IE56366B1 - Pharmaceutical compositions comprising an hydrogenated ergot alkaloid and heparin - Google Patents
Pharmaceutical compositions comprising an hydrogenated ergot alkaloid and heparinInfo
- Publication number
- IE56366B1 IE56366B1 IE2896/83A IE289683A IE56366B1 IE 56366 B1 IE56366 B1 IE 56366B1 IE 2896/83 A IE2896/83 A IE 2896/83A IE 289683 A IE289683 A IE 289683A IE 56366 B1 IE56366 B1 IE 56366B1
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- Ireland
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- composition according
- molecular weight
- pharmaceutically acceptable
- composition
- Prior art date
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- 229960003133 ergot alkaloid Drugs 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 229920000669 heparin Polymers 0.000 title description 33
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title description 18
- 229960002897 heparin Drugs 0.000 title description 18
- 239000000203 mixture Substances 0.000 claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003055 low molecular weight heparin Substances 0.000 claims abstract description 18
- 229940127215 low-molecular weight heparin Drugs 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 16
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 claims abstract description 9
- 229960004704 dihydroergotamine Drugs 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 40
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 230000003444 anaesthetic effect Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000007395 thrombosis prophylaxis Methods 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 229960001413 acetanilide Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- -1 sec.-butyl Chemical group 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 150000005846 sugar alcohols Polymers 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims 1
- 239000003708 ampul Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 19
- 206010050902 Postoperative thrombosis Diseases 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 5
- 239000005526 vasoconstrictor agent Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 229940124326 anaesthetic agent Drugs 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- ADYPXRFPBQGGAH-UMYZUSPBSA-N dihydroergotamine mesylate Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 ADYPXRFPBQGGAH-UMYZUSPBSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 2
- WROUIBGUWODUPA-UHFFFAOYSA-N 2-(butylamino)-n-(2-chloro-6-methylphenyl)acetamide;hydrochloride Chemical compound [Cl-].CCCC[NH2+]CC(=O)NC1=C(C)C=CC=C1Cl WROUIBGUWODUPA-UHFFFAOYSA-N 0.000 description 1
- SKOVXWGCQMGKQB-UHFFFAOYSA-N 2-amino-n,n-diphenylacetamide Chemical class C=1C=CC=CC=1N(C(=O)CN)C1=CC=CC=C1 SKOVXWGCQMGKQB-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- LIWOWASNSWUKPF-UHFFFAOYSA-N Tolycaine hydrochloride Chemical compound Cl.CCN(CC)CC(=O)NC1=C(C)C=CC=C1C(=O)OC LIWOWASNSWUKPF-UHFFFAOYSA-N 0.000 description 1
- 150000008061 acetanilides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical group CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- NQRDVLDEYJYWQR-SZGCSELGSA-N dihydroergovaline Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C)=C3C2=CNC3=C1 NQRDVLDEYJYWQR-SZGCSELGSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 239000002565 heparin fraction Substances 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- IYBQHJMYDGVZRY-UHFFFAOYSA-N lidocaine hydrochloride Chemical compound [Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C IYBQHJMYDGVZRY-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel pharmaceutical compositions comprising i) an hydrogenated ergot alkaloid having vaso-constrictor activity, for example dihydroergotamine, or a pharmaceutically acceptable acid addition salt thereof and ii) a low molecular weight heparin or pharmaceutically acceptable salt thereof, and process for their production. Components ii) suitably have an average molecular weight of less than 10,000. The compositions are especially useful in the prevention of post-operative thrombosis.
Description
The present invention relates to novel pharmaceutical compositions useful in thrombosis prophylaxis, in particular for the prevention of post-operative thrombosis as well as to processes for.the production of said compositions.
Heparin is a highly sulfated, dextro-rotatory mucopolysaccharide, having specific anti-coagulant properties and commonly employed inter al. in the prevention of post-operative thrombosis. It oc10 curs as a natural constituent of various tissues, especially liver and lung, in a variety of mammalian species and preparations isolated from differing sources are available commercially, both in free and in pharmaceutically acceptable salt form, e.g. in the form of various alkaline and alkaline-earth metal salts.
Whole heparin, i.e. as commonly isolated directly from source, comprises polymer units of non-uniform molecular weight commonly ranging from between 6,000 and 20,000 and with an average molecular weight of from 14,000 to 18,000, in which the basic polymer chain is composed of D-glucosamine and D-g1ucuron1c acid residues. The specific chemical and physical constitution, e.g. the precise degree of sulfation and the molecular weight characteristics vary according to the source, I.e. the animal material from which 1t Is obtained, as well as the precise means of isola25 tion. As further discussed hereinafter, various techniques are also known and described In the art for the obtentlon of heparin preparations of lower average molecular weight than is found In - 2 >> whole heparin preparations, e.g. as otherwise directly obtained from the animal source.
It is also known that administration of heparin together with hydrogenated ergot alkaloids having vaso-constrlctor activity, In particular di hydroergot amine, is of especial advantage In relation to thrombosis prophylaxis, especially the prevention of post-operative thrombosis - see e.g. UK patent specification no. 1,557,331 - and heparin/dihydroergotamIne therapy is now a valued and commonly employed treatment for patients at risk of thrombo10 sis, in particular following major surgery. Administration Is generally parenteral, e.g. by Intravenous injection, and various formulations, e.g. having Improved stability characteristics as compared with simple solutions, for use in this manner are known In the literature or are commercially available (see e.g. U.S.
Patent Specification No. 4,402,949).
In accordance with the present Invention It has now surprisingly been found that where combined therapy as described above is applied, especially advantagous results are obtained if the heparin component is a heparin of low molecular weight. In particular it has been found that by using a low molecular weight heparin in conjunction with hydrogenated ergot alkaloids having vaso-constrlctor activity, in particular di hydroergotamine, in place of conventionally employed whole heparin preparations, therapeutic effectiveness, e.g. duration of anti-thrombotic activity, 1s dramatically increased, whereby the dally dosage of both the heparin and hydrogenated ergot alkaloid component required for effective prophylactic therapy may be correspondingly reduced.
The present Invention therefore has the very important advantage of enabling significant reduction of the daily medication required for patient treatment. In that, as already noted, treatment is generally by means of i.v. injection, the present invention further provides the concomitant advantage of enabling reduction of the required dally Injection rate and hence substantial reduction of patient discomfort. This is of especial importance in relation to patients undergoing and recovering from . major surgery.
In accordance with the foregoing the present invention provides a pharmaceutical composition comprising: 1) an hydrogenated ergot alkaloid having vaso-constrictor activity, or pharmaceutically acceptable acid addition salt thereof, and ii) a low molecular weight heparin of average molecular weight of 10,000 or less, or pharmaceutically acceptable salt thereof.
Component i) of the compositions of the invention is suitably: a hydrogenated ergot alkaloid of formula I wherein R Is hydrogen or 0χ_4 alkyl, Rl 1s methyl, ethyl or Iso-propyl, R? Is iso-propyl, sec.-butyl. Iso-butyl or benzyl and X is hydrogen or methoxy, or a pharmaceutically acceptable acid addition salt thereof.
Preferably component 1) is dihydroergotamine, 6-nor-isopropyl9,10-dihydro-2'B-methy1-5'<*-benzy1-ergopeptine or dihydroergovaline or a pharmaceutically acceptable acid addition salt thereof, dihydroergotamine and its pharmaceutically acceptable acid XO addition salts being most preferred. Suitable pharmaceutically acceptable acid addition salts are e.g. the methanesulfonates, maleinates and tartrates, and, in the case of dihydroergotamine the methanesulfonate in particular. - 5 By the term a low molecular weight heparin is meant a heparin prepared.e.g. by isolative procedures or depol/nerisatlon such as hereinafter described, so as to achieve significant reduction of 4 average molecular weight as compared with whole heparin prepara5 tions.
Components il) for use in accordance with the present invention have an average molecular weight of ca. 10,000 or less, more preferably of ca. 8,000 or less. Preferably however the average molecular weight is not less than ca. 4,000, more preferably not less than ca. 5,000, most preferably not less than ca. 6,000. Especially preferred components 11) accordingly have an average molecular weight of from ca. 10,000 to ca. 4,000 in particular from ca. 3,000 to ca. 5,000, e.g. of ca. 7,000 ± 1,000 or of ca. 6,000 i 1,000. It is further preferred that components ii) should be of relatively uniform molecular weight, e.g. with at least 60 X, more preferably 80 X of polymer units having a molecular weight within the above defined average molecular weight limits, e.g. having a molecular weight of 10,000 or less.
Suitable pharmaceutically acceptable salts of low molecular weight heparlris as component ii) are e.g. the calcium and potassium and, in particular, the sodium salt.
The low molecular weight heparin or pharmaceutically acceptable salt thereof employed as component ii) may be obtained In accordance with methods known in the art, e.g. by Isolation of low mo25 lecular weight fractions from whole heparin preparations, e.g. by fractional precipitation and filtration, for example as described in German Offenlegungsschrift No. 29 45 591, or by depolymerisation of high molecular weight fractions of whole heparin - 6 e.g. by chemical cleavage, for example as described in Belgian Patent JHo? 8^,or European Patent Publication No. 27,089. Alternatively components ii) may be obtained by a combination of such techniques, e.g. by separation of low molecular weight heparin from whole heparin preparations, followed by depolymerisation of remaining higher molecular weight heparin fractions to yield further low molecular weight heparin and, optionally, combination of the two low molecular weight heparin preparations thus obtained.
Where low molecular weight heparin is prepared by chemical clea10 vage,. individual chain residues may undergo a measure of chemical modification in particular de-sulfatlsatlon. Where this occurs, for use in accordance with the present invention, components 11) Initially produced may, if desired, subsequently be reconstituted or otherwise appropriately modified in accordance with known techniques, for example analoguosly to the techniques disclosed in French patent specification No. 888,864.
Where low molecular weight heparin preparations obtained by chemical cleavage are used In the compositions of the invention, these will preferably be preparations which have undergone no, or substantially no additional chemical modification.
Components 1) and ii) are suitably present in a ratio of 1 mg of component i): 300 to 70,000, (e.g. 500 to 70,000), preferably 300 to 35,000 IU of component ii). More preferably components 1) and 11) are present in a ratio of 1 mg of component i): 1,000 to ,000, (e.g. 2,000 to 20,000) most preferably 1,000 to 10,000 IU of component ii). When component 1) and/or 11) is present in pharmaceutically acceptable salt form, the equivalent amount of salt form providing the indicated ratios is employed. * - 7 As previously indicated the compositions of the Invention will generally be administered by Injection. For direct application they will accordingly be In liquid form. Although e.g. simple aqueous or aqueous/alcoholic solutions are possible, these are generally not preferred since, In the absence of stabilizing means, components 1) and il) will react to form difficulty soluble salts which precipitate out of solution. Simple solutions accordingly can not be kept In reserve for periods of more than a few hours and are thus of limited practical value.
Preferred compositions In accordance with the present Invention are stabilized solutions of the type described In the aforementioned U.S. Patent No. 4,402,949 employing e.g., as an additional component 111) a pharmaceutically acceptable calcium or magnesium salt of ethylenedlamlnetetraacetlc acid (EDTA) as a stabilizing agent. For such solutions the solvent medium preferably comprises lv) water and v) a pharmaceutically acceptable mono- or poly-alcohol.
Indicated magnesium and calcium salts of EDTA as component ill) are the mono-magnesium and mono-calcium salts Including the pharmaceutically acceptable poly-metal salts Incorporating magnesium and, preferably, calcium together with mono-valent metal ions, e.g. sodium or potassium Ions. The preferred salt of EDTA for use in accordance with the Invention 1s the mono-calclum-bls-sodlum salt (CaNa^ EDTA) also known as calcium titrlplex. The monomagnes1um-b1s-potassium salt (Mg<2 EDTA) may also be mentioned.
Component HI) Is preferably present In a range of from about 1 to about 50 mg, more preferably 1 to 25 mg, most preferably 1 to 10 mg based on an amount of 5,000 IU of component 11).
When the solvent medium comprises components 1v) and v) i.e. as 5 diluent or carrier, these are preferably present In an amount of to 72 X and 28 to 55 X respectively, based on the total volume of the composition.
Preferred components v) are ethanol, propylene glycol, polyethylene glycol (suitably having an average molecular weight of ca. 400), diethylene glycol, triethylene glycol and glycerol, as well as mixtures thereof. More preferably v) comprises a mixture of a) ethanol and b) triethylene glycol or of c) glycerol and d) propylene glycol. In such mixtures a) and b) are preferably present In a ratio of from 1 : 6 to 10, more preferably 1:3 parts by weight and c) and d) are preferably present in a ratio of from 1 : 8 to 12, more preferably 1:10 parts by weight.
In a preferred embodiment, such solutions as aforesaid also comprise as a further component vi), a physiologically acceptable anaesthetic. Anaesthetic components vi) are preferably acetani20 IIde anaesthetics by which is meant any member of the class of physiologically acceptable acetanilide derivatives having anaesthetic activity, including the various known anaesthetically active 2-amino-N-phenyl-acetanilide derivatives and their pharmaceutically acceptable salts. Preferred acetanilide anaesthetics are 2-(diethylam1no)-N-(2,6-dimethylphenyl)-acetam1de (also known as Lidocaine), 2-(butylamino)-N*(2-chloro-6-methyl-phenyl)- 9 acetamide (also known as Hostacain) and 2-(2-d1ethylaminoacetamido)-m-toluic acid methyl ester (also known as Baycain). Commonly employed pharmaceutically acceptable salts of such acetanilide anaesthetics include e.g. their hydrochlorides. When present, component vi) is preferably present in an amount of from 1 to 2 % by weight based on the total weight of the composition.
Solutions, e.g. for injection, in accordance with the present invention suitably have a pH of from 4 to 6.
It will of course be appreciated that while solutions, e.g. as 10 described above, will generally be most convenient and preferred, the present Invention also includes other appropriate forms of composition comprising components i) and 11), such as lyophyllsed preparations e.g. for putting up in solution or other suitable liquid form, prior to administration. The compositions of the in15 vention may contain any further desired additives, e.g. carriers, diluents, stabilizing agents, preserving agents, colouring agents, and surfactants as known in the art.
Compositions of the invention are indicated for use for the prophylaxis of thrombosis, in particular for use In the prevention of post-operative thrombosis.
The advantageous properties of compositions of the invention as compared with compositions previously employed in the art may, for example, be demonstrated in clinical trials, e.g. employing the jbrinogen uptake test of K.H. Frey et al. [Med. Klin., tl - 10 70 (1975), pp. 1553-1558)], in which radiation from l!25_fibrlnogen, which is selectively concentrated in thrombotic material in leg veins, is measured externally in patients.
In this test, patients undergoing major surgery, for example to5 tai hip replacement, receive 100 uci of ll25-fibrinogen parenterally the day before surgery and their legs are scanned for 1^25 radiation each day for between 2 and 3 weeks thereafter. The fibrinogen injection is repeated 8 to 10 days after initial administration if the count rate remains low. A Logic 121 counter/ratemeter is used for recording radioactivity, counting being performed according to the technique of Kakkar et al. [Lancet, 1 (1970), p 540]. Deep vein thrombosis (DVT) is diagnosed if the count at any site differs by 20 X or more from those at an adjacent point on the same leg or the same position on the opposite leg, and if this difference persists or increases in the subsequent 24 hours.
In one such clinical trial subjects are divided into two groups. Group 1 receives 0.5 mg dlhydroergotamine methanesulfonate and 2,500 IU low molecular weight sodium heparinate (average molecu20 lar weight ca. 7,000 t 1,000) administered in the form of a stabilised solution i.v. lx dally. Group 2 receives 0.5 mg dihydroergotamine methanesulfonate and 5,000 IU whole sodium heparinate also administered In the form of a stabilised solution i.v. 2x daily. Results for group 1 receiving composition in accordance with the present invention are compared with those for group 2 receiving conventional therapy. Reduction of the incidence of DVP in both groups is found to be equivalent. -11Comparable results to those obtained In the above clinical trial with dally injection of a single dosage comprising 0.5 mg dihydroergotamine methane sulfonate and 2,500 IU low molecular weight sodium heparinate (7,000 ± 1,000) may also be obtained when the low molecular weight heparin dosage is reduced to 1,500 IU.
A suitable indicated daily dosage for the compositions of the invention, will accordingly be of the order of 1/3 of daily dosages employed using known compositions comprising whole heparin or a pharmaceutically acceptable salt thereof, with further reduction of the conventional heparin dosage, e.g. down to 1,500 IU dally being possible. Thus an indicated daily dosage for component 1) will be of the order of from ca. 0.2 to ca. 1.5 mg, e.g. ca. 0.5 mg and for component 11) ca. 1,000 to ca. 10,000 IU e.g. ca. 1,500 to ca. 5,000 IU. If desired the dally dosage may be administered in divided dosages e.g. 2 to 4x dally. Preferably however ft Is administered as a single dosage lx daily e.g in unit dosage form. Alternatively components i) and 11) may, if desired, be administered separately.
* Suitable unit dosage forms for the compositions of the Invention e.g. for stabilized injection solutions as hereinbefore described comprising e.g components 111), iv), v) and, optionally, vi), include Injection ampoules and throw-away syringes containing a pre-determined amount of the composition. Such unit dosage forms suitably contain from ca. 0.2 to ca. 1.5 mg, preferably ca. 0.5 mg, of component 1) and from ca. 1,000 (e.g. ca. 1,500), to ca. 10,000 IU, preferably ca. 1,500 IU (e.g. ca. 2,500), to ca. 5,000 IU of component 11). Most preferably they contain ca. 0.5 mg of component 1) and ca. 1,500, ca. 2,500 or ca. 5,000 IU of corn30 ponent 11). -12In addition to the foregoing the present invention also provides a process for the preparation of a pharmaceutical composition in accordance with the invention, which process comprises, bringing a component 1) Into intimate admixture with a component 11) for example, bringing a component 1) together with a component 11) Into solution In a pharmaceutically acceptable solvent medium. Where solutions are prepared comprising additional components iii), iv) and v) and, optionally, vi) as hereinbefore described, the process is suitably carried out by a step-wise procedure com10 prising 1) preparation of a solution of component i) and, optionally, component vi) in a solvent medium comprising component v); 2) preparation of a solution of component 11) and component 111) in a solvent medium comprising component lv); 3) combination of the solutions obtained via steps 1) and 2), and 4) optional addition of further component iv) and/or w).
For the preparation of solutions, the process of the invention Is preferably carried out with protective gassing, e.g. C02-gass1ng of the solutlon(s). If the pH of the obtained solution is outside the range pH 4 to 6, it is preferably adjusted to within this range, e.g. by the addition of an appropriate quantity of a pharmaceutically acceptable acid, e.g. a pharmaceutically acceptable organic acid. When a pharmaceutically acceptable acid addition salt is employed as component 1), added acid will preferably correspond to the salt form employed. Thus when component 1) is In methane sulfonate salt form, any adjustment of pH necessary will j -13preferably be effected by addition of methane sulfonic add.
The obtained composition may be put-up In unit dosage form as hereinbefore described, e.g. 1n the case of injectible solutions, by filling into ampoules after filtration, preferably with protective, e.g. CO2 gassing.
In a further aspect the present Invention also provides use of a component 1) as defined 1n any one of claims 1 to 12 and of a component ii) as defined in any one of claims 1 to 12 in the manufacture of a composition suitable for thrombosis prophylaxis, in particular to prevent occurrence of post-operative thrombosis.
Suitable dally dosages of components 1) and 11) for use In the above method are as hereinbefore described. Preferably components 1) and 11) are administered concomitantly in the form of a pharmaceutical composition as hereinbefore described.
In a yet further aspect the present invention also provides a pack or dispenser-device adapted for substantially concomitant presentation or administration of a component 1) as hereinbefore defined and of a component 11) as hereinbefore defined, said components 1) and 11) being contained in said pack or dispenser device apart. Conveniently the components 1) and 11) are each contained In the pack or dispenser device In unit dosage form, the quantities of components i) and 11) In each unit dosage being e.g. as hereinbefore described, I.e. with Individual dosage forms most preferably comprising ca. 0.5 mg of component 1) and 1*500, 2,500 or 5,000 1U of component 11). Preferably the pack or -14dispenser-device bears directions for the concomitant administration of a predetermined amount of each of components 1) and ID.
Suitable dispenser-devices in accordance with the present inven5 tion include multiple-, e.g. twln-chamberecl syringes In which components i) and ii) are contained in separate chambers thereof and which are adapted for concomitant or immediately consecutive administration of the contained components by Injection. Such multiple-chambered syringes are known In the art.
The following examples are illustrative of processes for the production of compositions in accordance with the present invention.. -15EXAMPLE 1 Processfor the production of low molecular weight sodium heparinates having an average molecular weight of from ca. 6,000 to ca. 9,000 1,000 g whole sodium heparinate having an average molecular weight of 15,000 are dissolved In 6.66 litres distilled water, the pH adjusted to 2.7 by the addition of ca. 145 ml 25 % HC1, and the whole passed through a 520 b 1/2 (0 320 mm) folded filter from the company Schleicher and Schiill. The obtained filtrate is pumped through a molecular filtration membrane having a nominal molecular weight exclusion limit of 10,000, (Pelllcon filtercasette: catalogue no. PT GC 00001 of the Millipore company) at room temperature and with the exclusion of light. The following conditions are employed: Entry pressure: Pressure at the residue Total through-flow: Residue flow: Filtrate flow: 3.2 x 105 pa. side: 1.2 χ 105 Pa. ca. 200 ml/min. ca. 196 ml/min. ca. 4 ml/min.
After pumping for 1 hour, the filtrate flow is lead into a separate container and collected. Filtration Is stopped after ca. 24 hours. The filtrate (ca. 1000 - 1200 ml) Is readjusted to the pH value of the original whole sodium heparinate solution (ca. pH 7) by the addition of ca. 3 ml 30 % aqueous NaOH. This solution is FRACTION I.
The residue Is adjusted to pH 3.5 by the addition of ca. 10 ml 30 X aqueous NaOH and re-filtered for ca. 24 hours under the same -16conditions as set forth the above. The filtrate (ca. 800 ml) is adjusted to the pH value of the original whole sodium heparinate solution (ca. pH 7) by the addition of aqueous NaOH. This solution is FRACTION II.
The residue is adjusted to pH 4.2 by the addition of ca. 60 ml 30 % aqueous NaOH and re-filtered for ca. 24 hours, again under the same conditions as set forth above. The filtrate (ca. 500 ml) is adjusted to the pH value of the original whole sodium heparinate solution (ca. pH 7). This solution is FRACTION III.
The three fractions are each separately further processed as follows: The sodium-heparinate Is first precipitated by the addition of I.lx the volume of acetone, the oily, viscous precipitate allowed to settle overnight and the solvent decanted off. The residue Is covered with ca. 3x the volume of methanol and the whole stirred thoroughly at ca. 1000 r.p.m. The sodium heparin subsequently precipitates as a whitish precipitate which is granulated in a mortar under methanol. The obtained suspension is filtered off and the residue dried at 60* at a pressure of ca. 200 Pa. In the event that the NaCl content is greater than 0.5 X re-precipitation in accordance with the same technique will be required.
The three fractions thus obtained have the following characteristics: FRACTION FRACTION FRACTION I II III ELEMENTARY ANALYSIS C 23.7 % 24.9 X 24.4 X H 3.3 X 3.1 X 3.2 X N 2.9 % 2.4 X 2.7 X 0 47.1 X 45.9 X 46.8 X S 11.7 It 11.9 X 11.6 X Na 12.3 X 11.8 X 11.3 X Activity (PTT-Test), based on WHO- Standard ΠΙ ca. 75-5 IU/mg ca. 80-5 IU/mg ca. 90¾ IU/mr Anti Xa-activity ca. 150-10 U/irg ca. 155-10 U/mg ca. 160-10 U/ m<3 Average mol · w^. ca. 6,000-1,000 ca. 8,000-1,000 ca. 9,000-1,000 NaCl content <0.5 X <0.5 X <0.5 X I -18EXAMPLE 2 Preparation of a 1,500 IU low molecular weight heparin/0.5 mg dlhydroergotamine injectible solution. 1) 18.4 kg propylene glycol and 1.84 kg anhydrous glycerol are poured into a 50 litre stirring vessel and the mixture stirred for 10 minutes with CO? gassing. 0.0286 kg dlhydroergotamine methane sulfonate and 0.426 kg lidocain hydrochloride are dissolved in the mixture with stirring and CO2 gassing over a period of a further 30 minutes. 2) 18.4 kg of water (suitable for injection) are poured into a litre stirring vessel and stirred for ca. 10 mins, with CO? gassing. 85.71 million IU ( ca. 1.7 to 2.5 kg) sodium heparlnate having an average molecular weight of 6,000 ± 1,000 and 0.114 kg of CaNa2 EOTA hexahydrate (commercially available under the name calciumtitriplex) are then dissolved in the water with stirring and CO2 gassing over a further 30 minutes. 3) The solution obtained via step 2) above Is added with stirring and CO2 gassing to the solution obtained via step 1).
The vessel in which solution 2) Is obtained is then washed out with 1 kg of water (suitable for Injection) and is also added to the step 1) solution. The combined solutions are stirred for a further 10 minutes with CO2 gassing. The pH of the solution is ca. 5.5. -194) The solution is made up to a weight of 42.810 kg (or 40 litres) by the addition of water (suitable for injection).
) The obtained solution is pre-filtered using a membranefilter (0.2 urn: Ultipor nm. Pall) and then passed via a sterilised pressure-filtration apparatus having.a membrane filter (0.2 um; Ultipor nm Pall) at 1.7 bar with COg directly into an ampoule-filling machine. The solution is filled In 0.8 ml dosages into 1 ml ampoules under sterile conditions. -20EXAMPLE 3 Preparation of injectible solutions comprising 0.5 mg dihydroergotamine and i) 2,500 and 5,000 IU low molecular weight heparin.
The procedure of example 2 1s repeated employing the same relative quantities of all Ingredients except that in a first run 1 and 2/3 and in a second run 3 and 1/3 the relative proportion of sodium heparinate (average molecular weight * 6,000 t 1,000) Is used.
EXAMPLE 4 Preparation of Injectible solutions comprising dihydroergotamine and low molecular weight heparin of average molecular weight « 1) 7,000 *1,000 and 11) 6,000 * 1,000.
The procedures of examples 2 and 3 are repeated but replacing the sodium heparinate of average molecular weight 6,000 * 1,000 with 1) sodium heparinate of average molecular weight 7,000 * 1,000 or 2) sodium heparinate of average molecular weight a 8,000 * 1,000. In each case the relative proportions of all ingredients remain the same as in example 2. The relative proportions of .sodium heparinate employed, are respectively ca. 3,000, ca. 5,000 and ca. 10,000 IU/lmg dihydroergotamine methane sulfonate.
Claims (24)
1. CLAIHS: 1. A pharmaceutical composition comprising 1) an hydrogenated ergot alkaloid having vaso-constrlctor activity, or pharmaceutically acceptable acid addition salt 5 thereof, and of average molecular weight of 10,000 or less, 11) a low molecular weight heparin far pharmaceutically acceptable salt thereof.
2. A composition according to claim 1 wherein component i) is a hydrogenated ergot alkaloid of formula I wherein R is hydrogen or Chalky!, R| is methyl, ethyl or iso-propyl, Rg is iso-propyl, sec.-butyl, iso-butyl or benzyl and X is hydrogen or methoxy, or a pharmaceutically acceptable acid addition salt thereof. -21
3. A composition according to claim 2, wherein component 1) Is dihydroergotanine or a pharmaceutically acceptable acid addition salt thereof, 3.
4. A composition according to claim 2, wherein component 1) Is 4. 5 6-nor-6-1so-propyl-9,10-d1 hydro-2'β-methyl -5' <-benzoergopeptine, or dlhydroergovallne, or a pharmaceutically acceptable acid addition salt thereof.
5. A composition according to any one of claims 1 to 4, wherein component 1) is the methane sulfonate, malelnate or tar10 trate of the anti-thrombotically active ergot alkaloid. 5.
6. A composition according to any one of claims 1 to 5, wherein component i) is dihydroergotamine methane sulphonate. 6.
7. A composition according to claim 6, wherein component ii) 15 has an average molecular weight of ca. 8,000 or less. 7.
8. A composition according to any one of claims 1 to 7, wherein component 11) has an average molecular weight of not less than ca. 4,000. 8.
9. A composition according to claim 8, wherein component ii) 20 has an average molecular weight of not less than ca. 5,000. 9.
10. A composition according to claim 9, wherein component 11) has an average molecular weight of not less than ca. 6,000. -22-
11. A composition according to any one of claims 1 to 10 wherein component ii) is the sodium salt of low molecular weight heparin.
12. 5 A composition according to any one of claims 1 to 10, wherein component ii) is the sodium, potassium or calcium salt of a low molecular weight heparin.
13. A composition according to any one of claims 1 to 12, wherein components 1) and 11) are present-in a ratio of 1 mg component 1):.300 to 70,000 IU component 11). 10
14. 1 A composition according to claim 13, wherein the ratio is 1 mg component i): 300 to 35,000 IU component 11).
15. A composition according to claim 14, wherein the ratio is 1 mg component 1): 1,000 to 20,000 IU component ii).
16. 15 A composition according to claim 15, wherein the ratio is 1 mg component 1): 1,000 to 10,000 IU component 11).
17. A composition according to any one of claims 1 to 16 in the form of a solution In a pharmaceutically acceptable solvent medium and additionally comprising 111) a pharmaceutically acceptable calcium or magnesium salt of EDTA. 20
18. A composition according to claim 17, wherein 111) is CaNa? EOTA. t -ty
19. A composition according to claim 17 or 18* wherein ill) is present In a range of from about 1 to about 50 mg based on an amount of about 5,000 IU of ill).
20. A composition according to claim 19, wherein the range Is from about 1 to about 25 mg.
21. A composition according to claim 20, wherein the range is from about 1 to about 10 mg.
22. A composition according to any one of claims 17 to 21, wherein.the solvent medium comprises: iv) water and v) a pharmaceutically acceptable mono- or poly-alcohol.
23. A composition according to claim 22, wherein component iv) is present in an amount of from 45 to 72 X based on the total volume of the composition. 10. 15
24. A composition according to claim 22 or 23, wherein component v) is present in an amount of from 28 to 55 £ based on the total volume of the composition. 26. A composition according to claim 25, wherein a) and b) are present in a ratio of from 1 : 6 to 10 parts of weight, or wherein c) and d) are present In a ratio of from 1 : 8 to 12 parts by weight. -2<27. A composition according to claim 26, wherein a) and b) are present In a ratio of from 1 : 8 parts by weight, or wherein c) and d) are present In a ratio of from 1 : 10 parts by weight. 5 28. A composition according to any one of claims 1 to 27, additionally comprising vi) a physiologically acceptable anaesthetic. 29. A composition according tp claim 28, wherein component vi) Is an acetanilide anaesthetic or a pharmaceutically accept10 able acid addition salt thereof. 30. A composition according to claim 28 or 29, wherein component vi) is present in an amount of from 1 to 2 X by weight based on the total weight of the composition. 31. A composition according to any one of claims 1 to 30 In 15 unit dosage form. 32. A composition according to claim 31 in ampoule form for Injection. 33. A composition according to claim 31 or 32 comprising from ca. 0.2 to ca. 1.5 mg of 1) and from ca. 1,000 to ca. 10,000 IU of 11). 34. A composition according to claim 33 comprising ca. 0.5 mg of 1) and from ca. 1,500 to ca. 5,000 IU of 11). - 26 10 35. A composition as defined in claim 1 containing 0.5 mg dihydroergotamine and 1500 IU low molecular weight heparin. 36. Use of a component i) as defined in any one of claims 1 to 12 and of component ii) as defined in any one of claims 1 to 12 in the manufacture of a composition suitable for thrombosis prophylaxis. 37. Use according to claim 36, wherein the composition is as defined in any one of claims 13 to 35. 38. Use according to claim 36, wherein component i) is in an amount such as to provide a daily dosage rate of from ca. 0.2 to ca. 1.5 mg and component ii) is in an amount such as to provide a daily dosage rate of from ca. 1,000 to ca. 10,000 IU. 39. Use according to claim 38, wherein component i) is in an amount such as to provide a daily dosage rate of ca. 0.5 mg and component ii) is in an amount such as to provide a daily dosage rate of ca. 1,500 to ca. 5,000 IU. 40. A pharmaceutical composition substantially as hereinbefore described by way of Example.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE3245695 | 1982-12-10 |
Publications (2)
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IE832896L IE832896L (en) | 1984-06-10 |
IE56366B1 true IE56366B1 (en) | 1991-07-03 |
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Application Number | Title | Priority Date | Filing Date |
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IE2896/83A IE56366B1 (en) | 1982-12-10 | 1983-12-09 | Pharmaceutical compositions comprising an hydrogenated ergot alkaloid and heparin |
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JP (1) | JPH0672101B2 (en) |
AT (1) | AT382514B (en) |
AU (1) | AU570658B2 (en) |
BE (1) | BE898356A (en) |
CA (1) | CA1224416A (en) |
CH (1) | CH656533A5 (en) |
CY (1) | CY1509A (en) |
DD (1) | DD215469B3 (en) |
DK (1) | DK162475C (en) |
FR (1) | FR2537435B1 (en) |
GB (1) | GB2131691B (en) |
GR (1) | GR79745B (en) |
HK (1) | HK23290A (en) |
HU (1) | HU190513B (en) |
IE (1) | IE56366B1 (en) |
IL (1) | IL70406A (en) |
IT (1) | IT1172368B (en) |
LU (1) | LU85127A1 (en) |
NL (1) | NL8304221A (en) |
NZ (1) | NZ206523A (en) |
PH (1) | PH23451A (en) |
PT (1) | PT77803B (en) |
SE (1) | SE468973B (en) |
SG (1) | SG53989G (en) |
ZA (1) | ZA839200B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3432661A1 (en) * | 1984-09-05 | 1986-03-06 | Albert Prof. Dr. 6907 Nußloch Landsberger | CARCINOM THERAPEUTIC |
EP0337327A1 (en) * | 1988-04-09 | 1989-10-18 | Bioiberica, S.A. | Process for the preparation of new oligosaccharide fractions by controlled chemical depolimerization of heparin |
IT1245761B (en) * | 1991-01-30 | 1994-10-14 | Alfa Wassermann Spa | PHARMACEUTICAL FORMULATIONS CONTAINING GLYCOSAMINOGLICANS ABSORBABLE ORALLY. |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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SE441142B (en) * | 1975-12-04 | 1985-09-16 | Sandoz Ag | PROCEDURE FOR PREPARING A THERAPEUTIC PREPARATION WITH ANTITHROMOBOTIC PROPERTIES |
DE2809618A1 (en) * | 1978-03-06 | 1979-09-20 | Sandoz Ag | NEW THERAPEUTIC PREPARATION AND METHOD FOR THE PRODUCTION THEREOF |
DE2554533C3 (en) * | 1975-12-04 | 1984-08-30 | Sandoz-Patent-Gmbh, 7850 Loerrach | Use of dihydroergotamine and heparin |
DE3020895A1 (en) * | 1979-06-12 | 1980-12-18 | Sandoz Ag | ERGOPEPTIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE ERGOPEPTIN DERIVATIVES |
DE2945636A1 (en) * | 1979-11-12 | 1981-05-21 | Sandoz-Patent-GmbH, 7850 Lörrach | STABLE SOLUTIONS OF HYDRATED ERGOTAL CALOIDS OR YOUR SALTS AND HEPARIN OR ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF |
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1983
- 1983-11-30 CH CH6407/83A patent/CH656533A5/en not_active IP Right Cessation
- 1983-12-02 BE BE1/10914A patent/BE898356A/en not_active IP Right Cessation
- 1983-12-02 FR FR8319446A patent/FR2537435B1/en not_active Expired
- 1983-12-06 PH PH29930A patent/PH23451A/en unknown
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- 1983-12-07 NL NL8304221A patent/NL8304221A/en not_active Application Discontinuation
- 1983-12-07 CY CY1509A patent/CY1509A/en unknown
- 1983-12-07 IT IT49456/83A patent/IT1172368B/en active
- 1983-12-07 GB GB08332653A patent/GB2131691B/en not_active Expired
- 1983-12-08 DK DK565783A patent/DK162475C/en active
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- 1983-12-08 AU AU22221/83A patent/AU570658B2/en not_active Ceased
- 1983-12-08 NZ NZ206523A patent/NZ206523A/en unknown
- 1983-12-08 HU HU834202A patent/HU190513B/en not_active IP Right Cessation
- 1983-12-08 SE SE8306792A patent/SE468973B/en unknown
- 1983-12-08 CA CA000442829A patent/CA1224416A/en not_active Expired
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- 1983-12-09 ZA ZA839200A patent/ZA839200B/en unknown
- 1983-12-09 JP JP58233457A patent/JPH0672101B2/en not_active Expired - Lifetime
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1989
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1990
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MM4A | Patent lapsed |