物等效的,如果对于AUC和Cmax的90%置信区间(CI)是在80%-125%之间(为调整目的时Tmax测量与生物等效无关)。以前按照欧洲EMEA准则,为了显示两种化合物或给药条件之间的生物等效性,对于AUC的90%CI必须在80%-125%之间,而对于Cmax的90%CI必须在70%-143%之间。
4.本发明卡维地洛组合物的溶解曲线
在另一本发明的实施方式中,本发明的卡维地洛组合物具有意想不到的速溶曲线。给药之后卡维地洛速溶是优选的,因为更快溶解可导致更快开始起作用并且生物利用度更大。
优选本发明卡维地洛组合物具有这样的溶解曲线,其中在约5分钟内至少约20%卡维地洛溶解。在本发明的其它实施方式中,至少约30%或至少约40%卡维地洛在约5分钟内溶解。在还有的其它本发明实施方式中,至少约40%,至少约50%,至少约60%,至少约70%,或至少约80%卡维地洛在约10分钟内溶解。最后,在另一本发明的实施方式中,至少约70%,至少约80%,至少约90%,或至少约100%卡维地洛在约20分钟内溶解。
优选在有差别的介质中测量溶解作用。使这样的溶解介质对于两种产品产生不同的活体外溶解曲线,该产品在胃液中具有不同的体内溶解曲线;即该产品在溶解介质中的溶解性能将是在体内溶解性能的预兆。一种示范性溶解介质是含有浓度为0.025M的表面活性剂硫酸月桂酯钠的水介质。可通过分光光度测定法来进行溶解量的测定。旋转叶片法(欧洲药典)可用于测量溶解作用。
5.本发明卡维地洛组合物的可再分散性曲线
在一种本发明实施方式中,纳米颗粒卡维地洛组合物被配制成固体剂型,并且该固体剂型再分散以使再分散卡维地洛颗粒的有效平均粒度小于约2微米。这是重要的,因为如果紧接着给药本发明纳米颗粒卡维地洛组合物之后没有再分散达到纳米颗粒粒度,则该剂型可能失去由卡维地洛形成纳米颗粒粒度提供的好处。
实际上,本发明纳米颗粒卡维地洛组合物受益于卡维地洛的小粒度;如果卡维地洛在给药时没有再分散成小粒度,则形成“凝块”或聚结卡维地洛颗粒,这是由于纳米颗粒系统的极高表面自由能以及为达到自由能全面缩减的热力学驱动力的缘故。由于形成了这种聚结的卡维地洛颗粒,当纳米颗粒活性剂分散良好时,该卡维地洛剂型的生物利用度可显著下降而观察不到。
此外,本发明纳米颗粒卡维地洛组合物被认为是在给药到哺乳动物例如人或动物时表现出了纳米颗粒卡维地洛广泛的可再分散性,如生物相关性水介质中的重构/可再分散性致使再分散的卡维地洛颗粒的有效平均粒度小于约2微米所证明的。这种生物相关性水介质可以是表现出所需离子强度和PH的任何水介质,其形成该介质生物相关性的基础。所需PH和离子强度是人体中发现的那些典型生理条件。该生物相关性水介质可以是例如含水电解质溶液或任何盐、酸或碱的水溶液、或其组合,其表现出理想的PH和离子强度。
生物相关性PH是本领域众所周知的,例如在胃部,PH值范围为略微小于2(但通常大于1)至4或5。在小肠,PH值范围可为4-6,而在结肠,其范围可为6-8。生物相关性离子强度也是本领域众所周知的,处于禁食状态的胃液的离子强度约为0.1M,同时处于禁食状态的肠液的离子强度约为0.14M,参见例如Lindahl等人的“Characterization ofFluids from the Stomach and Proximal Jejunum in Men and Women,(来自男人和女人的胃部和邻近空肠的液体特性描述)”Pharm.Res.,14(4):497-502(1997)。人们认为测试溶液的PH值和离子强度比特定的化学内含物更关键。因此,通过强酸、强碱、盐、一个或多个共轭酸碱对(即弱酸和该酸相应的盐)、一元和多元电解质等的许多组合可得到适当的PH和离子强度值。
典型电解质溶液可以是(但不限于)HCl溶液,浓度范围为约0.001-约0.1N,及NaCl溶液,浓度范围为约0.001-约0.1M,以及其混合物。例如,电解质溶液可以是(但不限于)约0.1N HCl或更小,约0.01N HCl或更小,约0.001N HCl或更小,约0.1M NaCl或更小,约0.01M NaCl或更小,约0.001M NaCl或更小,以及其混合物。在这些电解质溶液中,0.01N HCl和/或0.1M NaCl是最典型的处于禁食状态的人的生理环境,这是由于邻近胃肠道的PH和离子强度条件。
分别对应于pH 3、pH 2和pH 1,电解质浓度为0.001N HCl、0.01NHCl和0.1N HCl。因此,0.01 N HCl溶液模拟胃部得到的典型酸性环境。0.1M NaCl溶液提供遍及整个身体,包括胃肠液,得到的离子强度条件的适当近似值,虽然浓度高于0.1M可用于模拟人胃肠道内进食环境。
示范性的盐、酸、碱或其组合的溶液,其表现出所需PH和离子强度,包括(但不限于)磷酸/磷酸盐+钠、钾和钙的氯化盐,乙酸/乙酸盐+钠、钾和钙的氯化盐,碳酸/重碳酸盐+钠、钾和钙的氯化盐以及柠檬酸/柠檬酸盐+钠、钾和钙的氯化盐。
在本发明的其它实施方式中,本发明的再分散卡维地洛颗粒(再分散于水介质、生物相关性或任何其它适当介质中)的有效平均粒度小于约1900nm、小于约1800urn、小于约1700nm、小于约1600nm、小于约1500nm、小于约1400nm、小于约1300nm、小于约1200nm、小于约1100nm、小于约1000nm、小于约990nm、小于约980nm、小于约970nm、小于约960nm、小于约950nm、小于约940nm、小于约930nm、小于约920nm、小于约910nm、小于约900nm、小于约890nm、小于约880nm、小于约870nm、小于约860nm、小于约850nm、小于约840nm、小于约830nm、小于约820nm、小于约810nm、小于约800nm、小于约790nm、小于约780nm、小于约770nm、小于约760nm、小于约750nm、小于约740nm、小于约730nm、小于约720nm、小于约710nm、小于约700nm、小于约690nm、小于约680nm、小于约670nm、小于约660nm、小于约650nm、小于约640nm、小于约630nm、小于约620nm、小于约610nm、小于约600nm、小于约590nm、小于约580nm、小于约570nm、小于约560nm、小于约550nm、小于约540nm、小于约530nm、小于约520nm、小于约510nm、小于约500nm、小于约490nm、小于约480nm、小于约470nm、小于约460nm、小于约450nm、小于约440nm、小于约430nm、小于约420nm、小于约410nm、小于约400nm、小于约390nm、小于约380nm、小于约370nm、小于约360nm、小于约350nm、小于约340nm、小于约330nm、小于约320nm、小于约310nm、小于约300nm、小于约290nm、小于约280nm、小于约270nm、小于约260nm、小于约250nm、小于约240nm、小于约230nm、小于约220nm、小于约210urn、小于约200nm、小于约190nm、小于约180nm、小于约170nm、小于约160nm、小于约150nm、小于约140ran、小于约130nm、小于约120nm、小于约110nm、小于约100、小于约75nm或小于约50nm,由光散射方法、显微镜检查或其它适当方法测量。
利用本领域已知的任何适当方法可测试可再分散性。参见例如美国专利号6,375,986“含有聚合物表面稳定剂和磺基丁二酸二辛钠的协同组合的固体剂量纳米颗粒组合物”的实施例部分。
6.其它药物赋形剂
根据本发明的药物组合物还可包括一种或多种粘合剂、填充剂、润滑剂、悬浮剂、甜味剂、调味剂、防腐剂、缓冲剂、润湿剂、分解剂、泡腾剂、及其它赋形剂。这样的赋形剂是本领域已知的。
填充剂的例子是乳糖一水合物、无水乳糖和各种淀粉;粘合剂的例子是各种纤维素和交联聚乙烯吡咯烷酮,微晶纤维素,例如PH101和and PH102,微晶纤维素以及硅酸化微晶纤维素(ProSolv SMCCTM)。合适的润滑剂,包括对待压缩的粉剂的流动性起作用的试剂,是胶体二氧化硅,例如 200、滑石、硬脂酸、硬脂酸镁、硬脂酸钙和硅胶。甜味剂的例子是任何天然或人造的甜味剂,例如蔗糖、木糖醇、糖精钠、环磺酸盐、天冬甜素和安赛蜜(acsulfame)。调味剂的例子是(MAFCO的商标)、泡泡糖调味香料和水果调味香料等。
防腐剂的例子是山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸及其盐、对羟苯甲酸的其它酯例如对羟基苯甲酸丁酯,醇例如乙醇或苯甲醇、酚化合物例如苯酚,或四元化合物例如氯化苄烷铵。适当的稀释剂包括可药用惰性填料,例如微晶纤维素、乳糖、磷酸氢钙、糖类和/或任意前述的混合物。稀释剂的例子包括微晶纤维素如PH101和and PH102;乳糖如乳糖一水合物、无水乳糖和 DCL21;磷酸氢钙如甘露糖醇;淀粉;山梨糖醇;蔗糖;以及葡萄糖。
适当的分解剂包括少许交联的聚乙烯吡咯烷酮、玉米淀粉、马铃薯淀粉、玉米淀粉和改良淀粉、交联的羧甲基纤维素钠、交联聚维酮、羟基乙酸淀粉钠及其混合物。泡腾剂的例子是泡腾对例如有机酸和碳酸盐或重碳酸盐。适当的有机酸包括例如柠檬酸、酒石酸、苹果酸、富马酸、己二酸、琥珀酸和海藻酸以及酸酐和酸盐。适当的碳酸盐和重碳酸盐包括例如碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、甘氨酸碳酸钠、L-赖氨酸碳酸盐和精氨酸碳酸盐。另一方面,仅泡腾对的碳酸氢钠组分可以存在。
7.药物代谢分布组合物组合
在本发明又一实施方式中,形成了所需药物代谢分布的第一纳米颗粒卡维地洛组合物是一起给药、循序给药或与产生所需不同药物代谢分布的至少一种其它卡维地洛组合物结合。多于两种卡维地洛组合物可被一起给药、顺序给药或其结合。虽然第一纳米颗粒卡维地洛组合物具有纳米颗粒粒度,然而另外的一种或多种卡维地洛组合物可以是纳米颗粒的、溶解的或具有纳米颗粒粒度。
在以下方面第二、第三、第四等卡维地洛组合物可不同于第一卡维地洛组合物并且彼此不同,例如:(1)卡维地洛的有效平均粒度;(2)卡维地洛的剂量。这种组合物的组合可减小所需给药频率。如果第二卡维地洛组合物具有纳米颗粒粒度,则优选第二组合物的卡维地洛颗粒具有至少一种表面稳定剂与药物颗粒的表面缔合。该一种或多种表面稳定剂可以是与第一卡维地洛组合物具有的表面稳定剂相同或不同。
优选地,在需要一起给药“速效”制剂和“长效”制剂之处,这两种制剂被组合在一种组合物中,例如一种双释放组合物中。
8.控释的纳米颗粒卡维地洛组合物
在一种本发明的实施方式中,将纳米颗粒卡维地洛组合物配制成控释剂型。控释曲线包括例如缓释、延长释药、脉冲式释放和延迟释放曲线。与立即释放组合物形成对比,根据预定曲线控释卡维地洛组合物使卡维地洛传送到受治疗者经过一段延长的时间。与传统的迅立即释放放剂型相比,这种释放速率可提供治疗有效的卡维地洛水平持续一段延长的时间并因此提供了长期的药理学或诊断响应。这种长期响应提供了许多固有好处,这些好处是相应的短期作用、立即释放制剂不能达到的。
美国专利申请号20020012675 A1“控释纳米颗粒组合物”中描述了控释剂型纳米颗粒活性剂,特此将其引入作为参考。通常,控释卡维地洛组合物包括纳米颗粒卡维地洛、至少一种表面稳定剂和至少一种速度控制聚合物。速度控制聚合物的类型取决于所利用的速度控制剂型的类型。
有几种不同类型的速度控制剂型。在本发明第一方面中,纳米颗粒卡维地洛、至少一种表面稳定剂和一种或多种辅助赋形剂材料被压缩成片剂形式,紧接着涂覆速度控制聚合物材料。在第二方面中,纳米颗粒卡维地洛、至少一种表面稳定剂、速度控制聚合物材料和一种或多种辅助赋形剂材料被一起压缩形成控释骨架。控释骨架可任选地被涂覆速度控制聚合物来提供另外的控释性能。在第三方面中,纳米颗粒卡维地洛、至少一种表面稳定剂和一种或多种辅助赋形剂材料在涂覆速度控制聚合物材料之前被压缩成多层片剂形式。在第四方面中,纳米颗粒卡维地洛和至少一种表面稳定剂被分散于速度控制聚合物材料中并且被压缩成多层片剂,该多层片剂可任选地被涂覆速度控制聚合物来提供另外的控释性能。另一方面,该多层片剂的第一层包括根据本发明的控释组合物,而第二层包括传统的含活性剂组合物(例如卡维地洛或不同的活性剂),例如立即释放组合物。在第五方面中,纳米颗粒卡维地洛和至少一种表面稳定剂被混入含有被渗透膜包围的渗透剂的层或多层片剂中,半渗透膜限定了孔口。在该实施方式中,半渗透膜能透过水介质,例如胃肠液,但在溶液或其它形式中时不能透过溶解性差的卡维地洛。这种渗透性传送系统是本领域众所周知的,其中通过半渗透膜输入流体引起渗透剂膨胀从而驱使卡维地洛通过半渗透膜限定的孔口。在第六方面中,纳米颗粒卡维地洛、至少一种表面稳定剂、一种或多种辅助赋形剂和速度控制聚合物材料结合成多粒子形式。优选该多粒子形式包括离散的粒子、小球、小药片或其组合。在最终的口服剂型中,多粒子形式可以被装入胶囊,例如硬或软胶囊中。另一方面,多粒子形式可被引入其它最终剂型例如小药囊中。在包括离散粒子或小球的多粒子形式情形中,该多粒子形式可以任选地与附加的辅助赋形剂一起被压缩成片剂形式。压缩的多粒子片剂可任选地被涂覆速度控制聚合物材料以便提供另外的控释性能。
速度控制聚合物的选择首先取决于待利用的控释系统类型:即涂层系统或骨架系统。利用了涂层系统的速度控制组合物使用可形成水不能溶解主链的聚合物,例如聚(烷基甲基丙烯酸酯)作为速度控制聚合物。水溶性聚合物,例如聚乙烯吡咯烷酮(PVP)和聚乙二醇(PEG)也可用于涂层系统,但是它们必须与可形成水不能溶解主链的聚合物协同使用以得到控释制组合物。因此,如果在没有可形成水不能溶解主链的聚合物的条件下将水溶性聚合物PVP和PEG用于涂层系统,则所得组合物是立即释放组合物。
骨架控释系统可用作速度控制聚合物,其分子量高得足以形成粘性水凝胶的一种水溶性聚合物。水溶性聚合物例如羟丙基纤维素(HPC)和羟丙基甲基纤维素(HPMC)具有变“级”或分子量;高分子量聚合物是非常粘和坚固的,由该聚合物产生的粘性凝胶控制水和药物释放的扩散,得到速度控制性能。参见“Formulating for Controlled Release withMETHOCEL Premium Cellulose Ethers,”The Dow Chemical Company(1995)。
示范性速度控制聚合物包括(但不限于)能够阻止卡维地洛从本发明的组合物或剂型中释放的亲水性聚合物、疏水性聚合物以及亲水性和疏水性聚合物的混合物。用于在给药后产生卡维地洛有效控释的特别有益的速度控制聚合物包括植物分泌液(阿拉伯树胶)、海藻提取物(琼脂)、植物种子树胶或粘液(瓜尔胶)、谷类树胶(淀粉)、发酵树胶(右旋糖酐)、动物产品(明胶)、羟烷基纤维素例如羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)和羧基甲基纤维素钠(CMC)、瓜尔胶、果胶和角叉菜胶。另外的聚合物包括聚氧化乙烯、烷基纤维素例如乙基纤维素和甲基纤维素、羧甲基纤维素、亲水性纤维素衍生物、聚乙二醇、聚乙烯吡咯烷酮、醋酸纤维素、乙酸丁酸纤维素、邻苯二甲酸乙酸纤维素、苯三甲酸乙酸纤维素、聚醋酸乙烯基酯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素醋酸酯琥珀酸酯、聚乙缩醛二乙氨基乙酸乙烯基酯、聚(甲基丙烯酸烷基酯)和聚(醋酸乙烯基酯)。其它合适的疏水性聚合物包括由丙烯酸或甲基丙烯酸及其各自的酯、蜡、虫胶和氢化植物油衍生的聚合物和/或共聚物。两种或多种速度控制聚合物可被组合使用。这些聚合物是市场上可购得的和/或可通过本领域已知的方法制备。
9.与其它活性剂结合使用的卡维地洛组合物
本发明卡维地洛组合物可另外包括可用于治疗高血压、充血性心力衰竭(或相关情形例如血脂障碍、高血脂、血胆脂醇过多和心血管病症)、病毒感染、癌、精神病或相关情形的一种或多种无卡维地洛化合物。本发明的组合物与这样的不同活性剂一起配制,或本发明组合物可与该活性剂一起给药或顺序给药。
这样的活性剂的例子包括(但不限于):地高辛、CETP(胆固醇酯转移蛋白)抑制剂例如(torcetrapib)、胆固醇降低化合物(例如依替米贝降血糖剂、他汀类或羟甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂、抗高血压药、ACE抑制剂以及硝酸盐。
抗高血压药的例子包括(但不限于):利尿剂(“水丸”)、β阻断剂、α阻断剂、α-β阻断剂。交感神经抑制剂、血管紧张素转化酶(ACE)抑制剂、钙通道阻断剂、血管紧张素受体阻断剂(正式药名血管紧张素-受体-拮抗剂,简称为“沙坦类”)。
可用于治疗高血糖症的药物例子包括(但不限于):(a)胰岛素 (b)磺酰脲类,例如格列本脲( ),醋磺己脲氯磺丙脲格列美脲格列吡嗪格列齐特,妥拉磺脲和甲苯磺丁脲(c)格列奈类(meglitinides)例如瑞格列奈(repaglinide)和那格列奈(nateglinide)(d)缩二胍例如甲福明二甲双胍(Glycon,),(e)噻唑烷二酮例如罗格列酮(rosiglitazone)和吡格列酮(pioglitazone)和(f)g葡糖苷酶抑制剂,例如阿卡糖和米格列醇
他汀类或羟甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂的例子包括(但不限于):洛伐他丁( );普伐他汀辛伐他汀velostatin;阿托伐他汀及其它6-[2-(取代吡咯-1-基)烷基]吡喃-2-酮及衍生物如美国专利号4,647,576中所描述);氟伐他汀fluindostatin(SandozXU-62-320);甲瓦龙酸内酯衍生物的吡唑类似物,如PCT申请WO86/03488中所公开;西立伐他汀(也称为cerivastatin,)及其它吡啶基二羟基庚烯酸,如欧洲专利491226A中所公开;Searle′sSC-45355(3-取代戊二酸衍生物);二氯乙酸酯;甲瓦龙酸内酯的咪唑类似物,如PCT申请WO 86/07054中所公开;3-羧基-2-羟基-丙烷磷酸衍生物如法国专利号2,596,393中所公开;2,3-二-取代吡咯、呋喃及噻吩衍生物,如欧洲专利号0221025中所公开;甲瓦龙酸内酯的萘基类似物如美国专利号4,686,237中所公开;八氢化萘,例如美国专利号4,499,289中所公开的那些;洛伐他汀(lovastatin)的酮类似物,如欧洲专利申请号0,142,146A2中所公开;次膦酸化合物;罗苏伐他汀匹伐他汀以及其它羟甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂。
D.组合物
本发明提供包括纳米颗粒卡维地洛和至少一种表面稳定剂的组合物,优选该表面稳定剂吸附在或缔合在卡维地洛颗粒表面上。这里可用的表面稳定剂与卡维地洛颗粒或其自身不发生化学反应。优选地,该表面稳定剂的各个分子基本上没有分子间交联。该组合物可包括两种或更多种表面稳定剂。
本发明还包括纳米颗粒卡维地洛组合物和一种或多种无毒性的生理学可接受载体、助剂或赋形剂,全部称为载体。可将该组合物配制成用于注射(例如静脉内、肌肉或皮下)、口服固体、液体或气雾剂形式、阴道、鼻、直肠、眼、局部(粉剂、药膏或药水)、口腔、脑池内、腹膜内、或局部给药等。例如,本发明组合物可配制成:(a)用于选自以下的给药方式:口、肺部、直肠、眼、结肠、肠胃外、脑池内、阴道内、腹膜内、局部、口腔、鼻、耳和局部给药;(b)配制成选自以下的剂型:液体分散体、口服悬浮剂、凝胶、气雾剂、药膏、乳膏、片剂和胶囊;(c)配制成选自以下的剂型:控释制剂、速溶制剂、冻干制剂、缓释制剂、持续释放制剂、脉冲式释放制剂以及立即释放和控释混合制剂;或(d)其任意组合。
1.卡维地洛
卡维地洛可以是结晶相、非晶相、半晶相、半非晶相、或其混合物。在此使用的术语“卡维地洛”包括外消旋混合物、卡维地洛异构体,例如R(+)-卡维地洛和/或S(-)-卡维地洛,包括旋光异构体、卡维地洛的羟基咔唑衍生物、卡维地洛的可药用盐,以及其衍生物。
卡维地洛是一种具有a1-阻断活性的非选择性的b-肾上腺素阻断剂。它是(±)-1-(咔唑基-4-氧基)-3-[[2-(邻甲氧基苯氧基)乙基]氨基]-2-丙醇。它是具有如下结构的外消旋混合物。
卡维地洛是分子量为406.5并且分子式为C24H26N2O4的白色到黄白色粉剂。它大量地溶解于二甲亚砜中;溶解于二氯甲烷和甲醇中;少量地溶解于95%乙醇和异丙醇中;微溶于乙基醚中;以及几乎不溶于水、胃液(模拟,TS,pH 1.1)以及肠液(模拟,无胰酶TS,pH 7.5)。
卡维地洛、其异构体、或其衍生物可根据例如美国专利号4,503,067;5,760,069;5,902,821;6,699,997和6,730,326中所详述的那些规定程序来制备,特此将其全部引入作为参考。
2.表面稳定剂
优选地,本发明的纳米颗粒卡维地洛组合物包括至少一种表面稳定剂。本发明也可采用多于一种表面稳定剂的组合。
本发明可采用的有益的表面稳定剂包括(但不限于)已知的有机和无机药物赋形剂。这样的赋形剂包括各种聚合物、低分子量低聚物、天然产物和表面活性剂。示范性表面稳定剂包括非离子型、离子型、阴离子型、阳离子型和两性离子表面活性剂。
表面稳定剂的典型实例包括清蛋白,包括(但不限于)人血清清蛋白和牛血清清蛋白、羟丙基甲基纤维素(现称为hypromellose)、羟丙基纤维素、聚乙烯吡咯烷酮、十二烷基硫酸钠、二辛基磺基琥珀酸盐、明胶、酪蛋白、卵磷脂(磷脂)、葡聚糖、阿拉伯树胶、胆固醇、黄芪胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十八醇十六醇混合物、聚西托醇乳化蜡、脱水山梨糖醇酯、聚氧亚乙基烷基醚(例如聚乙二醇醚,如聚乙二醇1000单鲸蜡基醚)、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨醇脂肪酸酯(例如市售如Tween 和Tween (ICI专用化学品));聚乙二醇(例如Carbowaxs 和(美国联碳UnionCarbide));聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸盐、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇(PVA)、具有氧化乙烯和甲醛的4-(1,1,3,3-四甲基丁基)-苯酚聚合物(也称为四丁酚醛、superione和triton)、泊洛沙姆(例如luronics 和其为氧化乙烯和氧化丙烯的嵌段共聚物);泊洛沙胺(例如Tetronic 也称为Poloxamine 其为将氧化丙烯和氧化乙烯顺序添加到乙二胺而得的四官能化嵌段共聚物(BASF Wyandotte Corporation,Parsippany,NJ.));Tetronic (T-1508)(BASF Wyandotte Corporation),Tritons其为烷芳基聚醚磺酸盐(Rohm and Haas);Crodestas F-其为蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物(Croda Inc.);对-异壬基苯氧基聚(缩水甘油)、也称为Olin-或表面活性剂10-(OlinChemicals,Stamford,CT);Crodestas SL-(Croda,Inc.);以及SA9OHCO,其为C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2(Eastman Kodak Co.);癸酰基-N-甲基葡萄糖酰胺;正癸基β-D-吡喃葡萄糖苷;正癸基β-D吡喃麦芽糖苷;正十二烷基β-D吡喃葡萄糖苷;正十二烷基β-D麦芽糖苷;庚酰基-N-甲基葡萄糖酰胺;正庚基-β-D-吡喃葡萄糖苷;正庚基β-D-硫代葡糖苷;正己基β-D吡喃葡萄糖苷;壬酰基-N-甲基葡萄糖酰胺;正壬基-β-D-吡喃葡萄糖苷;辛酰基-N-甲基葡萄糖酰胺;正辛基-β-D吡喃葡萄糖苷;辛基β-D硫代吡喃葡萄糖苷;PEG-磷脂、PEG-胆固醇、PEG-胆固醇衍生物、PEG-维生素A、PEG-维生素E、溶菌酶、乙烯基吡咯烷酮和醋酸乙烯基酯的无规共聚物,例如 S630等等。
有益的阳离子表面稳定剂例子包括(但不限于)聚合物、生物聚合物、多糖、纤维素类、藻酸盐、磷脂和非聚合化合物,例如两性离子稳定剂、聚N-甲基吡啶鎓、氯化蒽基吡啶鎓、阳离子磷脂、壳聚糖、多熔素、聚乙烯咪唑、聚凝胺、聚甲基丙烯酸甲酯三甲基铵溴化物溴化物(PMMTMABr)、己基二苯乙酮基三甲基铵溴化物(HDMAB)以及聚乙烯吡咯烷酮-甲基丙烯酸2-二甲基氨乙基酯硫酸二甲基酯。
其它有益的阳离子稳定剂包括(但不限于)阳离子脂类、硫鎓、磷鎓和季铵化合物,例如氯化十八烷基三甲铵、苯甲基-二(2-氯乙基)乙基铵溴化物、氯化或溴化椰子油三甲基铵、椰子油甲基二羟乙基铵氯化物或溴化物、癸基三乙基铵氯化物、癸基二甲基羟乙基铵氯化物或溴化物、C12-15二甲基羟乙基铵氯化物或溴化物、椰子油二甲基羟乙基铵氯化物或溴化物、十四烷基三甲基铵甲基硫酸盐、十二烷基二甲基苯甲基铵氯化物或溴化物、、十二烷基二甲基(乙氧基)4铵氯化物或溴化物、N-烷基(C12-18)二甲基苯甲基铵氯化物、N-烷基(C14-18)二甲基苯甲基铵氯化物、N-十四烷基二甲基苯甲基铵氯化物一水合物、二甲基二癸基铵氯化物、N-烷基和(C12-14)二甲基1-萘甲基铵氯化物、卤化三甲铵、烷基-三甲基铵盐和二烷基-二甲基铵盐、十二烷基三甲基铵氯化物、乙氧基化的烷基酰胺基烷基二烷基铵盐和/或乙氧基化的三烷基铵盐、二烷基苯二烷基铵氯化物、N-二癸基二甲基铵氯化物、N-十四烷基二甲基苯甲基铵、氯化物一水合物、N-烷基(C12-14)二甲基1-萘甲基铵氯化物和十二烷基二甲基苯甲基铵氯化物、二烷基苯烷基铵氯化物、十二烷基三甲基铵氯化物、烷基苯甲基甲基铵氯化物、烷基苯甲基二甲基铵溴化物、C12,C15,C17三甲基铵溴化物、十二烷基苯甲基三乙基铵氯化物、聚-二烷基二甲基铵氯化物(DADMAC)、二甲基铵氯化物、烷基二甲基铵卤化物、三(十六烷基)甲基铵氯化物、癸基三甲基铵溴化物、十二烷基三乙基铵溴化物、十四烷基三乙基铵溴化物、十四烷基三甲基铵溴化物、甲基三辛基铵氯化物(ALIQUAT 336TM)、POLYQUAT10TM、溴化四丁铵、苯甲基三甲基铵溴化物、胆碱酯(例如脂肪酸的胆碱酯)、苯扎氯铵、司拉氯铵化合物(例如硬脂酰三甲基氯化铵和二硬脂酰二甲基氯化铵)、溴化或氯化十六烷基铵基吡啶鎓、季铵化的聚氧乙基烷基胺的卤化盐、MIRAPOLTM和ALKAQU ATTM(Alkaril ChemicalCompany)、烷基吡啶盐、胺类例如烷基胺、二烷基胺、链烷醇胺、多乙烯多胺、丙烯酸N,N-二烷基氨烷基酯和乙烯基嘧啶、胺盐例如十二烷基胺乙酸酯、硬脂酰胺乙酸酯、烷基吡啶鎓盐和烷基咪唑鎓盐以及氧化胺;酰亚胺一氮唑鎓盐;质子化的季丙烯酰胺;甲基化的季聚合物,例如聚[二烯丙基二甲基铵氯化物]和聚-[N-甲基乙烯基吡啶氯化物];以及阳离子瓜尔胶。
这类示范性阳离子表面稳定剂及其它有益的阳离子表面活性剂被描述在J.Cross and E.Singer,Cationic Surfactants:Analytical andBiological Evaluation(Marcel Dekker,1994);P.and D.Rubingh(Editor),Cationic Surfactants:Physical Chemistry(Marcel Dekker,1991);和J.Richmond,Cationic Surfactants:Organic Chemistry,(Marcel Dekker,1990)中。
非聚合物表面稳定剂是任意的非聚合的化合物,例如苯扎氯铵、碳鎓化合物、磷鎓化合物、氧鎓化合物、卤鎓化合物、阳离子有机金属化合物、季磷化合物、吡啶鎓化合物、苯胺鎓化合物、铵化合物、羟铵化合物、伯铵化合物、仲铵化合物、叔铵化合物以及具有下式NR1R2R3R4 (+)的季铵化合物,对于具有下式NR1R2R3R4 (+)的化合物:
(i)R1-R4都不是CH3;
(ii)R1-R4中的一个是CH3;
(iii)R1-R4中三个是CH3;
(iv)R1-R4全部是CH3;
(v)R1-R4中两个是CH3,R1-R4中的一个是C6H5CH2,以及R1-R4中的一个是7个碳或更少原子的烷基链;
(vi)R1-R4中两个是CH3,R1-R4中的一个是C6H5CH2,以及R1-R4中的一个是19个碳或更少原子的烷基链;
(vii)R1-R4中两个是CH3,以及R1-R4中的一个是C6H5(CH2)n族,其中n>1;
(viii)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,以及R1-R4中的一个包括至少一个杂原子;
(ix)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,以及R1-R4中的一个包括至少一种卤素;
(x)R1-R4中两个是CH3,R1-R4中的一个是C6H5CH2,以及R1-R4中的一个包括至少一个环片段;
(xi)R1-R4中两个是CH3,以及R1-R4中的一个是苯环;或者
(xii)R1-R4中两个是CH3,以及R1-R4中两个是纯脂族片段。
这样的化合物包括(但不限于)山嵛基苄基二甲基氯化铵、氯化苄乙氧基铵、氯化十六烷基吡啶鎓、山嵛基三甲基氯化铵、劳拉氯铵、西他氯铵、西曲溴铵、西曲氯铵、苯基乙胺氢氟化物、氯化氯烯丙基六亚甲基四胺(Quaternium-15)、二硬脂基二甲基氯化铵(Quaternium-5)、十二烷基二甲基乙基苯甲基铵氯化物(Quaternium-14)、Quaternium-22、Quaternium-26、Quaternium-18硅酸镁锂、二甲氨基乙基氯化物盐酸盐、半胱氨酸盐酸盐、二乙醇铵POE(10)油基醚磷酸酯、二乙醇铵POE(3)油基醚磷酸酯、牛脂苄基二甲基氯化铵、二甲基二十八烷基铵膨润土、司拉氯铵、度米芬、苯甲地那铵、十四烷基二甲基苄基氯化铵、月桂基三甲基氯化铵、二盐酸乙二胺、盐酸胍、盐酸吡哆辛、盐酸碘非他胺、盐酸葡甲胺、氯化甲基苄基乙氧铵、肉豆蔻基三甲基溴化铵、油基三甲基氯化铵、聚季胺盐-1、盐酸普鲁卡因、椰子甜菜碱、司拉氯铵膨润土、司拉氯铵水辉石(hectonite)、硬脂酰三羟乙基丙二胺二氢氟化物、牛脂三甲基氯化铵和十六烷基三甲基溴化铵。
特别优选的表面稳定剂包括(但不限于)聚合物表面稳定剂,特别是当与十二烷基硫酸钠和/或磺基丁二酸二辛钠(DOSS)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、聚乙烯吡咯烷酮、PlasdoneS-630,其为醋酸乙烯酯和乙烯吡咯烷酮的无规共聚物,以及其组合。该表面稳定剂是市场上可购得的和/或能够通过本领域已知的方法制备。这些表面稳定剂大多数是已知的药物赋形剂并且详细地描述在药物赋形剂手册中,由美国药学协会和英国药学会共同出版(The PharmaceuticalPress,2000),特在此将其引入作为参考。
3.纳米颗粒卡维地洛粒度
本发明组合物包括纳米颗粒卡维地洛,其具有下列有效平均粒度:小于约2000nm(即2微米),小于约1900nm,小于约1800nm,小于约1700nm,小于约1600nm,小于约1500nm,小于约1400nm,小于约1300nm,小于约1200nm,小于约1100nm,小于约1000nm,小于约990nm,小于约980nm,小于约970nm,小于约960nm,小于约950nm,小于约940nm,小于约930nm,小于约920nm,小于约910nm,小于约900nm,小于约890nm,小于约880nm,小于约870nm,小于约860nm,小于约850nm,小于约840nm,小于约830nm,小于约820nm,小于约810nm,小于约800nm,小于约790nm,小于约780nm,小于约770nm,小于约760nm,小于约750nm,小于约740nm,小于约730nm,小于约720nm,小于约710nm,小于约700nm,小于约690nm,小于约680nm,小于约670nm,小于约660nm,小于约650nm,小于约640nm,小于约630nm,小于约620nm,小于约610nm,小于约600nm,小于约590nm,小于约580nm,小于约570nm,小于约560nm,小于约550nm,小于约540nm,小于约530nm,小于约520nm,小于约510nm,小于约500nm,小于约490nm,小于约480nm,小于约470nm,小于约460nm,小于约450nm,小于约440nm,小于约430nm,小于约420nm,小于约410nm,小于约400nm,小于约390nm,小于约380nm,小于约370nm,小于约360nm,小于约350nm,小于约340nm,小于约330nm,小于约320nm,小于约310nm,小于约300nm,小于约290nm,小于约280nm,小于约270nm,小于约260nm,小于约250nm,小于约240nm,小于约230nm,小于约220nm,小于约210nm,小于约200nm,小于约190nm,小于约180nm,小于约170nm,小于约160nm,小于约150nm,小于约140nm,小于约130nm,小于约120nm,小于约110nm,小于约100,小于约75nm,或小于约50nm,由光散射法、显微镜方法、或其它适当方法测得。
“有效平均粒度为小于约2000nm”是指以重量或其它适当测量方法(即以体积、数量等)至少50%卡维地洛粒子的粒度小于有效平均值,即小于约2000nm、1900nm、1800nm等(如以上所列),这是在通过上述方法测量时所得的。在本发明其它实施方式中,通过以重量或其它适当测量方法(即以体积、数量等),至少约为60%,至少约为70%,至少约为80%,至少约为90%,至少约为95%或,至少约为99%卡维地洛粒子(例如分别为D60,D70,D80,D90,D95和D99粒度)的粒度小于有效平均值,即小于约2000nm、1900nm、1800nm、1700nm等(如以上所列),在本发明另一实施方式中,如上所述“有效平均粒度”是指该组合物的粒度(即本发明包括具有平均粒度小于约2000nm、...小于约1000nm、小于约990nm、小于约980nm、小于约970nm等等)。
在本发明中,纳米颗粒卡维地洛组合物的D50值是这样的粒度,以重量或其它适当测量方法(即以体积、数量等),50%卡维地洛粒子的粒度低于其值。类似地,D90是这样的粒度,以重量或其它适当测量方法(即以体积、数量等),90%卡维地洛粒子的粒度小低于其值,以及D99是这样的粒度,以重量或其它适当测量方法(即以体积、数量等),99%卡维地洛粒子的粒度小低于其值。
4.卡维地洛和表面稳定剂浓度
卡维地洛与一种或多种表面稳定剂的相对量可差异很大。各个组分的最佳量可取决于例如所选择的特定表面稳定剂、亲水亲油平衡(HLB)、熔点、以及稳定剂水溶液的表面张力等。
在一种实施方式中,卡维地洛浓度可从约99.5%到约0.001%不等,从约95%到约0.1%不等,或从约90%到约0.5%不等,以重量计,基于卡维地洛和至少一种表面稳定剂的组合总重量,不包括其它赋形剂。
在另一实施方式中,至少一种表面稳定剂的浓度可从约0.5%到约99.999%不等,从约5.0%到约99.9%不等,或从约10%到约99.5%不等,以重量计,基于卡维地洛和至少一种表面稳定剂的组合总干重,不包括其它赋形剂。
5.示范性纳米颗粒卡维地洛片剂制剂
以下给出了本发明几种示范性纳米颗粒卡维地洛片剂制剂。这些例子并不是试图在任何方面限制权利要求,而是提供本发明方法中可利用的本发明卡维地洛的示范性片剂制剂,该示范性片剂还可包括包衣剂。
E.制备卡维地洛制剂的方法
本发明另一方面,提供了一种制备本发明纳米颗粒卡维地洛制剂的方法。可利用例如碾磨(包括但不限于湿磨)、均化作用、沉淀、蒸发、脱水冷冻法、模板乳液技术、超临界流体技术、纳米-电喷射技术或其任意组合来制备本发明组合物。美国专利号5,145,684中描述了制备纳米颗粒活性剂组合物的示范性方法。美国专利号5,518,187“药物研磨方法”;美国专利号5,718,388“药物研磨连续法”;美国专利号5,862,999“药物研磨方法”;美国专利号5,665,331“纳米颗粒药剂与晶体生长改性剂的共微量沉淀”;美国专利号5,662,883 for“纳米颗粒药剂与晶体生长改性剂的共微量沉淀”;美国专利号5,560,932“纳米颗粒药剂的微量沉淀”;美国专利号5,543,133“含有纳米颗粒的X射线对比组合物的制备方法”;美国专利号5,534,270“稳定的药物纳米颗粒的制备方法”;美国专利号5,510,118“含有纳米颗粒的治疗组合物的制备方法”;以及美国专利号5,470,583“含有带电磷脂以减少聚集的纳米颗粒组合物的制备方法”中也描述了制备纳米颗粒活性剂组合物的示范性方法,特此将其全部引入作为参考。
在通过任何适当方法制备了纳米颗粒卡维地洛组合物之后,所得卡维地洛组合物可用于适当的给药剂型。
对于碾磨和均化作用,优选用于粉碎方法的分散介质是含水的。然而,卡维地洛在其中溶解性和分散性差的任何介质可用作分散介质。非水分散介质的例子包括(但不限于)含水盐溶液、红花油及溶剂例如乙醇、叔丁醇、己烷和乙二醇。
可将卡维地洛加入于其中它基本上不溶解的液体介质中以形成预混合料。表面稳定剂可存在于预混合料中,其可在粒度减小期间,或可在粒度减小之后将其加入药物分散体中。
可直接使用预混合料,通过使预混合料经过机械方法来降低分散体中的卡维地洛平均粒度以达到所需尺寸,优选小于约5微米。优选在采用球磨来研磨时直接使用预混合料。另一方面,利用适当的搅拌作用例如Cowles型混合机,可将卡维地洛和表面稳定剂分散于液体介质中,直至观察到均匀分散体,其中对于裸眼看不见大团块。优选在采用再循环介质磨来研磨时,对预混合料进行这样的预磨分散步骤。
研磨时间可差别很大并且主要取决于特定的机械方式和所选择的加工条件。对于球磨,可能需要加工时间为5天以内或更长。另一方面,在使用高剪切介质研磨机下,加工时间小于1天(停留时间为1分钟至几小时)是可能的。
优选地,使卡维地洛粒子在没有使卡维地洛显著分解的温度下尺寸减小。小于约30℃-小于约40℃的加工温度是通常优选的。如果需要,可用传统的冷却装置来冷却加工设备。预期的是例如通过用冷却液给磨膛加水套或浸渍其来控制温度。通常,本发明方法在室温和对于研磨方法是安全并且有效的加工压力条件下是方便进行的。环境加工压力是球磨、立式球磨和振动球磨机的特点。
1.研磨以得到纳米颗粒卡维地洛分散体
研磨卡维地洛以得到纳米颗粒分散体,包括将卡维地洛粒子分散于卡维地洛在其中溶解性差的液体分散介质中,紧接着在具有研磨介质的条件下应用机械方法以使卡维地洛粒度减至所需有效平均粒度。对于随所需尺寸范围和所选择的颗粒稳定剂而变化的介质尺寸和组成,研磨介质可以是同类或不同种类的。术语研磨被定义为包括其中有输入力输入颗粒系统以在所述系统内产生剪切力导致粒度减小的任何方法。分散介质可以是例如水、红花油、乙醇、叔丁醇、甘油、聚乙二醇(PEG)、己烷或乙二醇。优选的分散介质是水。
可在具有至少一种表面稳定剂的条件下减小卡维地洛粒子尺寸。另一方面,可使卡维地洛粒子与一种或多种表面稳定剂在研磨后接触。其它化合物,例如稀释剂可在粉碎过程期间被加入卡维地洛/表面稳定剂组合物中。可连续地或以间歇方式制备分散体。
在一种本发明的实施方式中,在研磨过程期间加热卡维地洛和一种或多种表面稳定剂的混合物。如果使用聚合物表面稳定剂,则温度升至该聚合物表面稳定剂的浊点以上,但是低于实际的或降低的卡维地洛熔点。采用加热对于研磨加工的按比例扩大可能是重要的,因为它可有助于一种或多种活性剂的溶解。
所应用的便于减小卡维地洛粒度的机械方法可采用分散磨的形式。合适的分散磨包括球磨、立式球磨、振动球磨机以及介质研磨例如砂磨机和玻珠研磨机。优选介质研磨,这是由于提供想要的粒度减小需要的研磨时间相对较短。对于介质研磨,预混合料的表观粘度优选为约100-约1000厘泊,并且对于球磨,预混合料的表观粘度优选为约1-约100厘泊。该范围往往会提供有效粒度减小和介质磨耗之间的最佳平衡,但决不是限制。
介质研磨是一种高能量研磨加工。将卡维地洛、表面稳定剂和液体置于储器中并且在含有介质和旋转轴/叶轮的膛中再循环。旋转轴搅动介质,其使得卡维地洛受到压紧和剪切力,由此减小卡维地洛粒度。
球磨是一种采用研磨介质、药物、稳定剂和液体的低能量研磨加工。将原料置于以最优速度旋转的研磨容器中以使该介质成瀑布落下并且由于压紧减小了药物粒度。所使用的介质必须具有高密度,因为用于减小粒子的能量是由重力和研磨介质的质量提供的。
研磨介质
用于粒度减小步骤的研磨介质可选自硬介质,优选为平均尺寸小于约3mm,更优选为小于约1mm的球形或微粒状。理想的是该介质可提供本发明粒度,其具有较短加工时间并且对于研磨设备磨损较小。研磨介质的原料选择不被认为是严格的。氧化锆例如用氧化镁、硅酸锆、陶瓷、不锈钢、二氧化钛、氧化铝稳定的95% ZrO,用钇稳定的95% ZrO,以及玻璃研磨介质是示范性研磨原料。
研磨介质可包括优选为大体上球形例如珠粒的粒子,基本上由聚合物树脂或玻璃或硅酸锆或其它适当的组合物组成。备选地,研磨介质可包括具有粘附在其上的聚合树脂涂层的芯。
通常,合适的聚合物树脂是化学和物理学上惰性的,大体上不含有金属、溶剂和单体,并且具有足够的硬度和脆性以使其能够避免在研磨期间成为碎片或被粉碎。合适的聚合树脂包括交联的聚苯乙烯,例如用二乙烯基苯交联的聚苯乙烯;苯乙烯共聚物;聚碳酸酯;聚缩醛例如(E.I.du Pont de Nemours and Co.);氯乙烯聚合物和共聚物;聚氨酯;聚酰胺;聚(四氟乙烯)例如(E.I du Pont de Nemours andCo.),及其它含氟聚合物;高密度聚乙烯;聚丙烯;纤维素醚和酯例如纤维素乙酸酯;聚羟基甲基丙烯酸酯;聚丙烯酸羟乙酯;以及含硅聚合物例如聚硅氧烷等等。硅聚合物可以是能生物降解的。示范性可生物降解的聚合物包括聚(丙交酯)、聚(乙交酯)、丙交酯和乙交酯的共聚物、聚酐类、聚(甲基丙烯酸羟乙酯)、聚(亚氨碳酸酯)、聚(N-酰基羟脯氨酸)酯、聚(N-棕榈酰羟脯氨酸)酯、乙烯-醋酸乙烯酯共聚物、聚(原酸酯)、聚(己内酯)及聚(磷腈)。对于可生物降解聚合物,来自介质本身的污染物可有利地在体内产生代谢变化成为可从身体排除的生物学上可接受产物。聚合树脂可具有约0.8-约3.0g/cm3的密度。
优选研磨介质的尺寸范围为约0.01-约3mm。对于精磨,研磨介质尺寸优选为约0.02-约2mm,并且更优选为约0.03-约1mm。
在一种本发明的实施方式中,卡维地洛粒子是连续制造的。这种方法包括将卡维地洛连续地引入磨膛,使卡维地洛与研磨介质接触,同时在膛中使卡维地洛粒度减小,以及连续地从磨膛中取出纳米颗粒卡维地洛。
利用传统的分离技术,在次级加工中例如通过简单过滤,通过筛网过滤器或筛网进行筛分等,可将研磨介质与研磨过的纳米颗粒卡维地洛分离开来。也可采用其它分离技术例如离心过滤。另一方面,在研磨加工期间可利用筛网在完成粒度减小之后除去研磨介质。
2.沉淀得到纳米颗粒卡维地洛组合物
形成所需纳米颗粒卡维地洛组合物的另一种方法是通过微量沉淀反应。这是在具有一种或多种表面稳定剂以及一种或多种胶体增强稳定性的表面活性剂而没有任何微量有毒溶剂或溶解的重金属杂质的条件下,制备溶解性差的活性剂的稳定分散体的一种方法。
这种方法包括例如(1)使卡维地洛溶解于适当的溶剂中;(2)将来自步骤(1)的制剂加入含有至少一种表面稳定剂的溶液;以及(3)利用适当的非溶剂使来自步骤(2)的制剂沉淀。该方法可接下来通过透析或膜渗滤除去任何所形成的盐(如果存在),以及通过常规方法浓缩该分散体。
3.均化作用得到纳米颗粒卡维地洛组合物
均化作用是一种不使用研磨介质的技术。卡维地洛、表面稳定剂和液体(或卡维地洛粒度减小之后加入卡维地洛和液体与表面稳定剂)组成被推入加工区的加工料流,该加工区在微流体化中被称为相互作用室。将待处理产物引入泵中,并且然后迫使其出来。微流体化的起动注水阀将空气清除出泵。一旦该泵充满了产物,起动注水阀就关闭并迫使产物通过相互作用室。相互作用室的几何形状产生强大的剪切力、冲击力以及空化作用,其引起卡维地洛粒度减小。特别地,在互作用腔里面,加压产物被分成两股物流并且被加速到特别高的速度。然后引导所形成的喷射流朝向彼此并且在相互作用室中碰撞。所得产物具有非常细和均匀的粒子或小滴尺寸。微流体化还提供了热交换器使产物能够冷却。特此引入作为参考的美国专利号5,510,118提及了一种使用微流体化得到纳米颗粒活性剂粒子的方法。其它化合物,例如稀释剂可在粉碎过程之前、期间或之后被加入卡维地洛/表面稳定剂组合物中。可连续地或以间歇式方式来制造分散体。
4.低温工艺得到纳米颗粒卡维地洛组合物
形成所需纳米颗粒卡维地洛组合物的另一种方法是利用喷雾冷冻成液体(“SFL”)来完成。该工艺包括卡维地洛与稳定剂的有机溶液或有机水溶液,将其注入低温液体例如液氮。卡维地洛溶液液滴在足以使结晶和颗粒生长最小化的速率下冻结,由此形成纳米结构卡维地洛粒子。取决于溶剂系统和加工条件的选择,纳米颗粒卡维地洛可具有不定粒子形态。在分离步骤中,可在避免卡维地洛粒子结块和成熟的条件下除去氮和溶剂。
作为SFL的补充技术,超速冷冻(“URF”)也可用于所制得的表面积极大增加的相当纳米结构卡维地洛颗粒。URF包括在低温基质之上的卡维地洛与稳定剂的有机溶液或有机水溶液。
5.乳液方法得到纳米颗粒卡维地洛组合物
形成所需纳米颗粒卡维地洛组合物的另一种方法是利用模板乳液。模板乳液形成具有受控粒度分布和速溶性能的纳米结构卡维地洛颗粒。该方法包括制备一种水包油乳液,然后用含有卡维地洛和稳定剂的非水溶液使其膨胀。卡维地洛颗粒的粒度分布是使卡维地洛具有在该方法中能够被控制并最优化的性能之前的乳液滴尺寸的直接结果。此外,通过选择使用溶剂和稳定剂,达到乳液稳定性,不具有或具有抑制的奥斯特瓦尔德熟化。随后除去溶剂和水,并将稳定的纳米结构卡维地洛颗粒回收。通过对加工条件的适当控制,可得到各种卡维地洛颗粒形态。
6.采用超临界流体技术得到纳米颗粒卡维地洛组合物
Pace等人的已公布国际专利申请号WO 97/14407(公开日1997年4月24日)公开了平均尺寸为100nm-300nm的水不溶解生物活性化合物粒子,它是通过将该化合物溶解于溶液中,然后在具有适当表面改性剂的条件下将该溶液喷射入压缩气体、液体或超临界流体中。“超临界流体”是温度和压力在其热力学临界点之上的任何物质。超临界流体的通常例子包括(但不限于)二氧化碳、乙烷、乙烯、丙烷、丙烯、三氟甲烷(氟仿)、氯三氟甲烷、三氯氟甲烷、氨水、水、环己烷、正戊烷和甲苯。
7.采用纳米-电喷射技术得到纳米颗粒卡维地洛组合物
在电喷射电离作用中,迫使一种液体通过带电非常小、通常是金属的毛细管。该液体含有所需物质,例如卡维地洛(或“被分析物”),其被溶解于大量溶剂中,其通常比分析物挥发性大得多。也经常将挥发性酸、碱或缓冲剂加入该溶液中,该被分析物作为溶液中的离子以质子化形式或作为阴离子而存在。由于同性电荷相斥,该液体迫使其自身离开毛细管并形成直径约为10μm的小滴的薄雾或气雾。该气雾滴喷射至少部分是通过以下方法产生的,该方法包括形成泰勒锥(Taylor cone)以及来自该锥尖端的喷射。一种中性载气,例如氮气,有时被用于帮助该液体成喷雾状以及促使小液滴中的中性溶剂蒸发。由于小液滴蒸发,悬浮于空气中,迫使带电的被分析物分子靠近在一起。由于带电相似的分子靠近在一起,液滴变得不稳定并且液滴再次破碎,这称为库仑分裂,因为是带电的被分析物分子之间的库仑排斥力驱动它。该方法重复其自身直至被分析物没有溶剂并且是独立的离子。
在纳米技术中,可使用电喷射方法在表面上沉积单一颗粒例如卡维地洛颗粒。这是通过喷射胶体并且确定平均起来每滴不多于一种粒子来完成的。结果使周围溶剂干燥导致形成所需类型的单一粒子气雾流。在这里该方法的电离性能对于应用不是至关紧要的,但是可用于该粒子的静电沉淀。
F.治疗方法
本发明还涉及利用本发明纳米颗粒卡维地洛组合物来治疗或预防以下情形的方法,例如高血压、充血性心力衰竭、癌症、病毒感染、与精神病相关的情况,如迟发性运动障碍、迟发性肌张力不全和迟发性静坐不能以及相关情形。另外,本发明纳米颗粒卡维地洛组合物可用于改进精神病的治疗,其中使用了多巴胺阻断药物,例如躁狂发作、严重抑郁发作以及精神病特别是精神分裂症和情感分裂性精神障碍。
例如,纳米颗粒卡维地洛组合物可用于治疗或预防高血压、充血性心力衰竭及相关情形。另外,纳米颗粒卡维地洛组合物可用于治疗癌症,例如结肠癌、卵巢癌、乳癌、前列腺癌、胰腺癌、肺癌、黑素瘤、恶性胶质瘤、口腔癌以及白血病。本发明的组合物利用特别有利于治疗由癌细胞的表皮生长因子和/或血小板衍生生长、蛋白激酶C(PKC)活性和/或环氧化酶2酶作为媒介引起的癌症。
这种治疗包括将本发明纳米颗粒卡维地洛制剂给药到受治疗者,此处使用的术语“受治疗者”是用于意指动物优选为哺乳动物,包括人或非人。术语病人和受治疗者可互换使用。
适用于注射剂的组合物可包括生理学可接受的无菌水溶液或非水溶液、分散体、悬浮液或乳液、以及用于重组成无菌可注射溶液或分散体的无菌粉剂。水性和非水性载体、稀释剂、溶剂、或赋形剂的合适例子包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其适当的混合物、植物油(例如橄榄油)以及可注射有机酯例如油酸乙酯。例如通过使用包衣如卵磷脂,通过在分散体情形下维持所需的粒度,并通过使用表面活性剂可保持适当的流动性。
纳米颗粒组合物还可含有助剂例如防腐剂、润湿剂、乳化剂和分散剂。通过各种抗菌剂和抗真菌剂,例如尼泊金酯类、氯丁醇、苯酚、山梨酸等可确保防止微生物生长。包含等渗剂例如糖、氯化钠等可能也是理想的。通过使用延迟吸收剂例如一硬脂酸铝和凝胶可导致可注射药物形式的延时吸收。
普通技术人员将领会到卡维地洛的有效量可完全根据经验来确定,并且能够以纯洁形式使用,或存在这种形式:可药用盐、酯或药物前体形式。本发明纳米颗粒组合物中的卡维地洛实际剂量水平是可变的,以得到对于给药的特定组合物和方法可有效地获得所需治疗反应的卡维地洛量。因此所选择的剂量水平取决于所需的治疗效果、给药路线、给药的卡维地洛的效力、所需治疗延续时间及其它因素。
剂量单位组合物可包含诸如可用于配制每日或其它适当的定量给药周期(例如每隔一天、每星期、每双周、每月等)这类的亚多剂量的量。然而,不言而喻的是,用于任何特定病人的特定剂量水平将取决于各种因素:待达到的细胞或生理反应类型和程度;所使用的特定剂或组合物的活性;所使用的特定试剂或组合物;年龄、体重、一般健康;性别;以及病人的日常饮食;给药时间;给药途径;以及该试剂的排泄速率;治疗延续时间;药物与特定剂组合使用或同时使用;以及医药领域中众所周知的类似因素。
给出以下实施例来举例说明本发明。然而,不言而喻的是本发明的精神和范围不限于这些实施例中所述的特定条件或细节,但应该仅由随后的权利要求书的范围限定。此处确定的全部参考文献,包括美国专利据此特别引入作为参考。
实施例1
该实施例的目的是制备一种纳米颗粒卡维地洛制剂。
5%(w/w)卡维地洛(Verion,Inc.(Lionville,PA))的水分散系与1.25%(w/w)羟丙基纤维素(HPC-SL)及0.05%(w/w)磺基丁二酸二辛基酯钠盐(DOSS)混合。然后利用具有0.8mm氧化钇处理过的氧化锆介质(Tosoh,Ceramics Division)的50%介质在滚压机(U.S.Stoneware,Mahwah,NJ)中在170rpm下将该混合物研磨46小时。
采用Lecia DM5000B和Lecia CTR 5000光源(Laboratory Instrumentsand Supplies Ltd.,Ashbourne Co.,Meath,Ireland),用显微镜检查磨过的卡维地洛样品,显示离散颗粒分散良好,该样品看来是可接受的。
研磨之后,采用Horiba LA 910粒度分析器,在去离子蒸馏水中测量磨过的卡维地洛颗粒粒度。磨过的卡维地洛的平均粒度为160nm,具有小于228nm的D90,纳米颗粒卡维地洛分散体的PH值为9.6。
在室温储藏三天之后,卡维地洛颗粒保留在分散体中(即未观察到沉淀或晶体生长),没有观察到明显的粒度增长或聚结。三天时间之后,卡维地洛平均粒度为163nm,具有小于229nm的D90。
然后在模拟生物流体中测量纳米颗粒卡维地洛分散体的稳定性。为了在模拟生物流体中测试,将该组合物于模拟胃液(氯化钠和胃蛋白酶于HCl和水中)、0.01N HCl(其模拟胃里发现的典型酸性环境)、以及模拟肠液(磷酸二氢钾、水、氢氧化钠和胰酶)中在40℃培养1小时。结果示于下表1。
表1:模拟生物流体中纳米颗粒卡维地洛组合物的稳定性
组合物 | 模拟胃液 | 0.01N HCl | 模拟肠液 |
5%卡维地洛1.25%HPC-SL0.05% DOSS | 颗粒生长 | 可接受的 | 稍微聚结 |
该结果证明纳米颗粒卡维地洛组合物在室温下是稳定的。此外,该组合物在模拟生物流体中培养时没有表现出显著的粒度增长。这些结果可预言体内生物利用度极好。
实施例2
该实施例的目的是制备一种纳米颗粒卡维地洛制剂。5%(w/w)卡维地洛(Verion,Inc.(Lionville,PA))的水分散系与1.25%(w/w)羟丙基甲基纤维素(HPMC)及0.05%(w/w)磺基丁二酸二辛基酯钠盐(DOSS)混合。然后利用0.8mm氧化钇处理的氧化锆研磨介质(Tosoh,Ceramics Division)(具有50%介质)在滚压机(U.S.Stoneware,Mahwah,NJ)上将该混合物研磨,将该混合物在170rpms的速度下研磨46小时。
采用Lecia DM5000B和Lecia CTR 5000光源(Laboratory Instrumentsand Supplies Ltd.,Ashbourne Co.,Meath,Ireland),用显微镜检查纳米颗粒卡维地洛样品,显示离散颗粒分散良好,该样品看来是可接受的。
研磨之后,采用Horiba LA 910粒度分析器,在去离子蒸馏水中测量磨过的卡维地洛颗粒粒度。磨过的卡维地洛的平均粒度为160nm,具有D90小于235nm,磨过的卡维地洛分散体的PH值为9.8。
在室温储藏三天之后,卡维地洛颗粒保留在分散体中(即未观察到沉淀或晶体生长),没有观察到明显的粒度增长或聚结。三天时间之后,卡维地洛平均粒度为157nm,具有小于223nm的D90。
然后在模拟生物流体中测量纳米颗粒卡维地洛分散体的稳定性。为了在模拟生物流体中测试,将该组合物于模拟胃液(氯化钠和胃蛋白酶于HCl和水中)、0.01 N HCl(其模拟胃里发现的典型酸性环境)、以及模拟肠液(磷酸二氢钾、水、氢氧化钠和胰酶)中在40℃培养1小时。结果示于下表2。
表2:模拟生物流体中纳米颗粒卡维地洛组合物的稳定性
组合物 | 模拟胃液 | 0.01N HCl | 模拟肠液 |
5%卡维地洛1.25%HPMC0.05% DOSS | 颗粒生长 | 可接受的 | 聚结 |
该结果证明纳米颗粒卡维地洛组合物在室温下是稳定的。此外,该组合物在模拟生物流体中培养时没有表现出显著的粒度增长,虽然实施例1中制备的制剂被证明在模拟生物流体中培养时聚结更少。这些结果可预言体内生物利用度良好。
实施例3
该实施例的目的是制备一种纳米颗粒卡维地洛制剂。
5%(w/w)卡维地洛(Verion,Inc.(Lionville,PA))的水分散系与1.25%(w/w)聚乙烯吡咯烷酮(PVP)及0.05%(w/w)磺基丁二酸二辛基酯钠盐(DOSS)混合。然后利用0.8mm氧化钇处理的氧化锆研磨介质(Tosoh,Ceramics Division)(具有50%介质)在滚压机(U.S.Stoneware,Mahwah,NJ)上将该混合物研磨,将该混合物在170rpms的速度下研磨5天。
采用Lecia DM5000B和Lecia CTR 5000光源(Laboratory Instrumentsand Supplies Ltd.,Ashbourne Co.,Meath,Ireland),用显微镜检查磨过的卡维地洛样品,显示离散颗粒分散良好,该样品看来是可接受的。
研磨之后,采用Horiba LA 910粒度分析器,在去离子蒸馏水中测量磨过的卡维地洛颗粒粒度。磨过的卡维地洛的平均粒度为107nm,具有D90为小于167nm。磨过的卡维地洛分散体的PH值为9.2。
然后在模拟生物流体中测量纳米颗粒卡维地洛分散体的稳定性。为了在模拟生物流体中测试,将该组合物于模拟胃液(氯化钠和胃蛋白酶于HCl和水中)、0.01N HCl(其模拟胃里发现的典型酸性环境)、以及模拟肠液(磷酸二氢钾、水、氢氧化钠和胰酶)中在40℃培养1小时。结果示于下表3。
表3:模拟生物流体中纳米颗粒卡维地洛组合物的稳定性
组合物 | 模拟胃液 | 0.01N HCl | 模拟肠液 |
5%卡维地洛1.25%PVP0.05% DOSS | 颗粒生长 | 可接受的 | 稍微聚结 |
该结果证明纳米颗粒卡维地洛组合物在模拟生物流体中培养时没有表现出显著的粒度增长。这些结果可预言体内生物利用度极好。
实施例4
该实施例的目的是制备一种纳米颗粒卡维地洛制剂。
5%(w/w)卡维地洛(Verion,Inc.(Lionville,PA))的水分散系与1.25%(w/w)Pluronic S-630(醋酸乙烯酯和乙烯吡咯烷酮的无规共聚物)及0.05%(w/w)磺基丁二酸二辛基酯钠盐(DOSS)混合。然后利用0.8mm氧化钇处理的氧化锆研磨介质(Tosoh,Ceramics Division)(具有50%介质)在滚压机(U.S.Stoneware,Mahwah,NJ)上将该混合物研磨,将该混合物在170rpms的速度下研磨46小时。
采用Lecia DM5000B和Lecia CTR 5000光源(Laboratory Instrumentsand Supplies Ltd.,Ashbourne Co.,Meath,Ireland),用显微镜检查纳米颗粒卡维地洛样品,显示离散颗粒分散良好,该样品看来是可接受的。
研磨之后,采用Horiba LA 910粒度分析器,在去离子蒸馏水中测量磨过的卡维地洛颗粒粒度。磨过的卡维地洛的平均粒度为189nm,具有D90小于279nm,磨过的卡维地洛分散体的PH值为8.9。
在室温储藏三天之后,卡维地洛颗粒保留在分散体中(即未观察到沉淀或晶体生长),没有观察到明显的粒度增长或聚结。三天时间之后,卡维地洛平均粒度为160nm,具有D90为小于224nm。
然后在模拟生物流体中测量纳米颗粒卡维地洛分散体的稳定性。为了在模拟生物流体中测试,将该组合物于模拟胃液(氯化钠和胃蛋白酶于HCl和水中)、0.01N HCl(其模拟胃里发现的典型酸性环境)、以及模拟肠液(磷酸二氢钾、水、氢氧化钠和胰酶)中在40℃培养1小时。结果示于下表4。
表4:模拟生物流体中纳米颗粒卡维地洛组合物的稳定性
组合物 | 模拟胃液 | 0.01N HCl | 模拟肠液 |
5%卡维地洛1.25%S-6300.05% DOSS | 颗粒生长 | 可接受的 | 聚结 |
该结果证明纳米颗粒卡维地洛组合物在室温下是稳定的。此外,该组合物在模拟生物流体中培养时没有表现出显著的粒度增长,虽然实施例1和3中制备的制剂被证明在模拟生物流体中培养时聚结更少。这些结果可预言体内生物利用度良好。
那些本领域技术人员将显而易见的是:在不背离本发明精神或范围的条件下,可对本发明方法和组合物进行改型和变化。因此,其意图是本发明包括本发明的改型和变化,倘若它们出现在所附权利要求书及其等价物范围内。
Claims (27)
1.一种稳定的纳米颗粒卡维地洛组合物,其包括:
(a)有效平均粒度小于约2000nm的卡维地洛、其盐、或其旋光异构体的颗粒;以及
(b)至少一种表面稳定剂。
2.权利要求1中所述的组合物,其中所述卡维地洛选自结晶相、非晶相、半晶相、半非晶相、及其混合物。
3.权利要求1中所述的组合物,其中所述纳米颗粒卡维地洛的有效平均粒度选自小于约1900nm、小于约1800nm、小于约1700nm、小于约1600nm、小于约1500nm、小于约1400nm、小于约1300nm、小于约1200nm、小于约1100nm、小于约1000nm、小于约990nm、小于约980nm、小于约970nm、小于约960nm、小于约950nm、小于约940nm、小于约930nm、小于约920nm、小于约910nm、小于约900nm、小于约890nm、小于约880nm、小于约870nm、小于约860nm、小于约850nm、小于约840nm、小于约830nm、小于约820nm、小于约810nm、小于约800nm、小于约790nm、小于约780nm、小于约770nm、小于约760nm、小于约750nm、小于约740nm、小于约730nm、小于约720nm、小于约710nm、小于约700nm、小于约690nm、小于约680nm、小于约670nm、小于约660nm、小于约650nm、小于约640nm、小于约630nm、小于约620nm、小于约610nm、小于约600nm、小于约590nm、小于约580nm、小于约.570nm、小于约560nm、小于约550nm、小于约540nm、小于约530nm、小于约520nm、小于约510nm、小于约500nm、小于约490nm、小于约480nm、小于约470nm、小于约460nm、小于约450nm、小于约440nm、小于约430nm、小于约420run、小于约410urn、小于约400nm、小于约390nm、小于约380nm、小于约370nm、小于约360nm、小于约350nm、小于约340nm、小于约330nm、小于约320nm、小于约310nm、小于约300nm、小于约290nm、小于约280nm、小于约270nm、小于约260nm、小于约250nm、小于约240nm、小于约230nm、小于约220nm、小于约210nm、小于约200nm、小于约190nm、小于约180nm、小于约170nm、小于约160nm、小于约150nm、小于约140nm、小于约130nm、小于约120nm、小于约110nm、小于约100、小于约75nm和小于约50nm。
4.权利要求3中所述的组合物,其中所述“有效平均粒度”选自平均粒度、D50、D60、D70、D80、D90、D95和D99粒度。
5.权利要求1中所述的组合物,其中所述组合物被:
(a)配制成用于选自以下的给药方式:口、肺部、直肠、眼、结肠、肠胃外、脑池内、阴道内、腹膜内、局部、口腔、鼻、耳和局部给药;
(b)配制成选自以下的剂型:液体分散体、口服悬浮液、凝胶、气雾剂、软膏、乳膏、片剂和胶囊;
(c)配制成选自以下的剂型:控释制剂、速熔制剂、冻干制剂、缓释制剂、持续释放制剂、脉冲式释放制剂以及立即释放和控释混合制剂;或者
(d)其任意组合。
6.权利要求5中所述的组合物,其中所述卡维地洛组合物被配制成控释剂型。
7.权利要求1中所述的组合物,其中所述组合物还包括一种或多种可药用赋形剂、载体或其组合。
8.权利要求1中所述的组合物,其中:
(a)卡维地洛的存在量选自:从约99.5%-约0.001%、从约95%-约0.1%以及从约90%-约0.5%重量,基于卡维地洛和至少一种表面稳定剂的混合总重量,不包括其它赋形剂;
(b)至少一种表面稳定剂的存在量选自:从约0.5%-约99.999%重量、从约5.0%-约99.9%重量以及从约10%-约99.5%重量,基于卡维地洛和至少一种表面稳定剂的混合总干重,不包括其它赋形剂;或者
(c)(a)和(b)的组合。
9.权利要求1中所述的组合物,其中至少一种表面稳定剂选自非离子型表面稳定剂、离子型表面稳定剂、阴离子型表面稳定剂、阳离子型表面稳定剂和两性离子表面稳定剂。
10.权利要求1中所述的组合物,其中至少一种表面稳定剂选自清蛋白、人血清清蛋白、牛血清清蛋白、氯化十六烷基吡啶鎓、明胶、酪蛋白、磷脂、葡聚糖、甘油、阿拉伯树胶、胆固醇、黄芪胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十八醇十六醇混合物、聚西托醇乳化蜡、脱水山梨糖醇酯、聚氧亚乙基烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨醇脂肪酸酯、聚乙二醇、十二烷基三甲基铵溴化物、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸盐、十二烷基硫酸钠、羧甲基纤维素钙、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇、聚乙烯吡咯烷酮、具有氧化乙烯和甲醛的4-(1,1,3,3-四甲基丁基)-苯酚聚合物、泊洛沙姆、泊洛沙胺、带电的磷脂、二辛基磺基琥珀酸酯、磺基琥珀酸钠的二烷基酯、十二烷基硫酸钠、烷基芳基聚醚磺酸盐、蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物、对异壬基苯氧基聚(缩水甘油)、癸酰基-N-甲基葡萄糖酰胺、正癸基β-D-吡喃葡萄糖苷;正癸基β-D吡喃麦芽糖苷;正十二烷基β-D吡喃葡萄糖苷;正十二烷基β-D麦芽糖苷;庚酰基-N-甲基葡萄糖酰胺;正庚基-β-D-吡喃葡萄糖苷;正庚基β-D-硫代葡糖苷;正己基β-D吡喃葡萄糖苷;壬酰基-N-甲基葡萄糖酰胺;正壬基-β-D-吡喃葡萄糖苷;辛酰基-N-甲基葡萄糖酰胺;正辛基-β-D吡喃葡萄糖苷;辛基β-D硫代吡喃葡萄糖苷;溶菌酶;PEG-磷脂,PEG-胆固醇、PEG-胆固醇衍生物、PEG-维生素A、PEG-维生素E、醋酸乙烯基酯和乙烯基吡咯烷酮的无规共聚物、阳离子聚合物、阳离子生物聚合物、阳离子多糖、阳离子纤维素、阳离子藻酸盐、阳离子非聚合化合物、阳离子磷脂、阳离子脂类、聚甲基丙烯酸甲酯三甲基铵溴化物、硫鎓化合物、聚乙烯吡咯烷酮-甲基丙烯酸2-二甲基氨乙基酯硫酸二甲基酯、十六烷基三甲基溴化铵、膦鎓化合物、季铵化合物、苯甲基-二(2-氯乙基)乙基铵溴化物、氯化椰子油三甲基铵、溴化椰子油三甲基铵、椰子油甲基二羟乙基铵氯化物、椰子油甲基二羟乙基铵溴化物、癸基三乙基铵氯化物、癸基二甲基羟乙基铵氯化物、癸基二甲基羟乙基铵氯化物溴化物、C12-15二甲基羟乙基铵氯化物、C12-15二甲基羟乙基铵氯化物溴化物、椰子油二甲基羟乙基铵氯化物、椰子油二甲基羟乙基铵溴化物、、十四烷基三甲基铵甲基硫酸盐、十二烷基二甲基苯甲基铵氯化物、十二烷基二甲基苯甲基铵溴化物、十二烷基二甲基(乙氧基)4铵氯化物、十二烷基二甲基(乙氧基)4铵溴化物、N-烷基(C12-18)二甲基苯甲基铵氯化物、N-烷基(C14-18)二甲基苯甲基铵氯化物、N-十四烷基二甲基苯甲基铵氯化物一水合物、二甲基二癸基铵氯化物、N-烷基和(C12-14)二甲基1-萘甲基铵氯化物、卤化三甲铵、烷基-三甲基铵盐、二烷基-二甲基铵盐、十二烷基三甲基铵氯化物、乙氧基化的烷基酰胺基烷基二烷基铵盐、乙氧基化的三烷基铵盐、二烷基苯二烷基铵氯化物、N-二癸基二甲基铵氯化物、N-十四烷基二甲基苯甲基铵、氯化物一水合物、N-烷基(C12-14)二甲基1-萘甲基铵氯化物、十二烷基二甲基苯甲基铵氯化物、二烷基苯烷基铵氯化物、十二烷基三甲基铵氯化物、烷基苯甲基甲基铵氯化物、烷基苯甲基二甲基铵溴化物、C12三甲基铵溴化物、C15三甲基铵溴化物、C17三甲基铵溴化物、十二烷基苯甲基三乙基铵氯化物、聚-二烷基二甲基铵氯化物(DADMAC)、二甲基铵氯化物、烷基二甲基铵卤化物、三(十六烷基)甲基铵氯化物、癸基三甲基铵溴化物、十二烷基三乙基铵溴化物、十四烷基三乙基铵溴化物、甲基三辛基铵氯化物、POLYQUAT 10TM、溴化四丁铵、苯甲基三甲基铵溴化物、胆碱酯、苯扎氯铵、司拉氯铵化合物、溴化十六烷基吡啶鎓、氯化十六烷基吡啶鎓、季铵化的聚氧乙基烷基胺的卤化盐、MIRAPOLTM、ALKAQU ATTM、烷基吡啶鎓盐、胺类、胺盐、氧化胺;酰亚胺一氮唑鎓盐、质子化的季丙烯酰胺;甲基化的季聚合物以及阳离子瓜尔胶。
11.权利要求1中所述的组合物,其中当给药之后在哺乳动物受治疗者的血浆中化验时,卡维地洛的AUC大于被以相同剂量给药非纳米颗粒状卡维地洛制剂的AUC。
12.权利要求1中所述的组合物,其中当给药之后在哺乳动物受治疗者的血浆中化验时,卡维地洛的Cmax大于被以相同剂量给药非纳米颗粒状卡维地洛制剂的Cmax。
13.权利要求1中所述的组合物,其中当给药之后在哺乳动物受治疗者的血浆中化验时,卡维地洛的Tmax小于被以相同剂量给药非纳米颗粒状卡维地洛制剂的Tmax。
14.权利要求1中所述的组合物,其中在进食条件下将所述组合物给药到人时具有与在禁食条件下相比相似的吸收速率。
15.权利要求1中所述的组合物,其中在进食条件下给药到受治疗人之后与在禁食条件下给药到受治疗人相比,所述组合物表现出生物等效性。
16.权利要求15中所述的组合物,其中生物等效性是通过:
(a)在80%-125%之间的AUC的90%置信区间,以及
(b)在80%-125%之间的Cmax的90%置信区间而确立的。
17.权利要求1中所述的组合物,其被配制成固体剂型,其中在给药后,所述卡维地洛颗粒再分散成小于约2微米的有效平均粒度。
18.权利要求17中所述的组合物,其中所述再分散卡维地洛粒度选自:小于约1900nm、小于约1800nm、小于约1700nm、小于约1600nm、小于约1500nm、小于约1400nm、小于约1300nm、小于约1200nm、小于约1100nm、小于约1000nm、小于约990nm、小于约980nm、小于约970nm、小于约960nm、小于约950nm、小于约940nm、小于约930nm、小于约920nm、小于约910nm、小于约900nm、小于约890nm、小于约880nm、小于约870nm、小于约860nm、小于约850nm、小于约840nm、小于约830nm、小于约820nm、小于约810nm、小于约800nm、小于约790nm、小于约780nm、小于约770nm、小于约760nm、小于约750nm、小于约740nm、小于约730nm、小于约720nm、小于约710nm、小于约700nm、小于约690nm、小于约680nm、小于约670nm、小于约660nm、小于约650nm、小于约640nm、小于约630nm、小于约620nm、小于约610nm、小于约600nm、小于约590nm、小于约580nm、小于约570nm、小于约560nm、小于约550nm、小于约540nm、小于约530nm、小于约520nm、小于约510nm、小于约500nm、小于约490nm、小于约480nm、小于约470nm、小于约460nm、小于约450nm、小于约440nm、小于约430nm、小于约420nm、小于约410nm、小于约400nm、小于约390nm、小于约380nm、小于约370nm、小于约360nm、小于约350nm、小于约340nm、小于约330nm、小于约320nm、小于约310nm、小于约300nm、小于约290nm、小于约280nm、小于约270nm、小于约260nm、小于约250nm、小于约240nm、小于约230nm、小于约220nm、小于约210nm、小于约200nm、小于约190nm、小于约180nm、小于约170nm、小于约160nm、小于约150nm、小于约140nm、小于约130nm、小于约120nm、小于约110nm、小于约100、小于约75nm以及小于约50nm。
19.权利要求1中所述的组合物,其被配制成固体剂型,其中所述卡维地洛颗粒在生物相关性介质中再分散,以使卡维地洛再分散颗粒的有效平均粒度具有小于约2000nm。
20.权利要求19中所述的组合物,其中所述卡维地洛再分散颗粒具有选自下列的有效平均粒度:小于约1900nm、小于约1800nm、小于约1700nm、小于约1600nm、小于约1500nm、小于约1400nm、小于约1300nm、小于约1200nm、小于约1100nm、小于约1000nm、小于约990nm、小于约980nm、小于约970nm、小于约960nm、小于约950nm、小于约940nm、小于约930nm、小于约920nm、小于约910nm、小于约900nm、小于约890nm、小于约880nm、小于约870nm、小于约860nm、小于约850nm、小于约840nm、小于约830nm、小于约820nm、小于约810nm、小于约800nm、小于约790nm、小于约780nm、小于约770nra、小于约760nm、小于约750nm、小于约740nm、小于约730nm、小于约720nm、小于约710nm、小于约700nm、小于约690nm、小于约680nm、小于约670nm、小于约660nm、小于约650nm、小于约640nm、小于约630nm、小于约620nm、小于约610nm、小于约600nm、小于约590nm、小于约580nm、小于约570nm、小于约560nm、小于约550nm、小于约540nm、小于约530nm、小于约520nm、小于约510nm、小于约500nm、小于约490nm、小于约480nm、小于约470nm、小于约460nm、小于约450nm、小于约440nm、小于约430nm、小于约420nm、小于约410nm、小于约400nm、小于约390nm、小于约380nm、小于约370nm、小于约360nm、小于约350nm、小于约340nm、小于约330nm、小于约320nm、小于约310nm、小于约300nm、小于约290nm、小于约280nm、小于约270nm、小于约260nm、小于约250nm、小于约240nm、小于约230nm、小于约220nm、小于约210nm、小于约200nm、小于约190nm、小于约180nm、小于约170nm、小于约160nm、小于约150nm、小于约140nm、小于约130nm、小于约120nm、小于约110nm、小于约100、小于约75nm以及小于约50nm。
21.权利要求1中所述的组合物,另外还包括一种或多种非卡维地洛活性剂。
22.权利要求21中所述的组合物,其中所述一种或多种非卡维地洛活性剂选自:抗高血压药物、可用于治疗充血性心力衰竭的活性剂和可用于治疗心血管疾病的活性剂。
23.权利要求22中所述的组合物,其中所述一种或多种非卡维地洛活性剂选自:地高辛、硝酸盐、利尿剂、β阻断剂、α阻断剂、α-β阻断剂、交感神经抑制剂、血管紧张素转化酶(ACE)抑制剂、钙通道阻断剂和血管紧张素受体阻断剂。
24.一种制备纳米颗粒卡维地洛组合物的方法,该方法包括使卡维地洛、其旋光异构体、或其盐的颗粒与至少一种表面稳定剂接触一定时间并且在足以形成有效平均粒度小于约2微米的卡维地洛组合物的条件下进行。
25.权利要求24中所述的方法,其中所述接触包括研磨、湿磨、均化、沉淀、蒸发、冷冻、产生超临界流体颗粒、模板乳液技术、纳米-电喷射技术或其组合。
26.一种用于治疗或预防高血压的方法,该方法包括向需要治疗或预防的受治疗者给药一种有效量的组合物,该组合物包括:
(a)有效平均粒度小于约2微米的卡维地洛纳米颗粒;
(b)至少一种表面稳定剂;以及
(c)至少一种可药用载体。
27.一种用于治疗充血性心力衰竭的方法,该方法包括向需要治疗或预防的受治疗者给药一种有效量的组合物,该组合物包括:
(a)有效平均粒度小于约2微米的卡维地洛纳米颗粒;
(b)至少一种表面稳定剂;以及
(c)至少一种可药用载体。
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-
2007
- 2007-02-09 CN CNA2007800139366A patent/CN101426477A/zh active Pending
- 2007-02-09 AU AU2007221471A patent/AU2007221471A1/en not_active Abandoned
- 2007-02-09 KR KR1020087023471A patent/KR20080105114A/ko not_active Application Discontinuation
- 2007-02-09 WO PCT/US2007/003479 patent/WO2007100466A2/en active Application Filing
- 2007-02-09 EP EP07750325A patent/EP1996161A2/en not_active Withdrawn
- 2007-02-09 CA CA002643492A patent/CA2643492A1/en not_active Abandoned
- 2007-02-09 BR BRPI0708343-2A patent/BRPI0708343A2/pt not_active IP Right Cessation
- 2007-02-09 JP JP2008557272A patent/JP2009528349A/ja active Pending
- 2007-02-09 MX MX2008011069A patent/MX2008011069A/es unknown
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Also Published As
Publication number | Publication date |
---|---|
BRPI0708343A2 (pt) | 2011-05-24 |
JP2009528349A (ja) | 2009-08-06 |
IL193692A0 (en) | 2009-08-03 |
WO2007100466A3 (en) | 2007-11-29 |
AU2007221471A1 (en) | 2007-09-07 |
WO2007100466A2 (en) | 2007-09-07 |
EP1996161A2 (en) | 2008-12-03 |
MX2008011069A (es) | 2008-11-14 |
CA2643492A1 (en) | 2007-09-07 |
ZA200807397B (en) | 2009-06-24 |
US20070202180A1 (en) | 2007-08-30 |
KR20080105114A (ko) | 2008-12-03 |
US8367112B2 (en) | 2013-02-05 |
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