WO2015071837A1 - Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents
Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- WO2015071837A1 WO2015071837A1 PCT/IB2014/065988 IB2014065988W WO2015071837A1 WO 2015071837 A1 WO2015071837 A1 WO 2015071837A1 IB 2014065988 W IB2014065988 W IB 2014065988W WO 2015071837 A1 WO2015071837 A1 WO 2015071837A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- complex
- cyclosporine
- sodium
- group
- acetate
- Prior art date
Links
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 85
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 84
- 229930105110 Cyclosporin A Natural products 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 32
- 230000008569 process Effects 0.000 title claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 28
- 238000010668 complexation reaction Methods 0.000 claims abstract description 23
- 230000003247 decreasing effect Effects 0.000 claims abstract description 14
- 210000002216 heart Anatomy 0.000 claims abstract description 12
- 210000003734 kidney Anatomy 0.000 claims abstract description 12
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 11
- 210000004185 liver Anatomy 0.000 claims abstract description 11
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 27
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 19
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 19
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 19
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 19
- 229920001400 block copolymer Polymers 0.000 claims description 17
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 17
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010521 absorption reaction Methods 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 12
- 229960001265 ciclosporin Drugs 0.000 claims description 12
- 239000000084 colloidal system Substances 0.000 claims description 12
- 229930182912 cyclosporin Natural products 0.000 claims description 12
- 230000035699 permeability Effects 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000003125 aqueous solvent Substances 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 229920001983 poloxamer Polymers 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 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
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 229920001577 copolymer Polymers 0.000 claims description 8
- 229920000578 graft copolymer Polymers 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229940117958 vinyl acetate Drugs 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 8
- 238000013149 parallel artificial membrane permeability assay Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000001836 Dioctyl sodium sulphosuccinate Substances 0.000 claims description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 229960004249 sodium acetate Drugs 0.000 claims description 5
- 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 5
- 238000001228 spectrum Methods 0.000 claims description 5
- 238000011200 topical administration Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000036765 blood level Effects 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 230000002035 prolonged effect Effects 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910016860 FaSSIF Inorganic materials 0.000 claims description 3
- 229910005429 FeSSIF Inorganic materials 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 230000000112 colonic effect Effects 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- 230000009246 food effect Effects 0.000 abstract description 5
- 235000021471 food effect Nutrition 0.000 abstract description 5
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 8
- 230000003993 interaction Effects 0.000 description 8
- 229940063121 neoral Drugs 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000020937 fasting conditions Nutrition 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012916 structural analysis Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 102400001018 Proadrenomedullin N-20 terminal peptide Human genes 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241001149960 Tolypocladium inflatum Species 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 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 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- -1 crospovidon Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940033200 cyclosporine oral solution Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229920000831 ionic polymer Polymers 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XJODGRWDFZVTKW-ZCFIWIBFSA-N n-methylleucine Chemical group CN[C@@H](C(O)=O)CC(C)C XJODGRWDFZVTKW-ZCFIWIBFSA-N 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- PIRWNASAJNPKHT-SHZATDIYSA-N pamp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)N)C(C)C)C1=CC=CC=C1 PIRWNASAJNPKHT-SHZATDIYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940053174 restasis Drugs 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 229940063122 sandimmune Drugs 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
- A61K9/145—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 with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
- A61K9/146—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 with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
- C07K7/645—Cyclosporins; Related peptides
Definitions
- the invention is directed to a stable complex with increased apparent solubility and increased dissolution rate comprising as active compound Cyclosporine A or derivatives thereof, which is useful in the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis. More specifically, the complex of the present invention possesses increased apparent solubility, permeability and enhanced biological performance including significantly decreased fed/fasted effect.
- the invention also relates to methods of formulating and manufacturing complex according to the invention, pharmaceutical compositions containing it, its uses and methods of treatment using the complex and its compositions.
- Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucylN- methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-a- amino-butyrylN-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).
- Cyclosporine A exhibits very poor solubility in water, therefore suspension and emulsion forms of the drug have been developed for oral administration and injection. Cyclosponne A was originally brought to market under the brand name Sandimmune.
- Cyclosporine A is taken by orally or given by injection.
- the oral medication is available either as a liquid or in capsule form.
- Liquid cyclosporine is available in 50-ml (5000-mg) bottles (100 mg is equal to 1 ml).
- Cyclosporine A capsules are available in 100-mg, 50-mg, and 25-mg doses.
- a topical emulsion of Cyclosporine A for treating inflammation caused by keratoconjunctivitis sicca has been marketed under the trade name Restasis (0.05%).
- Inhaled Cyclosporine A formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.
- Cyclosporine A is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Cyclosporine A has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.
- Cyclosporine A The exact mechanism of action of Cyclosporine A is not known. Experimental evidence suggests that the effectiveness of Cyclosporine A is due to specific and reversible inhibition of immunocompetent lymphocytes in the GO- or Gl -phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine A also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF).
- TCGF T-cell growth factor
- Cyclosporine A does not cause bone marrow suppression in animal models or man.
- C ma x Peak concentrations (C ma x) in blood and plasma are achieved at about 3.5 hours.
- C ma x and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400 mg.
- C ma x is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses).
- the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients.
- the bioavailability of Cyclosporine A in Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Cyclosporine A Oral Solution, (cyclosporine oral solution, USP).
- Cyclosporine is distributed largely outside the blood volume. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.
- Elimination The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine.
- Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the Cy-carbon of 2 of the leucine residues, Cn-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and N demethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.
- Cyclosporine A unformulated, is characterized by low water solubility, low bioavailability and significant food effect when administered orally.
- the drug is marketed under the trade name Neoral.
- Neoral is a self-forming emulsion concentrate containing organic solvents and emulsifying agents developed to increase bioavailability and reduce food effect. Yet, significant food effect can still be observed for Neoral.
- Cyclosporine A formula Another unfavorable pharmacokinetic property of the current Cyclosporine A formula is high inter- and intra-individual variability of blood levels following oral administration. This can become crucial in case of this active, as prolonged high plasma concentrations (repeated high Cmax) can result in renal toxicity, while too low trough plasma concentrations increase the frequency of organ transplant rejection. Part of the variability has been attributed to the food effect.
- a stable complex comprising as active compound selected from the group of Cyclosporine A or derivatives thereof; at least one agent selected from the group of a polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, D-a- Tocopherol polyethylene glycol 1000 succinate (TPGS); poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl- ether) (PMAMVE), preferably d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS).
- TPGS D-a- Tocopherol polyethylene glycol 1000 succinate
- PMAMVE poly(maleic acid-co-methyl-vinyl- ether)
- TPGS d-alpha tocopheryl polyethylene glycol 1000 succinate
- e) has a PAMPA permeability of at least 0.1 * 10 "6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 months; and f) is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at 1754 cm “1 , 1736 cm “1 , 1628 cm- 1 1466 cm “1 , 1455 cm “1 , 1412 cm “1 , 1360 cm “ 1342 cm “1 , 1279 cm “1 , 1241 cm “1 , 1216 cm “1 , 1147 cm “1 , 1102 cm “1 , 1060 cm “1 , 962 cm “1 , 947 cm “1 841 cm “1 , 588 cm “1 , 529 cm “1 , 509 cm “1 preferable at 1628 cm “1 .
- ATR infrared
- the invention is a complex formula having increased apparent solubility, permeability and decreased variability along with decreased fed/fasted effect.
- Cyclosporine A is generally used for Cyclosporine A, or its derivatives.
- said complexation agent is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS); poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE), preferably d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS).
- TPGS D-a-Tocopherol polyethylene glycol 1000 succinate
- PMAMVE poly(maleic acid-co-methyl-vinyl-ether)
- said additional active agent is selected from agents useful for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
- said complex has enhanced biological performance including significantly decreased fed/fasted effect.
- said complex possesses at least two of the properties described in a) - f).
- said complex possesses at least three of the properties described in a) - f).
- said complex has an increased dissolution rate.
- a stable complex comprising an active compound selected from the group of cyclosporine A, or derivatives thereof; at least one complexation agent chosen poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid- co-methyl -vinyl -ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS), and optionally at least one pharmaceutically accepted excipient selected from the group of sodium-lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene-polyoxypropylene block copolymers; wherein said complex obtainable via a mixing process.
- a complexation agent chosen poloxamers
- said complexation agent is a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS).
- TPGS D-a-Tocopherol polyethylene glycol 1000 succinate
- TPGS D-a-Tocopherol polyethylene glycol 1000 succinate
- a process for the preparation of the complex comprising the steps of mixing a solution of Cyclosporine A, or derivatives thereof, and at least one complexation agent selected from poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl -acetate; poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically acceptable excipient chosen from sodium- lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene- polyoxypropylene block copolymers.
- a complexation agent selected from poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-
- said process is performed in a continuous flow instrument.
- said continuous flow instrument is a microfluidic flow instrument.
- said pharmaceutically acceptable solvent is chosen from methanol, ethanol, i-propanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxyd, or tetrahydrofuran, or combinations thereof.
- said pharmaceutically acceptable solvent is methanol.
- said pharmaceutically acceptable solvent and said aqueous solvent are miscible with each other.
- said aqueous solvent comprises 0.1 to 99.9% weight of the final solution.
- said aqueous solvent comprises 50 to 90% weight of the final solution. In an embodiment, said aqueous solvent comprises 50 to 80% weight of the final solution.
- said aqueous solvent comprises 50 to 70% weight of the final solution.
- said aqueous solvent comprises 50 to 60% weight of the final solution.
- said aqueous solvent comprises 50 % weight of the final solution.
- a pharmaceutical composition comprising the complex together with pharmaceutically acceptable carrier.
- said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
- said composition is suitable for oral administration.
- said complex is for use in the manufacture of a medicament for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
- said complex is used for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
- a method of treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis comprises administration of a therapeutically effective amount of a complex or a pharmaceutical composition as described herein.
- a stable complex comprising a. 5 - 30%) by weight of Cyclosporine A, or derivatives thereof;
- b. 10 - 50% by weight of a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS); c. 1 - 35 % by weight of a sodium -lauryl-sulphate; and d. 30 - 80 % by weight of polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw l 0,000-20,000).
- said complex has a controlled particle size in the range between 50 nm and 600 nm; and wherein said complex is not obtained via a milling process or by high pressure homogenization process, encapsulation process and solid dispersion process, but it is obtained by a mixing process, preferable continuous flow mixing process.
- said complex shows reduced fed/fasted effect based on in vivo studies.
- said complex shows slower and more prolonged absorption delivering the necessary blood levels for longer time which results in lower inter- and intra-patient variability of Cyclosporine A pharmacokinetics based on in vivo studies.
- said complex is instantaneously redispersable in physiological relevant media.
- said complex is stable in solid form and in colloid solution and/or dispersion.
- said complex has apparent solubility in water.
- said complex has a PAMPA permeability of at least 0.1 * 10 "6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 months.
- said complex is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at least at 1628 cm "1 .
- ATR infrared
- said complex is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at least at 1754 cm “1 , 1736 cm “1 , 1628 cm “1 1466 cm “1 , 1455 cm “1 , 1412 cm “1 , 1360 cm “1 , 1342 cm “1 , 1279 cm “1 , 1241 cm “1 , 1216 cm “1 , 1147 cm “1 , 1102 cm “1 , 1060 cm “1 , 962 cm “1 , 947 cm “1 , 841 cm “1 , 588 cm “1 , 529 cm “1 , 509 cm “1 , preferable at 1628 cm “1 .
- ATR infrared
- the complexation agents and pharmaceutically acceptable excipients of the Cyclopsorine A complex formulae of the invention are selected from the group of pharmaceutically acceptable nonionic, anionic, cationic, ionic polymers, surfactants and other types of excipients.
- the complexation agents themselves or together with the pharmaceutically accepted excipients have the function to form a complex structure with an active pharmaceutical ingredient through non-covalent secondary interactions.
- the secondary interactions can form through electrostatic interactions such as ionic interactions, H-bonding, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, ⁇ - ⁇ interactions, and hydrophobic interactions.
- compositions may additionally include one or more pharmaceutically acceptable excipients, auxiliary materials, carriers, active agents or combinations thereof.
- active agents may include agents useful for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
- Another aspect of the invention is the complex formulae of the Cyclopsorine A with complexation agents and pharmaceutically acceptable excipients in which the complexation agents and pharmaceutically acceptable excipients preferably are associated or interacted with the Cyclosporine A especially as the results of the mixing process, preferably continuous flow mixing process.
- the structure of the complex Cyclosporine A formula is different from the core-shell type milled particle, precipitated encapsulated particles, micelles and solid dispersions.
- the pharmaceutical composition of the invention can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination of (a), (b), and (c).
- the compositions can be formulated by adding different types of excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
- compositions can be formulated by adding different types of pharmaceutically acceptable excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
- a preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
- Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.
- the active agent is admixed with at least one of the following excipients: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose and silicic acid; (c) binders, such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as crospovidon, sodium starch glycolate, effervescent compositions, croscarmellose sodium,, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (f)
- composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Advantages of the complex Cyclosporine A formulae of the invention include, but are not limited to (1) physical and chemical stability, (2) instantaneous redispersibility, (3) stability in colloid solution or dispersion in the therapeutic time window, (4) decreased variability, (5) decreased fed/fasted effect and (6) good processability.
- One of the preferred characteristics of the complex Cyclosporine A formulae of the present invention is their increased apparent solubility and permeability.
- the permeability of the complex Cyclosporine A formulae is at least 0.1 * 10 "6 cm/s, respectively.
- Another preferred characteristic of the complex Cyclosporine A formulae of the present invention relates to the enhanced pharmacokinetic performance of the complex Cyclosporine formulae.
- the complex Cyclosporine formulae have slower and more prolonged absorption delivering the necessary blood levels for longer time when compared to the conventional Cyclosporine formulation.
- Another aspect of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising a stable complex Cyclosporine A formulae or composition of them according to the invention and optionally pharmaceutically accepted auxiliary materials formulated for oral administration having decreased variability and eliminated fed/fasted effect compared to the commercial formulation of Cyclosporine A.
- FIG. 4 SEM photo of complex Cyclosporine A Figure 5.
- ATR spectra of crystalline Cyclosporine A (A), amorphous Cyclosporine A (B), complex Cyclosporine A (C), placebo sample (D), and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS)(E), polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw 10,000-20,000) (Lutrol F108) (F) and Sodium-lauryl- sulfate (G)
- Colloid solution of Cyclosporine A complex formula of the present invention was prepared by continuous flow mixing process in a flow instrument.
- a starting solution 2g Cyclosporine A and 3g TPGS dissolved in 100 mL methanol was used.
- the prepared solution was passed into the instrument with 4 mL/min flow rate.
- the colloid solution of the complex Cyclosporine A is continuously produced at atmospheric pressure.
- PAMPA permeability measurements were performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) pp 1007) with modifications based on S. Bendels et al (Pharmaceutical research, 23 (2006) pp 2525).
- Sample containing the reference compound was a suspension of crystals visible by the naked eye, while samples of the marketed drug and the novel complex were opalescent colloid solutions.
- Permeability was measured in a 96-well plate assay across an artificial membrane composed of dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA).
- the receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1% sodium dodecyl sulfate.
- the assay was performed at room temperature; incubation time was 1-24 hours.
- the concentration in the receiver compartment was determined by HPLC.
- PAMPA permeability of complex Cyclosporine A formula of Example 2 and the marketed drug was in the 2-3 * 10 "6 cm/s range, while PAMPA permeability of the reference compound was in the 0.5-1 * 10 "6 cm/s range with higher apparent permeability measured in the fed state simulation than in the fasted state simulation in all cases.
- mice Male Wistar rats (220-270 g) were treated orally with test articles one time via esophageal gavage technique following overnight fasting.
- Whole blood was sampled from the saphenous vein into heparinized tubes (approx. 0.1 mL to each tube) before and at 0.5, 1, 2, 3, 5, 7, 9, 12, 24, 48, and 72 hours after the oral administration of the test articles.
- Whole blood samples were stored at minus 20°C until analysis. Cyclosporine A concentrations were determined from whole blood samples by LC-MS/MS technique.
- Pharmacokinetic data were expressed as measured values and as normalized values. Measured values were normalized to the extraction recovery of the standard solution from whole blood. Extraction recovery of the standard solution from whole blood varied between 88.83% and 111.67%) (93.99%) in average).
- C ma x, AUCo-72, AUCo-inf, Frelo-72 and F re io-inf of complex Cyclosporine composition of the present invention following oral administration were significantly decreased (p ⁇ 0.05), however, t max was not changed as compared to same pharmacokinetic parameters of Neoral solution. Relative bioavailability of complex Cyclosporine A was approximately 30%> less than that of Neoral solution, i.e. Freio-72 and Freio-inf were both between 0.70 and 0.71 as calculated from both normalized and not normalized data.
- the absorption rate of the complex Cyclosporine A of the present invention was lower resulting in longer absorption phase with lower blood concentrations in the early phases, yet, trough concentrations measured at 24 hours were similar indicating that despite of the lower absorption rate the therapeutically relevant concentrations are maintained by both formulae in the same time window.
- the longer absorption phase might result in less variability.
Abstract
The present invention relates to pharmaceutically accepted complex formulae comprising complexes of Cyclosporine A or derivatives thereof and complexation agents and pharmaceutically accepted excipients, process for the preparation thereof and pharmaceutical compositions containing them. The complex formulae of the present invention have improved physicochemical properties and decreased variability and food effect and are useful in the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis and severe psoriasis.
Description
COMPLEXES OF CYCLOSPORINE A AND ITS DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM
FIELD OF THE INVENTION
The invention is directed to a stable complex with increased apparent solubility and increased dissolution rate comprising as active compound Cyclosporine A or derivatives thereof, which is useful in the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis. More specifically, the complex of the present invention possesses increased apparent solubility, permeability and enhanced biological performance including significantly decreased fed/fasted effect. The invention also relates to methods of formulating and manufacturing complex according to the invention, pharmaceutical compositions containing it, its uses and methods of treatment using the complex and its compositions.
BACKGROUND OF THE INVENTION
Background Regarding Cyclosporine A
Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucylN- methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-a- amino-butyrylN-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).
O \
Cyclosporine A exhibits very poor solubility in water, therefore suspension and emulsion forms of the drug have been developed for oral administration and injection. Cyclosponne A was originally brought to market under the brand name Sandimmune.
Cyclosporine A is taken by orally or given by injection. The oral medication is available either as a liquid or in capsule form. Liquid cyclosporine is available in 50-ml (5000-mg) bottles (100 mg is equal to 1 ml). Cyclosporine A capsules are available in 100-mg, 50-mg, and 25-mg doses. Since 2002, a topical emulsion of Cyclosporine A for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the trade name Restasis (0.05%). Inhaled Cyclosporine A formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.
Mechanism of Action: Cyclosporine A is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Cyclosporine A has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.
The exact mechanism of action of Cyclosporine A is not known. Experimental evidence suggests that the effectiveness of Cyclosporine A is due to specific and reversible inhibition of immunocompetent lymphocytes in the GO- or Gl -phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine A also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF).
No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Cyclosporine A does not cause bone marrow suppression in animal models or man.
Pharmacokinetics: The absorption of Cyclosporine A from the gastrointestinal tract is incomplete and variable. Peak concentrations (Cmax) in blood and plasma are achieved at about 3.5 hours. Cmax and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400 mg. As determined by a specific assay, Cmax is approximately 1.0
ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The bioavailability of Cyclosporine A in Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Cyclosporine A Oral Solution, (cyclosporine oral solution, USP).
Distribution: Cyclosporine is distributed largely outside the blood volume. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.
Elimination: The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine.
Metabolism: Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the Cy-carbon of 2 of the leucine residues, Cn-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-L-2-amino-6-octenoic acid and N demethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.
Cyclosporine A, unformulated, is characterized by low water solubility, low bioavailability and significant food effect when administered orally. The drug is marketed under the trade name Neoral. Neoral is a self-forming emulsion concentrate containing organic solvents and emulsifying agents developed to increase bioavailability and reduce food effect. Yet, significant food effect can still be observed for Neoral.
Another unfavorable pharmacokinetic property of the current Cyclosporine A formula is high inter- and intra-individual variability of blood levels following oral administration. This can become crucial in case of this active, as prolonged high plasma concentrations (repeated high Cmax) can result in renal toxicity, while too low trough plasma concentrations increase the
frequency of organ transplant rejection. Part of the variability has been attributed to the food effect.
A variety of strategies have been used to attempt to overcome these issues, see for example WO/2001/017546, US20020016290, US5798333, JP2000229878, CN1625391, EP2079456, US6306434, and CN101810560.
DESCRIPTION OF THE INVENTION
Disclosed herein is a stable complex comprising as active compound selected from the group of Cyclosporine A or derivatives thereof; at least one agent selected from the group of a polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, D-a- Tocopherol polyethylene glycol 1000 succinate (TPGS); poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl- ether) (PMAMVE), preferably d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS). a) is instantaneously redispersable in physiological relevant media
b) is stable in solid form and in colloid solution and/or dispersion;
c) apparent solubility in water of at least 1 mg/mL;
d) shows X-ray amorphous character in the solid form;
e) has a PAMPA permeability of at least 0.1 * 10"6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 months; and f) is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at 1754 cm"1, 1736 cm"1, 1628 cm-1 1466 cm"1, 1455 cm"1, 1412 cm"1, 1360 cm" 1342 cm"1, 1279 cm"1, 1241 cm"1, 1216 cm"1, 1147 cm"1, 1102 cm"1, 1060 cm"1, 962 cm"1, 947 cm"1 841 cm"1, 588 cm"1 , 529 cm"1 , 509 cm"1 preferable at 1628 cm"1.
The invention is a complex formula having increased apparent solubility, permeability and decreased variability along with decreased fed/fasted effect.
We have found that only the selected combinations of complexation agents and pharmaceutically accepted excipients disclosed in the present invention result in a stable complex formula having improved physicochemical characteristics and decreased variability along with decreased fed/fasted effect.
The expression Cyclosporine A is generally used for Cyclosporine A, or its derivatives.
In an embodiment, said complexation agent is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS); poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE), preferably d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS).
In an embodiment, said complexfurther comprises at least one additional active agent selected from the group of sodium-lauryl-sulfate, dioctyl sodium sulfosuccinate and polyoxyethylene- polyoxypropylene block copolymers, preferably sodium-lauryl-sulfate and polyoxyethylene- polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw= 10,000- 20,000).
In an embodiment, said additional active agent is selected from agents useful for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
In an embodiment, said complex has enhanced biological performance including significantly decreased fed/fasted effect. In an embodiment, said complex possesses at least two of the properties described in a) - f).
In an embodiment, said complex possesses at least three of the properties described in a) - f).
In an embodiment, said complex has an increased dissolution rate.
Further disclosed herein is a stable complex comprising an active compound selected from the group of cyclosporine A, or derivatives thereof; at least one complexation agent chosen poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid- co-methyl -vinyl -ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS), and optionally at least one pharmaceutically accepted excipient selected from the group of sodium-lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene-polyoxypropylene block copolymers; wherein said complex obtainable via a mixing process.
In an embodiment, said complexation agent is a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS).
In an embodiment, said pharmaceutically acceptable excipients are sodium-lauryl-sulphate and polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=10,000- 20,000).
In an embodiment, said complex is obtained via a continuous flow mixing process. In an embodiment, a complex comprises a complexation agent which is a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) and a pharmaceutically acceptable excipients which are sodium-lauryl-sulphate and polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw= 10,000- 20,000), in a total amount ranging from about 1.0 weight% to about 95.0 weight % based on the total weight of the complex. In an embodiment, a complex comprises a complexation agent which is a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) and a pharmaceutically acceptable excipients which are sodium-lauryl-sulphate and polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw= 10,000- 20,000), in a total amount ranging from about 50.0 weight% to about 95.0 weight % based on the total weight of the complex. Further disclosed herein is a process for the preparation of the complex, comprising the steps of mixing a solution of Cyclosporine A, or derivatives thereof, and at least one complexation agent selected from poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl -acetate; poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically acceptable excipient chosen from sodium- lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene- polyoxypropylene block copolymers.
In an embodiment, said process is performed in a continuous flow instrument. In an embodiment, said continuous flow instrument is a microfluidic flow instrument.
In an embodiment, said pharmaceutically acceptable solvent is chosen from methanol, ethanol, i-propanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxyd, or tetrahydrofuran, or combinations thereof. embodiment, said pharmaceutically acceptable solvent is methanol.
In an embodiment, said pharmaceutically acceptable solvent and said aqueous solvent are miscible with each other.
In an embodiment, said aqueous solvent comprises 0.1 to 99.9% weight of the final solution.
In an embodiment, said aqueous solvent comprises 50 to 90% weight of the final solution. In an embodiment, said aqueous solvent comprises 50 to 80% weight of the final solution.
In an embodiment, said aqueous solvent comprises 50 to 70% weight of the final solution.
In an embodiment, said aqueous solvent comprises 50 to 60% weight of the final solution.
In an embodiment, said aqueous solvent comprises 50 % weight of the final solution.
In an embodiment, a pharmaceutical composition comprising the complex together with pharmaceutically acceptable carrier.
In an embodiment, said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
In an embodiment, said composition is suitable for oral administration. In an embodiment, said complex is for use in the manufacture of a medicament for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
In an embodiment, said complex is used for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis. In an embodiment, a method of treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis comprises administration of a therapeutically effective amount of a complex or a pharmaceutical composition as described herein.
Further disclosed herein is a stable complex comprising a. 5 - 30%) by weight of Cyclosporine A, or derivatives thereof;
b. 10 - 50% by weight of a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS); c. 1 - 35 % by weight of a sodium -lauryl-sulphate; and
d. 30 - 80 % by weight of polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=l 0,000-20,000). wherein said complex has a controlled particle size in the range between 50 nm and 600 nm; and wherein said complex is not obtained via a milling process or by high pressure homogenization process, encapsulation process and solid dispersion process, but it is obtained by a mixing process, preferable continuous flow mixing process.
In an embodiment, said complex shows reduced fed/fasted effect based on in vivo studies.
In an embodiment, said complex shows slower and more prolonged absorption delivering the necessary blood levels for longer time which results in lower inter- and intra-patient variability of Cyclosporine A pharmacokinetics based on in vivo studies.
We have found that only the selected combinations of complexation agents and pharmaceutically accepted excipients disclosed in the present invention result in a stable complex formula having improved physicochemical characteristics and decreased variability along with decreased fed/fasted effect.
In an embodiment, said complex is instantaneously redispersable in physiological relevant media.
In an embodiment, said complex is stable in solid form and in colloid solution and/or dispersion.
In an embodiment, said complex has apparent solubility in water.
In an embodiment, said complex has a PAMPA permeability of at least 0.1 * 10"6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 months.
In an embodiment, said complex is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at least at 1628 cm"1.
In an embodiment, said complex is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at least at 1754 cm"1, 1736 cm"1, 1628 cm"1 1466 cm"1, 1455 cm"1, 1412 cm"1, 1360 cm"1, 1342 cm"1, 1279 cm"1, 1241 cm"1, 1216 cm"1, 1147 cm"1,
1102 cm"1, 1060 cm"1, 962 cm"1, 947 cm"1, 841 cm"1, 588 cm"1, 529 cm"1, 509 cm"1, preferable at 1628 cm"1.
The complexation agents and pharmaceutically acceptable excipients of the Cyclopsorine A complex formulae of the invention are selected from the group of pharmaceutically acceptable nonionic, anionic, cationic, ionic polymers, surfactants and other types of excipients. The complexation agents themselves or together with the pharmaceutically accepted excipients have the function to form a complex structure with an active pharmaceutical ingredient through non-covalent secondary interactions. The secondary interactions can form through electrostatic interactions such as ionic interactions, H-bonding, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, π-π interactions, and hydrophobic interactions. The complexation agents, pharmaceutically accepted excipients and active ingredients are selected from the group of complexation agents, pharmaceutically accepted excipients and active ingredients which are able to form such complex structures through non-covalent secondary interactions. In some embodiments, the compositions may additionally include one or more pharmaceutically acceptable excipients, auxiliary materials, carriers, active agents or combinations thereof. In some embodiments, active agents may include agents useful for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis. Another aspect of the invention is the complex formulae of the Cyclopsorine A with complexation agents and pharmaceutically acceptable excipients in which the complexation agents and pharmaceutically acceptable excipients preferably are associated or interacted with the Cyclosporine A especially as the results of the mixing process, preferably continuous flow mixing process. In some embodiment, the structure of the complex Cyclosporine A formula is different from the core-shell type milled particle, precipitated encapsulated particles, micelles and solid dispersions.
The pharmaceutical composition of the invention can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c)
into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination of (a), (b), and (c). The compositions can be formulated by adding different types of excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
The compositions can be formulated by adding different types of pharmaceutically acceptable excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is admixed with at least one of the following excipients: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose and silicic acid; (c) binders, such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as crospovidon, sodium starch glycolate, effervescent compositions, croscarmellose sodium,, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (f) solution retarders, such as acrylates, cellulose derivatives, paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as polysorbates, cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Advantages of the complex Cyclosporine A formulae of the invention include, but are not limited to (1) physical and chemical stability, (2) instantaneous redispersibility, (3) stability in colloid solution or dispersion in the therapeutic time window, (4) decreased variability, (5) decreased fed/fasted effect and (6) good processability.
Beneficial features of the present invention are as follows: the good/instantaneous redispersibility of solid complex formulae of Cyclosporine A in water, biologically relevant media, e.g.; physiological saline solution, pH=2.5 HC1 solution, FessiF and FassiF media and gastro intestinal fluids and adequate stability in colloid solutions and/or dispersion in the therapeutic time window.
One of the preferred characteristics of the complex Cyclosporine A formulae of the present invention is their increased apparent solubility and permeability. In some embodiments, the permeability of the complex Cyclosporine A formulae is at least 0.1 * 10"6 cm/s, respectively.
Another preferred characteristic of the complex Cyclosporine A formulae of the present invention relates to the enhanced pharmacokinetic performance of the complex Cyclosporine formulae. In some embodiments, the complex Cyclosporine formulae have slower and more prolonged absorption delivering the necessary blood levels for longer time when compared to the conventional Cyclosporine formulation.
Another aspect of the invention is a pharmaceutical composition comprising a stable complex Cyclosporine A formulae or composition of them according to the invention and optionally pharmaceutically accepted auxiliary materials formulated for oral administration having decreased variability and eliminated fed/fasted effect compared to the commercial formulation of Cyclosporine A.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. Complexation agent screening for formula selection
Figure 2. Particle size of redispersed solid complexes in colloid solution
Figure 3. Comparative PAMPA assays of complex Cyclosporine A formula, the marketed drug and the unformulated compound
Figure 4. SEM photo of complex Cyclosporine A
Figure 5. ATR spectra of crystalline Cyclosporine A (A), amorphous Cyclosporine A (B), complex Cyclosporine A (C), placebo sample (D), and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS)(E), polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=10,000-20,000) (Lutrol F108) (F) and Sodium-lauryl- sulfate (G)
Figure 6. Plasma concentration of Cyclosporine A following the oral administration of the marketed drug (Neoral) and Cyclosporine A complex to rats under the fasting conditions (n=4, dose: 15 mg/kg).
Figure 7. Pharmacokinetic parameters following the oral administration of the marketed drug (Neoral) and the Cyclosporine A complex to rats under the fasting conditions (n=4, dose: 15 mg/kg).
EXAMPLES
1. Selection of complexation agents and pharmaceutically accepted excipients for the production of complex Cyclosporine A formulae
Several complexation agents and pharmaceutically accepted excipients and their combinations were tested in order to select the formulae having instantaneous redispersibility.
2. Process for producing stable colloid solution and or dispersion of solid complex Cyclosporine A formula
Colloid solution of Cyclosporine A complex formula of the present invention was prepared by continuous flow mixing process in a flow instrument. As a starting solution, 2g Cyclosporine A and 3g TPGS dissolved in 100 mL methanol was used. The prepared solution was passed into the instrument with 4 mL/min flow rate. Meanwhile, antisolvent containing 10 g sodium- lauryl-sulphate and 2.25 g polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=10,000-20,000) in 500 mL water was passed into the instrument with 16 mL/min flow rate, where Cyclosporine A was mixed to form complex Cyclosporine A composition. The colloid solution of the complex Cyclosporine A is continuously produced at atmospheric pressure. The produced colloid solution was frozen on dry-ice and then it was lyophilized using Scanvac CoolSafe 110-8 freeze drier equipped with - 110°C ice condenser, with a Vacuubrand RZ6 vacuum pump. Particle size of complex Cyclosporine A was measured in reconstituted colloid solution right after the lyophilization.
3. Comparative in vitro PAMP A assays
PAMPA permeability measurements were performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) pp 1007) with modifications based on S. Bendels et al (Pharmaceutical research, 23 (2006) pp 2525). Sample containing the reference compound was a suspension of crystals visible by the naked eye, while samples of the marketed drug and the novel complex were opalescent colloid solutions. Permeability was measured in a 96-well plate assay across an artificial membrane composed of dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA). The receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1% sodium dodecyl sulfate. The assay was performed at room temperature; incubation time was 1-24 hours. The concentration in the receiver compartment was determined by HPLC.
PAMPA permeability of complex Cyclosporine A formula of Example 2 and the marketed drug was in the 2-3 * 10"6 cm/s range, while PAMPA permeability of the reference compound was in the 0.5-1 * 10"6 cm/s range with higher apparent permeability measured in the fed state simulation than in the fasted state simulation in all cases.
4. Structural analysis
Morphology of complex Cyclopsorine A was investigated using FEI Quanta 3D scanning electron microscope. Complex Cyclosprine A of the present invention consists of spherical particles (Figure 4.).
Structural analysis was performed by using Bruker Vertex 70 FT-IR spectrometer with Bruker Platinum diamond ATR unit. Continuous flow mixing of Cyclosprine A in the presence of selected pharmaceutically accepted excipients, such as D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS), sodium-lauryl-sulphate and polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=l 0,000-20, 000) resulted in a stable complex of Cyclosporine A. In a preferred embodiment the complex or the pharmaceutical composition according to the invention characterized by at least one of the following characteristic Raman or ATR band/peak (Figure 8):
1754 cm"1, 1736 cm"1, 1628 cm"1 1466 cm"1, 1455 cm"1, 1412 cm"1, 1360 cm"1, 1342 cm"1, 1279 cm"1, 1241 cm"1, 1216 cm"1, 1147 cm"1, 1102 cm"1, 1060 cm"1, 962 cm"1, 947 cm"1, 841 cm"1, 588 cm"1, 529 cm"1, 509 cm"1, preferable at 1628 cm"1.
5. Comparative in vivo pharmacokinetic tests
Male Wistar rats (220-270 g) were treated orally with test articles one time via esophageal gavage technique following overnight fasting. Whole blood was sampled from the saphenous vein into heparinized tubes (approx. 0.1 mL to each tube) before and at 0.5, 1, 2, 3, 5, 7, 9, 12, 24, 48, and 72 hours after the oral administration of the test articles. Whole blood samples were stored at minus 20°C until analysis. Cyclosporine A concentrations were determined from whole blood samples by LC-MS/MS technique.
Pharmacokinetic data were expressed as measured values and as normalized values. Measured values were normalized to the extraction recovery of the standard solution from whole blood. Extraction recovery of the standard solution from whole blood varied between 88.83% and 111.67%) (93.99%) in average). Cmax, AUCo-72, AUCo-inf, Frelo-72 and Freio-inf of complex Cyclosporine composition of the present invention following oral administration were significantly decreased (p<0.05), however, tmax was not changed as compared to same pharmacokinetic parameters of Neoral solution. Relative bioavailability of complex Cyclosporine A was approximately 30%> less than that of Neoral solution, i.e. Freio-72 and Freio-inf were both between 0.70 and 0.71 as calculated from both normalized and not normalized data.
The absorption rate of the complex Cyclosporine A of the present invention was lower resulting in longer absorption phase with lower blood concentrations in the early phases, yet, trough concentrations measured at 24 hours were similar indicating that despite of the lower absorption rate the therapeutically relevant concentrations are maintained by both formulae in the same time window. The longer absorption phase, however, might result in less variability.
Claims
1. A stable complex with increased apparent solubility and increased dissolution rate comprising as active compound selected from the group of Cyclosporine A or derivatives thereof; optionally an additional active agent; at least one complexation agent selected from the group of poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) said complex characterized in that it possesses at least one of the following properties: a) is instantaneously redispersable in physiological relevant media;
b) has increased dissolution rate;
c) is stable in solid form and in colloid solution and/or dispersion;
d) increased apparent solubility in water;
e) has a PAMPA permeability of at least 0.1 * 10"6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 12 months;
f) is characterized by infrared (ATR) spectrum having main/characteristic absorption peaks at least at 1628
absorption peaks; and g) said complex has slower and more prolonged absorption delivering the necessary blood levels for longer time when compared to the conventional Cyclosporine formulation; h) said complex has decreased variability and eliminated fed/fasted effect compared to the commercial formulation of Cyclosporine A.
2. The complex according to Claim 1, wherein said complexation agent is selected from the group of poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene- glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE) and D-a- Tocopherol polyethylene glycol 1000 succinate (TPGS), preferably D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS).
3. The complex according to Claims 1 or 2, wherein said complex further comprises at least one pharmaceutically acceptable excipient selected from the group of sodium- lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene- polyoxypropylene block copolymers, preferably the pharmaceutically accepted excipients are sodium-lauryl-sulfate and polyoxyethylene-polyoxypropylene block copolymers terminated with primary hydroxyl groups (Mw=10,000- 20,000).
4. The complex according to any of Claims 1 to 3, wherein said complex further comprises one or more additional active agents, preferable the additional active agent is selected from the group of agents useful for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
5. A stable complex according to any of Claims 1 to 4 comprising an active compound selected from the group of Cyclosporine A, or derivatives thereof; at least one complexation agent selected from the group of poloxamers; polyvinylcaprolactam- polyvinyl acetate-polyethylene-glycol graft copolymers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid-co-methyl-vinyl- ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS); and at least one pharmaceutically acceptable excipient selected from the group of sodium-lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene-polyoxypropylene block copolymers; wherein said complex obtained via a mixing process, preferable continuous flow mixing process, more preferable microfluidic flow mixing process.
6. A complex according to any of Claims 1 to 5 comprising a complexation agent which is a D-a-Tocopherol polyethylene glycol 1000 succinate and pharmaceutically acceptable excipients which are sodium-lauryl-sulfate and polyoxyethylene- polyoxypropylene block copolymers terminated with primary hydroxyl groups (Mw=10,000- 20,000), in a total amount ranging from about 1.0 weight% to about 95.0 weight % based on the total weight of the complex.
7. A process for the preparation of the complex according to any of Claims 1 to 6, comprising the steps of mixing a solution of Cyclosporine A, or derivatives thereof, and at least one complexation agent selected from the group of poloxamers; polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers;
polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; poly(maleic acid-co-methyl-vinyl-ether) (PMAMVE) and D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient selected from the group of sodium-lauryl-sulphate, dioctyl sodium sulphosuccinate, sodium-acetate and polyoxyethylene-polyoxypropylene block copolymers.
8. The process according to Claim 7, wherein said process is performed in a continuous flow instrument, preferable in microfluidic instrument.
9. The process according to Claims 7 or 8, wherein said pharmaceutically acceptable solvent is selected from the group of methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, and combinations thereof, preferable the solvent is methanol.
10. The process according to any of Claims 7 to 9, wherein the solvent and the aqueous solvent are miscible with each other and the aqueous solvent comprises 0.1 to 99.9% weight of the final solution.
11. A pharmaceutical composition comprising the complex according to any of Claims 1 to 6 together with pharmaceutically acceptable carrier.
12. A pharmaceutical composition according to Claim 11, wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration, preferable the composition is suitable for oral administration.
13. A complex according to any of Claims 1 to 6 for use in the manufacture of a medicament for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
The use of the complex according to any of Claims 1 to 6 for the treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
15. A method of treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis comprising administration of a therapeutically effective
amount of the complex according to any of Claims 1 to 6 or the pharmaceutical composition according to Claim 11 orl2.
16. A method for reducing the therapeutically effective dosage of Cyclosporine A compared to orally available formulations, said method comprising oral administration of a pharmaceutical composition according to Claims 11 or 12.
17. A stable complex comprising a) 5 - 30% by weight of Cyclosporine A, or derivatives thereof;
b) 10 - 50% by weight of a D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS);
c) 1 - 35 % by weight of a sodium-lauryl-sulphate; and
d) 30 - 80 % by weight of polyoxyethylene-polyoxypropylene block copolymer terminated with primary hydroxyl groups (Mw=l 0,000-20,000). wherein said complex has a controlled particle size in the range between 50 nm and 600 nm; and wherein said complex is obtained according to any of claims 7 to 10.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP1300647 | 2013-11-12 | ||
HU1300647A HUP1300647A2 (en) | 2013-11-12 | 2013-11-12 | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015071837A1 true WO2015071837A1 (en) | 2015-05-21 |
Family
ID=89991321
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2014/065988 WO2015071837A1 (en) | 2013-11-12 | 2014-11-12 | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
Country Status (2)
Country | Link |
---|---|
HU (1) | HUP1300647A2 (en) |
WO (1) | WO2015071837A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017025588A1 (en) * | 2015-08-11 | 2017-02-16 | Eyesiu Medicines B.V. | Pegylated lipid nanoparticle with bioactive lipophilic compound |
WO2017187338A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2017187336A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2017187340A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
IT201700004019A1 (en) * | 2017-01-16 | 2018-07-16 | Gk Pharma Consultans Sa | COMPOSITION INCLUDING CARNITINE, SODIUM COLATATE, SODIUM ACETATE AND EVENTUALLY SILVER FOR USE IN THE TREATMENT OF PSORIASIS, VITILIGINE AND ROSACEA |
US10376501B2 (en) | 2016-04-25 | 2019-08-13 | Druggability Technologies Ip Holdco Limited | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
US10383865B2 (en) | 2016-04-25 | 2019-08-20 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998008490A1 (en) * | 1996-09-01 | 1998-03-05 | Pharmos Corporation | Solid coprecipitates for enhanced bioavailability of lipophilic substances |
US5798333A (en) | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
US5891845A (en) * | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
JP2000229878A (en) | 1999-02-08 | 2000-08-22 | Toyo Capsule Kk | Cyclosporine capsule |
WO2001017546A1 (en) | 1999-09-09 | 2001-03-15 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions |
US6306434B1 (en) | 1997-02-12 | 2001-10-23 | Chong Kun Dang Corp. | Pharmaceutical composition comprising cyclosporin solid-state microemulsion |
US20020016290A1 (en) | 1996-03-25 | 2002-02-07 | Floc'h Robert | Cyclosporin a formulations as nanoparticles |
CN1625391A (en) | 2002-02-01 | 2005-06-08 | 株式会社太平洋 | Cyclosporin-containing sustained release pharmaceutical composition |
EP2079456A2 (en) | 2007-04-04 | 2009-07-22 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
CN101810560A (en) | 2009-02-20 | 2010-08-25 | 北京大学 | Cyclosporine A polymeric micelles composition |
-
2013
- 2013-11-12 HU HU1300647A patent/HUP1300647A2/en unknown
-
2014
- 2014-11-12 WO PCT/IB2014/065988 patent/WO2015071837A1/en active Application Filing
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020016290A1 (en) | 1996-03-25 | 2002-02-07 | Floc'h Robert | Cyclosporin a formulations as nanoparticles |
WO1998008490A1 (en) * | 1996-09-01 | 1998-03-05 | Pharmos Corporation | Solid coprecipitates for enhanced bioavailability of lipophilic substances |
US5798333A (en) | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
US6306434B1 (en) | 1997-02-12 | 2001-10-23 | Chong Kun Dang Corp. | Pharmaceutical composition comprising cyclosporin solid-state microemulsion |
US5891845A (en) * | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
JP2000229878A (en) | 1999-02-08 | 2000-08-22 | Toyo Capsule Kk | Cyclosporine capsule |
WO2001017546A1 (en) | 1999-09-09 | 2001-03-15 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions |
CN1625391A (en) | 2002-02-01 | 2005-06-08 | 株式会社太平洋 | Cyclosporin-containing sustained release pharmaceutical composition |
EP2079456A2 (en) | 2007-04-04 | 2009-07-22 | Sigmoid Pharma Limited | Pharmaceutical cyclosporin compositions |
CN101810560A (en) | 2009-02-20 | 2010-08-25 | 北京大学 | Cyclosporine A polymeric micelles composition |
Non-Patent Citations (2)
Title |
---|
M. KANSI ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, 1998, pages 1007 |
S. BENDELS ET AL., PHARMACEUTICAL RESEARCH, vol. 23, 2006, pages 2525 |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108348468A (en) * | 2015-08-11 | 2018-07-31 | Eyesiu医疗股份有限公司 | Pegylated lipids nanoparticle with bioactive lipophilic compounds |
US10945966B2 (en) | 2015-08-11 | 2021-03-16 | Eyesiu Medicines B.V. | PEGylated lipid nanoparticle with bioactive lipophilic compound |
TWI709410B (en) * | 2015-08-11 | 2020-11-11 | 荷蘭商艾西優藥物股份有限公司 | Pegylated lipid nanoparticle with bioactive lipophilic compound |
WO2017025588A1 (en) * | 2015-08-11 | 2017-02-16 | Eyesiu Medicines B.V. | Pegylated lipid nanoparticle with bioactive lipophilic compound |
US10525012B2 (en) | 2015-08-11 | 2020-01-07 | Eyesiu Medicines B.V. | Pegylated lipid nanoparticle with bioactive lipophilic compound |
WO2017187340A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
CN109475547A (en) * | 2016-04-25 | 2019-03-15 | 成药技术Ip控股有限公司 | The compound of Lu Makatuo and its salt and derivative, preparation method and the pharmaceutical composition containing them |
CN109475546A (en) * | 2016-04-25 | 2019-03-15 | 成药技术Ip控股有限公司 | Including according to the pharmaceutical combination composition for the compound formulation for cutting down Kato and Lu Makatuo and its salt and derivative, preparation method and containing their pharmaceutical composition |
CN109475548A (en) * | 2016-04-25 | 2019-03-15 | 成药技术Ip控股有限公司 | According to cutting down the compound of Kato and its salt and derivative, preparation method and containing their pharmaceutical composition |
US10376501B2 (en) | 2016-04-25 | 2019-08-13 | Druggability Technologies Ip Holdco Limited | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
US10383865B2 (en) | 2016-04-25 | 2019-08-20 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
WO2017187336A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
WO2017187338A1 (en) * | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
EP3348307A1 (en) * | 2017-01-16 | 2018-07-18 | GK Pharma Consultants SA | Composition comprising carnitine, sodium cholate, sodium acetate and optionally silver for use in the treatment of psoriasis, vitiligo e rosacea |
IT201700004019A1 (en) * | 2017-01-16 | 2018-07-16 | Gk Pharma Consultans Sa | COMPOSITION INCLUDING CARNITINE, SODIUM COLATATE, SODIUM ACETATE AND EVENTUALLY SILVER FOR USE IN THE TREATMENT OF PSORIASIS, VITILIGINE AND ROSACEA |
Also Published As
Publication number | Publication date |
---|---|
HUP1300647A2 (en) | 2015-05-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2015071837A1 (en) | Complexes of cyclosporine a and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
EP3104844B1 (en) | Complexes of sirolimus and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
CN113768879A (en) | Edaravone dosage form | |
US10688110B2 (en) | Complexes of Celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
JP2936209B2 (en) | Cyclosporin-containing composition and method for producing the same | |
CN111356445A (en) | Pharmaceutical composition for oral administration comprising pemetrexed and preparation method thereof | |
US10611757B2 (en) | Crystalline form of chemical compound, and preparation method, composition, and application thereof | |
KR101427781B1 (en) | Amphiphilic cyclic phosphazene trimer and hydrophobic drugs micelle-encapsulated by the trimer | |
US10500202B2 (en) | Pharmaceutical formulation containing tadalafil | |
AU2002213965B2 (en) | Amorphous form of cell cycle inhibitor | |
AU2002213965A1 (en) | Amorphous form of cell cycle inhibitor | |
CN101277681A (en) | Oral solid pharmaceutical formulation of the tribulin inhibitor indibulin | |
US20200078303A1 (en) | Pharmaceutical formulations of suvorexant | |
KR101859200B1 (en) | Pharmaceutical composition of monoacetyldiacylglycerol compound for oral administration and solid pharmaceutical preparation | |
CN114177149B (en) | Solid dispersion loaded with 20 (S) -protopanoxadiol and preparation method and application thereof | |
CN115252614B (en) | Pharmaceutical composition of FL118 or 7-position structure modified derivative thereof, and preparation method and application thereof | |
Boukhris et al. | NEW APPROACH FOR PRE-FORMULATION OF AN ORAL CYCLOSPORINE. | |
CN113081970A (en) | Cyclosporine solid dispersion and preparation method of tablet thereof | |
KR101799539B1 (en) | Solid lipid nanoparticles composition comprising docetaxel for oral formulation | |
US20020156119A1 (en) | Amorphous form of cell cycle inhibitor having improved solubility and bioavailability | |
Srividya | In-Vitro Dissolution and In-Vivo Bioavailability of a Novel Solid Dispersion of Losartan Potassium and Hydrochlorothiazide. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14815021 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14815021 Country of ref document: EP Kind code of ref document: A1 |