DE19521974A1 - Pharmaceutical preparation with cyclosporin A - Google Patents
Pharmaceutical preparation with cyclosporin AInfo
- Publication number
- DE19521974A1 DE19521974A1 DE19521974A DE19521974A DE19521974A1 DE 19521974 A1 DE19521974 A1 DE 19521974A1 DE 19521974 A DE19521974 A DE 19521974A DE 19521974 A DE19521974 A DE 19521974A DE 19521974 A1 DE19521974 A1 DE 19521974A1
- Authority
- DE
- Germany
- Prior art keywords
- cyclosporin
- pharmaceutical preparation
- content
- preparation according
- vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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 48
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 48
- 229960001265 ciclosporin Drugs 0.000 title claims abstract description 46
- 229930105110 Cyclosporin A Natural products 0.000 title claims abstract description 42
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000003772 α-tocopherols Chemical class 0.000 claims abstract description 8
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 5
- 239000000194 fatty acid Substances 0.000 claims abstract description 5
- 229930195729 fatty acid Natural products 0.000 claims abstract description 5
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 5
- 239000008158 vegetable oil Substances 0.000 claims abstract description 5
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 4
- 238000007046 ethoxylation reaction Methods 0.000 claims abstract description 4
- 239000003925 fat Substances 0.000 claims abstract description 4
- 235000019197 fats Nutrition 0.000 claims abstract description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 15
- 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 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229960000984 tocofersolan Drugs 0.000 claims description 4
- 239000002076 α-tocopherol Substances 0.000 claims description 4
- 235000004835 α-tocopherol Nutrition 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000002562 thickening agent Substances 0.000 claims description 3
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 229960004592 isopropanol Drugs 0.000 claims 1
- 229930182912 cyclosporin Natural products 0.000 description 13
- 229930003427 Vitamin E Natural products 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 11
- 229940046009 vitamin E Drugs 0.000 description 11
- 239000011709 vitamin E Substances 0.000 description 11
- 235000019165 vitamin E Nutrition 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 201000004681 Psoriasis Diseases 0.000 description 7
- 231100000417 nephrotoxicity Toxicity 0.000 description 7
- 239000008389 polyethoxylated castor oil Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 206010029155 Nephropathy toxic Diseases 0.000 description 6
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000007694 nephrotoxicity Effects 0.000 description 6
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 6
- 150000003180 prostaglandins Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 229940127293 prostanoid Drugs 0.000 description 5
- 150000003814 prostanoids Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
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- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
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- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- 108010036941 Cyclosporins Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- 206010047631 Vitamin E deficiency Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FMNQRUKVXAQEAZ-JNRFBPFXSA-N (5z,8s,9r,10e,12s)-9,12-dihydroxy-8-[(1s)-1-hydroxy-3-oxopropyl]heptadeca-5,10-dienoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@@H](O)[C@H]([C@@H](O)CC=O)C\C=C/CCCC(O)=O FMNQRUKVXAQEAZ-JNRFBPFXSA-N 0.000 description 1
- ZAUYNCUCMJDAHW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;hydrogen peroxide;molecular iodine Chemical compound OO.II.C=CN1CCCC1=O ZAUYNCUCMJDAHW-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 206010002216 Anaphylactoid reaction Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000009693 Gingival Hyperplasia Diseases 0.000 description 1
- 208000002682 Hyperkalemia Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 206010023439 Kidney transplant rejection Diseases 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 101710089859 Nephrocan Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- XNRNNGPBEPRNAR-UHFFFAOYSA-N Thromboxane B2 Natural products CCCCCC(O)C=CC1OC(O)CC(O)C1CC=CCCCC(O)=O XNRNNGPBEPRNAR-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000004362 fungal culture Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 231100000268 induced nephrotoxicity Toxicity 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000936 membranestabilizing effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- VJZLQIPZNBPASX-OJJGEMKLSA-L prednisolone sodium phosphate Chemical compound [Na+].[Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 VJZLQIPZNBPASX-OJJGEMKLSA-L 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Die Erfindung bezieht sich auf pharmazeutische Zubereitungen, die eine wirksame Menge Cyclosporin A in Kombination mit emul gierenden Vitamin E-Derivaten sowie einem weiteren Emulgator enthalten.The invention relates to pharmaceutical preparations, which is an effective amount of cyclosporin A in combination with emul liberating vitamin E derivatives and another emulsifier contain.
Cyclosporin A ist ein zyklisches, wasserunlösliches, unpolares Undekapeptid. Die Verbindung ist ein gut wirksames Immunsuppres sivum, gewonnen aus Pilzkulturen (Cane et al., Transplant TROC. 13, 349-358 (1981); Ferguson et al., Surgery 92, 175-182 (1982)). Der Arzneistoff wird zur Vorbeugung der Abstoßung transplantierter allogener Organe eingesetzt (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North Am. 66, 435-449 (1986)). Seine immunsuppressive Wirkung beruht auf einer selektiven Hemmung der Zellfunktion, die ein Überleben von z. B. Herztransplantaten ohne Myelozytensuppression erlaubt (Myers et al, New England Journal of Medicine 311, 699 (1984)). Zusätzlich zur Verwendung bei Transplantationen haben neuere klinische Prüfungen gezeigt, daß Cyclosporin A bei der Behand lung einer großen Anzahl von Autoimmunerkrankungen wirksam ist. Beispielsweise wurden klinische Prüfungen zur Behandlung von Polymyositis, systemischen Lupus Erythematodes, Rheumatischer Arthritis oder sogar von jugendlichem insulinabhängigen Diabetes durchgeführt (siehe die entsprechenden Kapitel in: Cyclosporine in Autoimmune Diseases, Herausgeber Schindler, Springer Verlag, Berlin 1985).Cyclosporin A is a cyclic, water insoluble, nonpolar Undecapeptide. The compound is a well-effective immune suppressant sivum derived from fungal cultures (Cane et al., Transplant TROC. 13, 349-358 (1981); Ferguson et al., Surgery 92, 175-182 (1982)). The drug becomes a prevention of rejection transplanted allogeneic organs (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North At the. 66, 435-449 (1986)). Its immunosuppressive effect is based on a selective inhibition of cell function, which is a survival from Z. B. Heart transplants without myelocytic suppression allowed (Myers et al, New England Journal of Medicine 311, 699 (1984)). In addition to use in transplants have newer clinical trials have shown that Cyclosporin A can be used in the treatment of a large number of autoimmune diseases is effective. For example, clinical trials have been used to treat Polymyositis, Systemic Lupus Erythematosus, Rheumatoid Arthritis or even juvenile insulin-dependent diabetes (see the corresponding chapter in: Cyclosporine in Autoimmune Diseases, publisher Schindler, Springer Verlag, Berlin 1985).
Cyclosporin A ist ein lipophiles Molekül mit einem Molekular gewicht von 1202 Dalton. Aufgrund der schlechten Wasserlöslich keit und der hohen Lipophilie des Cyclosporin A besitzen dessen pharmezeutische Zusammensetzungen mit üblichen festen oder flüs sigen pharmazeutischen Trägerstoffen oft Nachteile. So werden die Cyclosporine aus solchen Zusammensetzungen nicht zufrieden stellend resorbiert (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), oder die Zusammensetzun gen werden nicht gut vertragen, oder sie sind bei der Lagerung nicht genügend stabil, beispielsweise gegen die Auskristallisa tion des Cyclosporins. Oft ist die gelöste Konzentration in Re lation zur Dosis von bis zu 1 g täglich niedrig, z. B. nur 3%, was die Einnahme von 30 g Lösung bedeutet. Eine höhere Löslich keit wird in DE-B-29 07 460 angeführt, worin eine Lösung von Cy closporin in Pflanzenöl, wie Olivenöl oder Maisöl, Ethanol und einem Emulgator aus einem nicht ionischen Ester eines Tri glyzerids mit einem Polyalkylenglycol beschrieben wird. Bei spiele der von diesem Patent bevorzugt angegebenen Zusammen setzungen sind Trinklösung, Trinkemulsion, Injektionslösung und in Kapseln befindliche Lösung. Cyclosporin A is a lipophilic molecule with a molecular weight weight of 1202 daltons. Due to the poor water solubility and the high lipophilicity of cyclosporin A have this pharmezeutische compositions with conventional solid or flüs Often pharmaceutical excipients often disadvantages. So be the cyclosporins from such compositions are not satisfied resorbing (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), or the compositions conditions are not well tolerated or they are in storage not sufficiently stable, for example against the Auskristallisa tion of cyclosporin. Often the dissolved concentration is in Re lation to the dose of up to 1 g daily low, z. Eg only 3%, which means taking 30 g of solution. A higher solubility This is cited in DE-B-29 07 460, wherein a solution of Cy closporin in vegetable oil, such as olive oil or corn oil, ethanol and an emulsifier of a nonionic ester of a tri glycerides with a polyalkylene glycol is described. at play the together preferred by this patent are drinking solution, drinking emulsion, solution for injection and in capsules solution.
Die Verabreichung der obigen Zusammensetzung erfolgt vorzugs weise intramuskulär oder subkutan oder insbesondere oral. Cy closporin A, appliziert mit obigen Arzneiformen, zeichnet sich durch eine gute Bioverfügbarkeit aus. Nach der Resorption bindet die Substanz schnell an Plasmaproteine und hat eine terminale Halbwertzeit von 24 Stunden. Es wird zu einem hohen Prozentsatz in der Leber metabolisiert, wobei die biliäre Exkretion die Haupteliminationsroute ist (Beverige, Cyclosporin A; in: Pro ceedings of International Symposium, Cambridge, Herausgeber White, Seiten 35-44 (1982)).The administration of the above composition is preferred wise intramuscularly or subcutaneously or in particular orally. Cy closporin A, applied with the above dosage forms, excels through a good bioavailability. After absorption binds the substance rapidly binds to plasma proteins and has a terminal Half-life of 24 hours. It becomes a high percentage metabolized in the liver, with biliary excretion the The main elimination route is (Beverige, Cyclosporin A, in: Pro cedings of International Symposium, Cambridge, publisher White, pages 35-44 (1982)).
Trotz des großen Wertes als Immunsuppressivum ist die klinische Verwendung von Cyclosporin A durch die Hauptnebenwirkung bei der chronischen Anwendung limitiert, die in der Nephrotoxizität des Wirkstoffes selber besteht (Van Buren, Surg. Clin. North Am. 66, 435-449 (1986)) . Auch in etwa 80% der Nierentransplantations patienten tritt Nierentoxizität auf (Kahan, Dial. Transplant. 12, 620-30 (19883)), und zwar durch diese substanzimmanente Ne benwirkung, die zum Schutz des Transplantates vor der Abstoßung angewendet wird.Despite its great value as an immunosuppressive drug, it is clinical Use of cyclosporin A by the major side effect in the limited chronic use, which in the nephrotoxicity of the Itself consists of (Van Buren, Surg, Clin North North 66, 435-449 (1986)). Also in about 80% of kidney transplants renal toxicity occurs in patients (Kahan, Dial. Transplant. 12, 620-30 (19883)), by this substance-inherent Ne to protect the transplant from rejection is applied.
Häufige Nebeneffekte von Cyclosporinbehandlungen bei verschie denen Autoimmunerkrankungen schließen neben der Nephrotoxizität die Hypertension, Hyperkaliämie, Hyperurikoämie, Hepatotoxizi tät, Anämie, Hypertrichiose, Gingivalhyperplasie, gastrointesti nale Nebenwirkungen, Tremor und Paresthesien ein (Von Graffen ried et al., Cyclosporine in Autoimmune Diseases, Herausgeber Schindler, Springer Verlag, Berlin, Seiten 59-73 (1985)). Von den hier zitierten Nebenwirkungen ist die häufigste die Nephro toxizität. Die akute, durch Cyclosporin induzierte Nephrotoxizi tät ist dosisabhängig und korreliert mit den Cyclosporinblut spiegeln. Sie ist reversibel nach Dosisreduktion oder nach Been digung der Cyclosporintherapie (Chapman et al., Lancet I, 128 (1985)). Common side effects of cyclosporin treatments in various which autoimmune diseases in addition to nephrotoxicity Hypertension, hyperkalemia, hyperuricemia, hepatotoxic anemia, hypertrichiosis, gingival hyperplasia, gastrointesti nal side effects, tremor and paresthesia (Von Graffen ried et al., Cyclosporins in Autoimmune Diseases, publisher Schindler, Springer Verlag, Berlin, pages 59-73 (1985)). From the side effects cited here are the most common ones are the nephro toxicity. The acute cyclosporin-induced nephrotoxicity It is dose-dependent and correlates with the cyclosporin blood reflect. It is reversible after dose reduction or after Been cyclosporine therapy (Chapman et al., Lancet I, 128 (1985)).
Akute Cyclosporinnephrotoxizität geht morphologisch einher mit tubulären Läsionen, die durch Einschlußkörperchen, isometrische Vakuolisierung und Mikrocalzifizierung gekennzeichnet sind (Mihatsch et al., Transplant. Proc. 15, 2821 (1983)). Dieses führt zu einer Abnahme der glomerulären Filtrationsrate, wie an hand des schnellen Anstiegs von Serumkreatinin in cyclosporin behandelten Patienten erkannt werden kann. Ein Grund dafür könnte die Störung der Mikrozirkulation durch Interaktion von Cyclosporin mit der lokalen Prostacyclinsynthese sein (Neild et al.; in: Cyclosporine, Herausgeber Kahan, Gruen & Stratton, Or lando, Florida, Seite 182 (1984)).Acute cyclosporinephrotoxicity is associated morphologically with tubular lesions by inclusion bodies, isometric Vacuolization and microcalzification are characterized (Mihatsch et al., Transplant, Proc., 15, 2821 (1983)). This leads to a decrease in the glomerular filtration rate, as on Hand of rapid increase of serum creatinine in cyclosporin treated patients can be detected. One reason for that could be the disruption of microcirculation through interaction of Cyclosporin with the local Prostacyclinsynthese be (Neild et al .; in: Cyclosporine, publisher Kahan, Gruen & Stratton, Or Lando, Florida, page 182 (1984)).
Obwohl der Mechanismum der renalen Dysfunktion noch nicht voll ständig aufgeklärt ist, konnte gezeigt werden, daß die renale Synthese von Thromboxan während des Fortschreitens von immun- und nicht immunvermittelten Modellen renaler Schädigung auftritt (Lianos et al., J. Clin. Invest. 72, 1439-1448 (1983); Okegawa et al., J. Clin. Invest. 71, 81-90 (1983)). Thromboxan ist ein Prostanoid und damit Metabolit der Arachidonsäure aus dem Cyclooxigenasezyklus. Die anderen Prostanoide sind Prosta glandine und Prostacycline. Prostanoide sind sehr wirksame Me diatoren, die während immunologisch erzeugter Entzündungspro zesse entstehen. Sie können grundlegend die renale Hämodynamik ändern (Morley; in: Lymphokines, Herausgeber Pic, Academic Press, New York, 4, 377-391 (1981)).Although the mechanism of renal dysfunction is not yet full was constantly enlightened, could be shown that the renal Synthesis of thromboxane during the progression of immune and non-immune-mediated models of renal damage (Lianos et al., J. Clin Invest 72, 1439-1448 (1983); Okegawa et al., J. Clin. Invest. 71, 81-90 (1983)). Thromboxane is a Prostanoid and thus metabolite of arachidonic acid from the Cyclooxigenasezyklus. The other prostanoids are Prosta glandine and prostacyclins. Prostanoids are very effective me diators produced during immunologically generated inflammatory pro tesse arise. You can fundamentally improve the renal hemodynamics (Morley, in: Lymphokines, Editor Pic, Academic Press, New York, 4, 377-391 (1981)).
EP-A-0 305 400 beschreibt die Zusammenhänge zwischen gestörter Prostanoidsynthese und Nephrotoxizität. Danach geht die Verab reichung von Cyclosporin mit einer erhöhten Synthese von Throm boxan B2, einem Mediator von Entzündungen, einher. Cyclosporin soll dementsprechend ebenfalls die Bildung von Prostaglandinen der E-Serie, ebenfalls Entzündungsmediatoren, fördern. Die Ab stoßung menschlicher Nierentransplantate konnte in Verbindung gebracht werden mit einem schnellen Anstieg von renal eliminier tem Thromboxan B2. EP-A-0 305 400 describes the relationships between disturbed ones Prostanoid synthesis and nephrotoxicity. After that, the admin administration of cyclosporin with increased synthesis of thrombin boxan B2, a mediator of inflammation. cyclosporine should accordingly also the formation of prostaglandins the E-series, also inflammatory mediators promote. The Ab Human kidney transplant rejection could be related be eliminated with a rapid increase of renal elimination Thromboxane B2.
EP-A-0 305 400 beschreibt ferner den Einsatz von w3-ungesättig ten Fettsäuren in Kombination mit Dyclosporin A zur Hemmung der Prostaglandin- bzw. Thromboxanbildung.EP-A-0 305 400 further describes the use of w3-unsaturated fatty acids in combination with Dyclosporin A to inhibit Prostaglandin or thromboxane formation.
Ein Nachteil einer längerfristigen w3-Fettsäuregabe liegt in der Ausbildung eines Vitamin E-Mangelzustandes. Mangelzustände sind z. B. Hämolyse und eine verkürzte Lebensdauer der Erythrozyten. Im Tierexperiment führt Vitamin-E-Mangel zu degenerativen Mus kelveränderungen, Kreatinurie, erhöhter Hämolyse der Erythrozy ten und zur Beeinflussung bestimmter Hormone und Enzyme sowie des Protein- und Arachidonsäurestoffwechsels (Machlin, Vitamin E; in: Machlin, Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects, Seiten 99-145, Marcel Dekker, New York, 1984).A disadvantage of a longer-term w3 fatty acid administration lies in the Formation of a vitamin E deficiency condition. Deficiencies are z. B. hemolysis and a shortened life of the erythrocytes. In animal experiments vitamin E deficiency leads to degenerative Mus Changes in the calvulae, creatinuria, increased hemolysis of the erythrocytes and influencing certain hormones and enzymes as well as of protein and arachidonic acid metabolism (Machlin, Vitamin e; in: Machlin, Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects, pages 99-145, Marcel Dekker, New York, 1984).
Ein weiterer Nachteil dieser Zusammensetzung mit w3-ungesättig ten Fettsäuren (Fischölen) ist die offenbar geringe zu errei chende Wirkstoffkonzentration in diesem Öl. So beschreibt EP-A-0 305 400 lediglich eine Konzentration mit 12,5 mg Cyclosporin A pro Gramm Fischöl. Bei einer üblichen täglichen Dosis von mehr als 300 mg Cyclosporin A bedeutet das eine Gesamteinnahmemenge von etwa 24 Gramm der Zubereitung und bei 1 g Cyclosporin A von 80 g Zubereitung. Dieses ist eine für Patienten unzumutbar hohe Ölmenge, die beispielsweise in Weichgelatinekapseln verkapselt zu einer täglichen Einnahme von 24 Kapseln mit 300 mg Cyclospo rin A führen würde. Die parenterale Applikation per Infusion würde bei einer, optimistisch gerechnet, 10-proz. ölhaltigen In fusionsemulsion eine Menge von ca. 240 ml Emulsion mit 300 mg Cyclosporin A bedeuten, ein Volumen, das nur über längere Zeit infundiert werden kann. Beide Aspekte stehen einer chronischen Anwendung, wie sie bei Transplantationspatienten notwendig ist, absolut entgegen.Another disadvantage of this composition with w3-unsaturated The lower fatty acids (fish oils) are apparently the low low concentration of active substance in this oil. Thus, EP-A-0 305 400 only one concentration with 12.5 mg cyclosporin A. per gram of fish oil. At a usual daily dose of more as 300 mg cyclosporin A, this means a total intake of about 24 grams of the preparation and 1 g of cyclosporin A from 80 g preparation. This is an unreasonable high for patients Quantity of oil encapsulated for example in soft gelatin capsules to a daily intake of 24 capsules with 300 mg Cyclospo Rin A would lead. Parenteral administration by infusion would be optimistic, 10 percent. oil-containing In a quantity of about 240 ml of emulsion with 300 mg Cyclosporin A means a volume that only lasts for a long time can be infused. Both aspects are chronic Application as needed in transplant patients absolutely contrary.
Die Formulierungen entsprechend der DE-B-29 07 460 zeichnen sich zwar durch ein sehr hohes Lösungsvermögen für Cyclosporin A aus, haben jedoch den Nachteil, daß sie nur Pflanzenöle umfassen, die keinerlei Prostaglandin- oder Thromboxansynthese-hemmende Stoffe enthalten. Das heißt, daß durch die Zubereitungen die Nephro toxizität des Cyclosporin A nicht gehemmt wird. Die im Handel befindliche parenterale Lösung des Cyclosporin A (SandimmunR) enthält in 1 ml Lösung 50 mg Cyclosporin A, 32,9% Ethanol und 650 mg Cremophor EL, ein ethoxyliertes, hydriertes Rizinusöl. Neben der Ethanolmenge von 2 g pro Anwendung, die eine Belastung für die Leber darstellt, ist nach Literaturberichten Cremophor EL nephrotoxisch ähnlich wie Cyclosporin A selber (Thiel et al., Clin. Nephrol. 25 (Suppl. 1), 540-542 (1986); Finn et al., Renal Failure 11, 3-15 (1989)) . So führt Cremophor EL in der isolier ten, perfundierten Rattenniere zu einer deutlichen renalen Vaso konstriktion mit reduziertem renalen Blutfluß und tubulärer Dys funktion (Besarab et al., Transplantation 44, 195-201 (1987); Luke et al., Transplantation 43, 795-799 (1987)). Im weiteren verursacht Cremophor EL anaphylaktische Reaktionen bis zum Schock (Chapuis et al., Engl. J. Med. 312, 1259 (1985), Leunis sen et al., Lancet 1, 637 (1986); Magalini et al., Transplanta tion 42, 443-444 (1986)) . Als Ursache der anaphylaktoiden Reak tion wurde Cremophor EL angesehen, da es zu Histaminliberation führt (Ennis et al., Agents Action 12, 64-80 (1982)) . In einigen Therapiefällen mit der i. v. Lösung wurde die allergische Reak tion bei der ersten Anwendung am Menschen beobachtet (Friedmann et al., Am. J. Med. 78, 343-345 (1985); Magalini et al., Trans plantation 42, 443-444 (1986)). Nachteil der handelsüblichen parenteralen Zubereitung ist demnach der Inhaltsstoff Cremophor EL. Es ist daher eine Formulierung anzustreben, die die obigen Nebenwirkungen vermeidet und die Arzneimittelsicherheit erhöht.Although the formulations according to DE-B-29 07 460 are distinguished by a very high dissolving power for cyclosporin A, they have the disadvantage that they comprise only vegetable oils which do not contain any prostaglandin or thromboxane synthesis-inhibiting substances. This means that the preparations do not inhibit the nephro toxicity of cyclosporin A. The commercially available parenteral solution of cyclosporin A (Sandimmun R ) contains in 1 ml solution 50 mg cyclosporin A, 32.9% ethanol and 650 mg Cremophor EL, an ethoxylated, hydrogenated castor oil. In addition to the amount of ethanol of 2 g per application, which is a burden on the liver, according to literature reports Cremophor EL nephrotoxisch similar to cyclosporin A itself (Thiel et al., Clin Nephrol 25 (Suppl.) 1, 540-542 (1986 Finn et al., Renal Failure 11, 3-15 (1989)). Thus, Cremophor EL in the isolated, perfused rat kidney leads to marked renal vasoconstriction with reduced renal blood flow and tubular dysfunction (Besarab et al., Transplantation 44, 195-201 (1987); Luke et al., Transplantation 43, 795) -799 (1987)). Furthermore, Cremophor EL causes anaphylactic reactions until shock (Chapuis et al., Engl. J. Med. 312, 1259 (1985), Leunis sen et al., Lancet 1, 637 (1986); Magalini et al., Transplantation 42, 443-444 (1986)). Cremophor EL was considered to be the cause of the anaphylactoid reaction since it leads to histamine liberation (Ennis et al., Agents Action 12, 64-80 (1982)). In some therapy cases with the iv solution, the allergic reaction was observed in the first human administration (Friedmann et al., Am. J. Med., 78, 343-345 (1985); Magalini et al., Transplantation 42, 443) -444 (1986)). Disadvantage of the commercial parenteral preparation is therefore the ingredient Cremophor EL. It is therefore desirable to have a formulation that avoids the above side effects and increases drug safety.
Die günstigen immunsuppressiven Eigenschaften von Cyclosporin A werden bei der Behandlung der Psoriasis ausgenutzt. Aufgrund seines hohen Molekulargewichts und seiner sehr hohen Lipophilie ist jedoch Cyclosporin A nicht imstande, intakte Haut, speziell das Stratum Corneum, zu durchdringen. Aus diesem Grunde werden schwere Psoriasisfälle mit der oralen und parenteralen Cyclospo ringabe behandelt. Nachteil dieser Anwendung sind die systemi schen Nebenwirkungen auf den Kreislauf (Hypertonie) und die Nie renfunktion. Topische Zubereitungen zur Behandlung der Psoria sis, womit die systemischen Nebenwirkungen reduziert würden, benötigen Resorptionsförderer, wie z. B. Propylenglycol und Azone (Duncan et al., British Journal of Dermatology 123, 631-640 (1990)). Nun ist aber gerade von Azone bekannt, daß seine permeationsfördernden Eigenschaften auf eine Störung oder sogar Zerstörung der Schutzfunktion des Stratum Corneum zurückzuführen sind. Propylenglycol führt zu einem Austrocknen der Haut. Beide Substanzen würden also ehr der Abheilung der Psoriasis hinder lich als förderlich sein. Aus diesem Grunde wäre eine topische Zubereitung mit einem therapeutisch ausreichenden Cyclosporin-A- Gehalt in Kombination mit den Heilungsprozeß fördernden Stoffen wünschenswert. Darüber hinaus sollte die Kombination die Permea tion des Cyclosporin A durch intakte Haut fördern.The favorable immunosuppressive properties of cyclosporin A are used in the treatment of psoriasis. by virtue of its high molecular weight and very high lipophilicity however, Cyclosporin A is unable to maintain intact skin, especially the stratum corneum, to penetrate. That's why severe psoriasis with the oral and parenteral Cyclospo treated ringabe. Disadvantage of this application are the systemi side effects on the circulation (hypertension) and the Nie renfunktion. Topical preparations for the treatment of Psoria sis, which would reduce the systemic side effects, need absorption conveyor, such as. For example, propylene glycol and Azone (Duncan et al., British Journal of Dermatology 123, 631-640 (1990)). But it is now known by Azone that his permeation enhancing properties on a fault or even Destruction of the protective function of the stratum corneum are. Propylene glycol causes the skin to dry out. Both Substances would therefore hinder the healing of psoriasis be beneficial. For that reason, a topical would be Preparation with a therapeutically sufficient cyclosporin A Content in combination with the healing process promoting substances desirable. In addition, the combination should be the permea tion of cyclosporin A through intact skin.
Aufgabe der vorliegenden Erfindung ist es nun, ein vorteilhaftes Lösungsmittelsystem zu finden, das Cyclosporin A in ausreichen der Menge löst, so daß es in der therapeutisch gebräuchlichen täglichen Dosierung oral eingenommen werden kann, die nephro toxische Wirkung reduzieren kann und bei topischer Applikation sowohl die Hautpermeation fördern als auch den Heilungsprozeß bei der Behandlung der Psoriasis unterstützen kann.Object of the present invention, it is now an advantageous Solvent system find that cyclosporin A in sufficient the amount triggers, so that it is in the therapeutically common daily dosage can be taken orally, the nephro can reduce toxic effects and topical application promote both the skin permeation and the healing process assist in the treatment of psoriasis.
Die der Erfindung zugrundeliegende Aufgabe wird nun durch eine pharmazeutische Zubereitung gelöst, die aus Cyclosporin A, einem emulgierenden α-Tocophero1-Derivat, einem Ethoxylierungsprodukt von Pflanzenölen, Fettsäuren oder Fetten als weiterem Emulgator und einem pharmazeutisch üblichen Alkohol besteht oder sie ent hält.The problem underlying the invention will now be described by a Pharmaceutical preparation dissolved in cyclosporin A, a emulsifying α-tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as further emulsifier and a pharmaceutically usual alcohol or ent holds.
Diese pharmazeutische Zubereitung kann durch D-α-Tocopherolpoly ethylenglykol-1000-Succinat (Vitamin E-TPGS) als α-Tocopherol- Derivat gekennzeichnet sein.This pharmaceutical preparation can be prepared by D-α-tocopherol poly ethylene glycol 1000 succinate (Vitamin E-TPGS) as α-tocopherol Be characterized by a derivative.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an α-Tocopherol-Derivat von bis zu 900% auf Basis von Cyclospo rin A gekennzeichnet sein.The pharmaceutical preparation may further by a content to α-tocopherol derivative of up to 900% based on cyclospo be characterized in A.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an Cyclosporin A 10% auf Basis der Zusammensetzung gekenn zeichnet sein.The pharmaceutical preparation may further by a content cyclosporin A 10% based on the composition gekenn be distinguished.
Die pharmazeutische Zubereitung kann ferner durch seinen Gehalt an Ethanol oder Isopropanol als pharmazeutisch üblicher Alkohol, insbesondere in Mengen bis 20%, gekennzeichnet sein.The pharmaceutical preparation may also be characterized by its content ethanol or isopropanol as a pharmaceutically usual alcohol, especially in amounts up to 20%.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an ethoxyliertem Rizinusöl als weiterem Emulgator gekennzeichnet sein.The pharmaceutical preparation may further by a content ethoxylated castor oil as further emulsifier his.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an Verdickungsmittel gekennzeichnet sein.The pharmaceutical preparation may further by a content be characterized by thickening agents.
Erfindungsgemäß wurde also überraschend gefunden, daß emulgie rende α-Tocopherol-Derivate , wie D-α-Tocopherolpolyethylengly col-1000-Succinat, ein ausgezeichnetes Emulgier- bzw. Lösungsvermögen für Cyclosporin A aufweisen, gleichzeitig die Synthese von Prostanoiden wie Prostaglandinen und Thromboxanen hemmen, was zur Reduktion der Nephrotoxizität und zum Abklingen von Entzündungsreaktionen in der Haut ausgenützt werden kann und gleichzeitig die Resorption von Cyclosporin A durch die intakte Haut fördert. Der besondere Vorteil der erfindungsgemäßen Lösungen besteht neben der Erzielung hoher Konzentrationen an gelöstem Cyclosporin A von über 10% darin, daß die D-α- Tocopherol-Derivate als Derivat von natürlichem Vitamin E Eigenwirkungen besitzen, die einerseits toxischen Wirkungen von Cyclosporin A bei den üblichen hohen Dosen bei oraler Anwendung entgegenwirken und andererseits den beabsichtigten immunsuppressiven Effekt bei der topischen Behandlung der Psoriasis über die resorptionsfördernde Wirkung verstärken.According to the invention was therefore surprisingly found that emulgie α-tocopherol derivatives such as D-α-tocopherol polyethylene glycol col-1000 succinate, an excellent emulsifying or Have dissolving power for cyclosporin A, while the Synthesis of prostanoids such as prostaglandins and thromboxanes inhibit, resulting in the reduction of nephrotoxicity and subsidence can be exploited by inflammatory reactions in the skin and at the same time the absorption of cyclosporin A by the intact Promotes skin. The particular advantage of the invention Solutions exist in addition to achieving high concentrations dissolved cyclosporin A of more than 10% in that the D-α- Tocopherol derivatives as a derivative of natural vitamin E. Own effects, on the one hand toxic effects of Cyclosporin A at the usual high doses when administered orally counteract and on the other hand the intended immunosuppressive effect in the topical treatment of Reinforce psoriasis via the absorption-promoting effect.
So beeinflussen Vitamin E bzw. seine Derivate den Arachidon säurestoffwechsel im Sinne einer Hemmung der prostaglandin-, Thromboxan- und Leukotrienbiosynthese und einer Erhöhung der Prostacyclinbildung. Diese Eigenschaften stehen mit einer biolo gischen Entzündungshemmung und mit thrombotischen Erkrankungen in Zusammenhang (Machlin, Vitamin E.; in: Machlin, Handbook of Vitamins: Ntritional, Biochemical and Clinical Aspects, Seiten 99-145, Marcel Dekker, New York, 1984). Vitamin E kann nach ora ler Einnahme ebenfalls die Aktivität nicht steroidaler entzün dungshemmender Arzneistoffe fördern (Bertolini et al., Rivista di Pharmakologia et Therapia 8, Seiten 27-34 (1982); Klein & Blankenhorn, Vergleich der klinischen Wirksamkeit von Vitamin E und Diclofenac Natrium bei Spondylitis Ancylosans (Morbus Bech terew), Vitaminspur 2, Seiten 137-142 (1987)). Nach topischer Anwendung permeiert Vitamin E sehr gut das Stratum Corneum. Es wurden quantitative Resorptionsstudien an der Haut von Versuchs tieren durchgeführt. So wurde 16 Stunden nach Applikation von 300 µg einer 5-proz. Vitamin E-Lösung in Ethanol pro cm² 10,7% Vitamin E in der Hornschicht und ca. 40,9% in darunterliegenden Hautschichten wiedergefunden (Djerassi et al., Vitamin E: Bio chemical function and its role in cosmetics, Drug & Cosmetic Industry 13, Nr. 1, Seiten 29-31, 34, 78 (1986)). Lokal appli ziert wirkt Vitamin E als membranstabilisierendes Antioxydans und hemmt die Freisetzung von Histamin und hydrolytischen Enzy men z. B. aus den Mastzellen und den Lysosomen durch Stabilisie rung ihrer Membranen. Ebenfalls hemmt es die Synthese bestimmter Prostaglandine, desaktiviert Sauerstoffradikale und entgiftet entsprechende Folgeprodukte (Sies, Bildung von Superoxidradika len und Peroxiden; In: Superoxiddismutase - Biochemie und thera peutischer Einsatz; Herausgeber Puhl & Ries, Perimed Verlag, Erlangen, 1982). Zudem erhöht Vitamin E die Hautfeuchtigkeit und wirkt quasi als Okklusionsmittel. Alle diese beschriebenen Eigenschaften sind bei der Behandlung der Psoriasis von Vorteil.Thus, vitamin E or its derivatives affect the arachidon acid metabolism in the sense of an inhibition of prostaglandin, Thromboxane and leukotriene biosynthesis and an increase in the Prostacyclin. These features are available with a biolo anti-inflammatory and thrombotic diseases in connection (Machlin, Vitamin E, in: Machlin, Handbook of Vitamins: Ntritional, Biochemical and Clinical Aspects, p 99-145, Marcel Dekker, New York, 1984). Vitamin E may orally after Ingestion also does not stimulate the activity of non-steroidal inflammation anti-inflammatory drugs (Bertolini et al., Rivista di Pharmacologia et Therapia 8, pages 27-34 (1982); Small & Blankenhorn, Comparison of the Clinical Effectiveness of Vitamin E and diclofenac sodium in ankylosing spondylitis (Bech Terew), Vitaminspur 2, pages 137-142 (1987)). After topical Vitamin E application very well permeates the stratum corneum. It were quantitative resorption studies on the skin of trial animals performed. So was 16 hours after application of 300 μg of a 5 percent Vitamin E solution in ethanol per cm² 10.7% Vitamin E in the horny layer and about 40.9% in the lower layer Skin layers rediscovered (Djerassi et al., Vitamin E: Bio chemical function and its role in cosmetics, drug & cosmetics Industry 13, No. 1, pages 29-31, 34, 78 (1986)). Local appli In addition, vitamin E acts as a membrane-stabilizing antioxidant and inhibits the release of histamine and hydrolytic enzymes men z. B. from the mast cells and the lysosomes by stabilization tion of their membranes. It also inhibits the synthesis of certain Prostaglandins, deactivates oxygen radicals and detoxifies corresponding secondary products (ie, formation of superoxide radicals len and peroxides; In: Superoxide Dismutase - Biochemistry and Thera peutic use; Publisher Puhl & Ries, Perimed Verlag, Erlangen, 1982). In addition, vitamin E increases the skin moisture and acts as a kind of occlusion agent. All these described Properties are beneficial in the treatment of psoriasis.
Cyclosporin A löst sich nun völlig unerwartet in einer so hohen Konzentration < 10% in erfindungsgemäßen Zubereitungen, daß die Kombination als Lösung therapeutisch sinnvoll sowohl in Weich gelatinekapseln als auch in topischen Formulierungen einsetzbar ist.Cyclosporin A dissolves completely unexpectedly in such a high Concentration <10% in preparations according to the invention that the Combination as a solution makes sense therapeutically in both soft gelatin capsules as well as in topical formulations is.
Des weiteren können die Formulierungen Verdickungsmittel, wie kolloidale Kieselsäure oder Polyacrylsäure oder Polyacrylsäure derivate oder Cellulosederivate, sowie Antioxydantien und Ge schmackshilfsstoffe enthalten.Furthermore, the formulations may contain thickening agents, such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, as well as antioxidants and Ge flavor additives.
Die Zusammensetzung der Formulierung war wie folgt:The composition of the formulation was as follows:
Die Mischung wurde in Hartgelatinekapseln abgefüllt und im cross-over-Versuch an Hunden im Vergleich zu einem Handelspro dukt (Sandimmun OptivalR) geprüft. Die Blutspiegelanalytik wurde mittels Fluoreszenz-Immun-Essay durchgeführt.The mixture was filled into hard gelatine capsules and tested in cross-over on dogs compared to a commercial product (Sandimmun Optival R ). The blood level analysis was carried out by fluorescence immune essay.
Aus Fig. 1 ist eindeutig ersichtlich, daß die erfindungsgemäße Kapselzubereitung dem Handelsprodukt gleichwertig ist.From Fig. 1 it is clearly evident that the capsule preparation according to the invention is equivalent to the commercial product.
Claims (7)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19521974A DE19521974A1 (en) | 1995-06-16 | 1995-06-16 | Pharmaceutical preparation with cyclosporin A |
| CA002224792A CA2224792C (en) | 1995-06-16 | 1996-06-13 | Pharmaceutical preparation containing cyclosporin a |
| EP96922803A EP0833655A1 (en) | 1995-06-16 | 1996-06-13 | Pharmaceutical preparation with cyclosporin a |
| PCT/EP1996/002559 WO1997000080A1 (en) | 1995-06-16 | 1996-06-13 | Pharmaceutical preparation with cyclosporin a |
| AU63556/96A AU705155B2 (en) | 1995-06-16 | 1996-06-13 | Pharmaceutical preparation containing cyclosporin A |
| ZA965087A ZA965087B (en) | 1995-06-16 | 1996-06-14 | Pharmaceutical preparation containing cyclosporin a |
| US09/204,782 US6696413B2 (en) | 1995-06-16 | 1998-12-03 | Pharmaceutical preparation with cyclosporin A |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19521974A DE19521974A1 (en) | 1995-06-16 | 1995-06-16 | Pharmaceutical preparation with cyclosporin A |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19521974A1 true DE19521974A1 (en) | 1996-12-19 |
Family
ID=7764554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19521974A Withdrawn DE19521974A1 (en) | 1995-06-16 | 1995-06-16 | Pharmaceutical preparation with cyclosporin A |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0833655A1 (en) |
| AU (1) | AU705155B2 (en) |
| CA (1) | CA2224792C (en) |
| DE (1) | DE19521974A1 (en) |
| WO (1) | WO1997000080A1 (en) |
| ZA (1) | ZA965087B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2216342C2 (en) * | 1998-12-23 | 2003-11-20 | Рациофарм Гмбх | Cyclosporin solution |
| US7060672B2 (en) | 2001-10-19 | 2006-06-13 | Isotechnika, Inc. | Cyclosporin analog formulations |
| US7332472B2 (en) | 2001-10-19 | 2008-02-19 | Isotechnika Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
| US7358229B2 (en) | 1997-10-08 | 2008-04-15 | Isotechnika Inc. | Deuterated cyclosporin analogs and their use as immunomodulating agents |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999029316A1 (en) | 1997-12-10 | 1999-06-17 | Severson, Mary, L. | Pharmaceutical compositions containing an omega-3 fatty acid oil |
| US6979456B1 (en) | 1998-04-01 | 2005-12-27 | Jagotec Ag | Anticancer compositions |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2551005B1 (en) * | 1983-08-25 | 1987-06-12 | Galland Jean Claude | DEVICE FOR EXPLORING THE DEADLINED ANGLE OF THE OPTICAL MIRROR FOR A MOTOR VEHICLE OR THE LIKE |
| JP3644543B2 (en) * | 1993-10-22 | 2005-04-27 | ヘクサル・アーゲー | Pharmaceutical composition containing cyclosporin A and α-tocopherol |
| US5430021A (en) * | 1994-03-18 | 1995-07-04 | Pharmavene, Inc. | Hydrophobic drug delivery systems |
| HU215966B (en) * | 1994-11-21 | 1999-07-28 | BIOGAL Gyógyszergyár Rt. | Oral multiple emulsion-preconcentrate containing cyclosporin |
-
1995
- 1995-06-16 DE DE19521974A patent/DE19521974A1/en not_active Withdrawn
-
1996
- 1996-06-13 EP EP96922803A patent/EP0833655A1/en not_active Ceased
- 1996-06-13 WO PCT/EP1996/002559 patent/WO1997000080A1/en not_active Application Discontinuation
- 1996-06-13 AU AU63556/96A patent/AU705155B2/en not_active Expired
- 1996-06-13 CA CA002224792A patent/CA2224792C/en not_active Expired - Lifetime
- 1996-06-14 ZA ZA965087A patent/ZA965087B/en unknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7358229B2 (en) | 1997-10-08 | 2008-04-15 | Isotechnika Inc. | Deuterated cyclosporin analogs and their use as immunomodulating agents |
| US7521421B2 (en) | 1997-10-08 | 2009-04-21 | Isotechnika Inc. | Deuterated cyclosporine analogs and methods of making the same |
| US7538189B2 (en) | 1997-10-08 | 2009-05-26 | Isotechnika Inc. | Methods of making deuterated cyclosporin analogs |
| RU2216342C2 (en) * | 1998-12-23 | 2003-11-20 | Рациофарм Гмбх | Cyclosporin solution |
| US7060672B2 (en) | 2001-10-19 | 2006-06-13 | Isotechnika, Inc. | Cyclosporin analog formulations |
| US7332472B2 (en) | 2001-10-19 | 2008-02-19 | Isotechnika Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
| US7429562B2 (en) | 2001-10-19 | 2008-09-30 | Isotechnika Inc. | Cyclosporin analog formulations |
| US9765119B2 (en) | 2001-10-19 | 2017-09-19 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
| US10472394B2 (en) | 2001-10-19 | 2019-11-12 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
| USRE48226E1 (en) | 2001-10-19 | 2020-09-29 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA965087B (en) | 1997-01-22 |
| EP0833655A1 (en) | 1998-04-08 |
| AU705155B2 (en) | 1999-05-13 |
| CA2224792C (en) | 2003-01-07 |
| WO1997000080A1 (en) | 1997-01-03 |
| CA2224792A1 (en) | 1997-01-03 |
| AU6355696A (en) | 1997-01-15 |
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