IE47791B1 - Stable solutions of hydrogenated ergopeptide alkaloids - Google Patents
Stable solutions of hydrogenated ergopeptide alkaloidsInfo
- Publication number
- IE47791B1 IE47791B1 IE1598/78A IE159878A IE47791B1 IE 47791 B1 IE47791 B1 IE 47791B1 IE 1598/78 A IE1598/78 A IE 1598/78A IE 159878 A IE159878 A IE 159878A IE 47791 B1 IE47791 B1 IE 47791B1
- Authority
- IE
- Ireland
- Prior art keywords
- solution
- component
- weight
- mixture
- water
- Prior art date
Links
- 229930013930 alkaloid Natural products 0.000 title claims description 6
- 239000000203 mixture Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 36
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- QHZUABXEBRGBLP-LKWYKXIFSA-N (6aR,9R,10aR)-N-[(2R,4R,9aS,9bR)-4-benzyl-9b-hydroxy-3,5-dioxo-2-propan-2-yl-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide (6aR,9R,10aR)-N-[(2R,4R,9aS,9bR)-9b-hydroxy-3,5-dioxo-2,4-di(propan-2-yl)-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide (6aR,10aR)-N-[(2S,4S,9bS)-9b-hydroxy-4-(2-methylpropyl)-3,5-dioxo-2-propan-2-yl-3a,4,7,8,9,9a-hexahydrofuro[3,2-g]indolizin-2-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide methanesulfonic acid Chemical compound 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)C4[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]2CC(CN(C)[C@@H]2C2)C(=O)N[C@@]3(C(=O)C4[C@@H](C(N5CCCC5[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(C21)=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 QHZUABXEBRGBLP-LKWYKXIFSA-N 0.000 claims description 6
- 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 description 6
- 229960004704 dihydroergotamine Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000003708 ampul Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 4
- 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 abstract description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 35
- 239000011877 solvent mixture Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 2
- 229950001817 alpha-ergocryptine Drugs 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- SEALOBQTUQIVGU-QNIJNHAOSA-N dihydroergocornine 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(C)C)=C3C2=CNC3=C1 SEALOBQTUQIVGU-QNIJNHAOSA-N 0.000 description 2
- 229960004290 dihydroergocornine Drugs 0.000 description 2
- 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 2
- 238000011049 filling Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010054880 Vascular insufficiency Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PBUNVLRHZGSROC-VTIMJTGVSA-N dihydro-alpha-ergocryptine 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)CC(C)C)C(C)C)=C3C2=CNC3=C1 PBUNVLRHZGSROC-VTIMJTGVSA-N 0.000 description 1
- 229960002032 dihydroergocryptine Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical group 0.000 description 1
- 208000023577 vascular insufficiency disease Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives of the formula I in which R represents hydrogen or alkyl having 1-4 carbon atoms with the exception of tert-butyl, R1 represents methyl, ethyl or isopropyl, R2 represents isopropyl, sec-butyl, isobutyl or benzyl and X represents hydrogen or methyl, and their pharmacologically acceptable salts in a mixture of pharmacologically acceptable alcohols or mixtures thereof and water having a dielectric constant of not more than 50, and process for the preparation of the stable solutions.
Description
This invention relates to stable solutions of hydrogenated ergopeptide alkaloids (ergot alkaloids) and salt forms thereof.
Solutions of such compounds in predominantly aqueous 5 media have the disadvantage that the concentration of the active species decreases on storage, because of various decomposition reactions. For this reason it is normal practice to pass inert gas through the solution during filling of the vessels in which the solution is to be sold, and to protect the contents from air, light and high temperatures.
It has now been found that the stability of hydrogenated ergot alkaloids in solution is a function of the dielectric constant of the solution, and that stable solutions can be obtained by the use of a solvent system comprising a mixture of water and one or more alcohols, said solutions having a dielectric constant between 30 and 46.
The present invention provides a stable solution comprising a) a hydrogenated ergopeptide alkaloid of formula X, in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl, is methyl, ethyl or isopropyl, R2 is isopropyl, sec-butyl, isobutyl or benzyl, and X is hydrogen or methoxy or a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof, b) a pharmacologically acceptable alcohol or mixture thereof, and c) water, said solution having a dielectric constant between 30 and 46.and the concentration of water in the solution being from 15 to 40s by weight.
Preferred compounds of formula I are those in which R is methyl, X is hydrogen and is isopropyl or methyl, provided that R^ is methyl only when R2 is benzyl.
Particular preferred compounds in which R is methyl and X is hydrogen are dihydro-a-ergocryptine (R^ = isopropyl R2 = isobutyl), dihydro-p-ergocryptine (R^ = isopropyl, R2 = ———' dihydroergocornine (r^ = = isopropyl), dihydroergocrlstine (R^ = isopropyl, R2 = benzyl) and dihydroergotamine (R^ = methyl, R2 = benzyl), together with their salt forms. Suitable salt forms are salts of pharmacologically acceptable acids, for example the methanesulfonate, maleate and tartrate salt forms.
Particularly preferred are dihydroergotamine (DHE) and a 1:1:1 molar mixture of dihydroergocryptine (2:1 α:β), dihydroergocornine and dihydroergocrlstine (dihydroergotoxin).
Pharmacologically acceptable alcohols include pharmacologically acceptable monofunctional alcohols having up to 18 carbon atoms, preferably up to 10 carbon atoms and most preferably up to 3 carbon atoms. An especially preferred alcohol of this type is ethanol. Further alcohols which may be used according to the invention include pharmacologically acceptable polyfunctional alcohols having up to 6, preferably 2 to 3 hydroxy groups, and up to S, preferably 2 or 3 carbon atoms, especially glycerol and propylene glycol. Polyfunctional alcohols may also be used in polymeric form, for example polyalkylene glycols, especially polyethylene glycol, polypropylene glycol or their copolymers, having a molecular weight from 200 to 20,000, preferably from 200 to 600. A particular suitable polyalcohol is a polyethylene glycol with a molecular weight of approximately 400.
The above mono- and polyfunctional alcohols may be used according to the invention either alone or, advantageously, in the form of mixtures. If one of the monoor polyfunctional alcohols should be a solid at romm temperature, an alcohol which is liquid at room temperature may suitably be used as a co-solvent.
When a mixture of monofunctional and polyfunctional alcohols is used, the monofunctional and the polyfunctional alcohols should be present in a ratio of from 1:0.1 to 1:100 by weight, preferably in a ratio of from 1:1 to 1:10, more preferably of from 1:1 to 1:4 by weight. A particularly preferred range of ratios is from 1:1 to 1:2, preferably 1:2 by weight. Mixtures of ethanol and propylene glycol or ethanol, propylene glycol and glycerol, are particularly i^referred.
The solutions according to the invention may further contain, as additional solvents, pharmacologically acceptable organic esters and ethers, particularly those formed from the above-mentioned mono- and polyfunctional alcohols and fatty acids having from 12-18 carbon atoms, for example stearic acid, palmitic acid and oleic acid; or fatty alcohols having from 12 to 18 carbon atoms, for example lauryl alcohol, cetyl alcohol and stearyl alcohol.
The dielectric constant of the solution may be measured by standard methods, for example with the help of an immersion condenser such as the model DFI 4 modified according to ASTM D 1531-595, sold by WissenschaftlichTechnische WerkstStten GmbH of Weilheim, W. Germany. Preferably, the dielectric constant of the solution lies between 34 and 46 .
The water content is limited by the requirement that the dielectric constant of the solution shall not be greater than 46 . Water has a dielectric constant of approximately 80 and alcohols generally in the range of approximately -40, and it is found that solutions having a mixture of water and one or more alcohols as solvent can generally contain not more than 40% by weight of water if the : dielectric constant is to be less than 4fi . The preferred ranges of dielectric constant given above may be obtained by regulating the water content? within the range of 15-40% water by weight.
Although the concentration of the compound of formula X in the solutions is not critical, it is preferred to use solutions with a concentration of active species of from 0.01 to 1% wt,/volume, preferably from 0.1 to 0.5% wt./volume. It is to be understood that the concentration to be used will depend upon the application for which the solution is intended.
The solutions may in addition contain further solubilising additives for example acids, particularly methanesulfonic acid, maleic acid and tartaric acid, but if such ionically dissociable additives are to be present, it is to be understood that the dielectric constant of the solution is to be measured in the absence of such additives.
The preparation of the compositions according to the invention is carried out by dissolving the compound of formula I in the solvent or solvent mixture by stirring at room temperature (15-25°C). This may be done under an atmosphere of inert gas and with exclusion of daylight, but these precautions are not essential in view of the improved stability of the solutions according to the ., 47791 invention. The solution may be filtered under pressure, preferably under inert gas pressure, and used to fill suitable vessels. It is not essential to carry out the filling operation under an inert gas atmosphere.
The preparation of solvent mixtures is carried out in conventional manner, and where one of the solvent components is solid at room temperature, mixing is suitably carried out at higher temperatures, e.g. at up to 80°C. Ethanol may advantageously be used as co-solvent.
Compositions according to the invention are useful as pharmaceuticals in the same way as corresponding aqueous solutions of the same active species. They may be administered orally, and may for this purpose be made up in vessels designed to dispense unit dosages, for example dropper bottles; or parenterally, in which case the solutions will normally be sterilized and may be sealed in ampoules of unit dosage. The compositions may also be administered in the form of nasal drops or nasal spray.
For oral administration, a preferred solvent mixture is an ethanol/propylene glycol or ethanol/propylene glycol/glycerol mixture as described above, containing from 15 to 40% by weight of water. Compositions containing 15% or more by weight of water have a more palatable taste for oral administration. For parenteral administration, it is undesirable to use solvent mixtures containing more than 5% of ethanol, and a pre7 4779 1 ferred solvent is propylene glycol containing from 15 to 40% by weight of water. The presence of 153 or more by weight of water lowers the viscosity of the solvent and thereby allows easier and less painful injection of the composition.
As is well known, dihydroergotoxin may, for example, be used in the treatment of conditions arising from cerebral vascular insufficiency and arteriosclerosis.
A recommended oral dosage is 1.5 ml of a 0.1% wt./vol.solution, three times daily. As is also well known, dihydroergotamine is indicated, for example, in the treatment of orthostatic hypotension and the prophylaxis of migraine, suitable oral dosages being 0.5-1.5 ml of a 0.2% wt./ vol. solution, to 3 times daily. Dihydroergotamine may also be ad15 ministered parenterally for the relief of acute migraine attacks, a suitable dose being one ampoule containing 1 ml of a 0.1% wt./vol.solution, administered 1-3 times as required at 30 minute intervals.
The following Examples illustrate the invention.
A) P£t;Liil£ation_o£_solyent_mixtures Solvent mixtures 1-3 were prepared by mixing together the quantities of solvents shown in the following table. The table also gives the water content in % by weight (taking into account the 6% water content of the 94% ethanol), and the measured dielectric constant. In all four mixtures, ethanol, glycerol and propylene glycol were present in 33:26:41 ratio by weight.
Mixture No. 1 2 3 Weights (g) ethanol (94%) 1051 1992 1728 glycerol 773 1464 1272 propylene glycol 1236 2344 2040 15 distilled water 686 2256 3056 Water content by wt. 20.05 29.5% 39.0% Dielectric constant 37.7 41.6 45.8 20 13} Preparation of solutions Example Ϊ: In 1 litre of solvent mixture 1 was dis solved 1.0 g of dihydroergotoxin methanesulfonate, by stirring at room temperature under a nitrogen atmosphere. After filtration under nitrogen pressure, the solution was used to fill dropper bottles. The dielectric constant of the mixture remained unchanged. 4779 1 EXAMPLE 2 : In 1 litre of solvent mixture 1, prepared under sterile conditions, was dissolved 2.0 g of dihydroergotamine methanesulfonate, by stirring at room temperature.
After filtration under nitrogen pressure, the solution was used to fill dropper bottles.
EXAMPLES 3-6 : Following the procedure of Examples 1 and 2, solutions were prepared using solvent mixtures 2-4 in place of solvent mixture 1.
EXAMPLE 7 : In 100 ml of a mixture of 80 parts by wt. sterile propylene glycol and 20 parts by wt. water for injection was dissolved, by stirring at room temperature, 0.1 g of dihydroergotamine methanesulfonate. After filtration under nitrogen pressure, the solution was sealed into sterile ampoules, each containing 1 ml of solution of dielectric constant 41.
EXAMPLE 8 ; .0 g of polyethylene glycol of molecular weight 400 was dissolved in a mixture of 40.0 g 94% ethanol and 23.0 g propylene glycol. 20.0 g water was added, to give 100 ml of solvent mixture of dielectric constant 38, in which was dissolved 0.1 g dihydroergotoxin methanesulfonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper hotties.
EXAMPLE 9.: 6.0 g of mixture of cetyl and stearyl alcohol was dissolved in 68.6 g 94¾ ethanol. 8.5 g water was added, to give 100 ml of solvent mixture of dielectric constant , in which was dissolved 0.1 g dihydroergotoxin methanesulfonate by stirring at room temperature. After filtration under nitrogen pressure, the solution was used to fill dropper bottles.
Claims (15)
1. A stable solution comprising a) a hydrogenated ergopeptide alkaloid of formula I, in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, otner than t-butyl, R^ is methyl, ethyl or isopropyl, R 2 is isotropyi 3ec -butyl, isobutyl or benzyl, and X is hydrogen or methoxy or a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof, b) a pharmacologically acceptable alcohol or mixture 15 thereof, and c) water, said solution having a dielectric constant between 30 and 46 and the concentration of water in the solution beinc from 15 to 40% by weight. 20
2. , A solution as claimed in Claim 1 having a dielectric constant between 34 and 46,
3. A solution as claimed in Claim 1 or Claim 2 in which component a) is a compound of formula I, stated in Claim 1, in which R is methyl X is hydrogen and R^ is isopropyl or methyl, provided that R^ is methyl only when R 2 is benzyl.
4. A solution as claimed in Claim 3 in which component a) is dihydroergotamine.
5. A solution as claimed in Claim 3 in which component a) is dihydroergotoxin.
6. A solution as claimed in any one of Claims 3,4 or 5 in which component a) is present in a concentration of from 0.01 to 1% weight/volume. 7 , A solution as claimed in any one of the preceding claims in which component b) is propylene glycol.
7. 8. A solution as claimed in any one of Claims 1 - 6 in which component b) is a mixture of bp a pharmacologically acceptable monofunctional alcohol having up to 18 carbon atoms, or mixtures thereof, and bp a polyfunctional alcohol having up to 6 carbon atoms and 6 hydroxy groups or a polymeric polyfunctional alcohol having a molecular weight of from 200 to 20,000, or mixtures thereof, the weight ratio of component bp to component bp being from 1:0.1 to 1:100. 4779 1
8. 9. A solution as claimed in Claim P in which component b^) has up to 3 carbon atoms. 19. A solution as claimed in Claim 8 or Claim 9 in which component b^) is a polyfunctional alcohol of 2 to 5 3 carbon atoms and 2 to 3 hydroxyl groups.
9. 11 . A solution as claimed in Claim 8 or Claim 9 in which component b^) is a polymeric polyfunctional alcohol having a molecular weight of 200 to 600.
10. 12. A solution as claimed in Claim 9 and Claim 10 10 in which component b^) is ethanol and component b 2 ) is propylene glycol or glycerol or mixtures thereof.
11. 13 . A solution as claimed in any one of Claims 812 in which the ratio of component b^) to component b 2 ) is from 1:1 to 1:10 by weight.
12. 15 14 . A solution as claimed in Claim 13 in which the said ratio is from 1:1 to 1:2 by weight. 15 . A stable solution of a hydrogenated ergopeptide alkaloid substantially as described in any one of the Examples .
13. 16 . A dropper bottle containing a solution as claimed in any one of the preceding claims.
14. 17 . A sterilised, sealed ampoule containing a solution as claimed in any one of Claims 1-15.
15. 18. A method of preparing a stable hydrogenated ergopeptide alkaloid solution as claimed in Claim 1 which comprises dissolving a compound of formula I, stated in Claim 1, or a pharmaceutically acceptable acid addition salt thereof or a mixture thereof in a solvent consisting essentially of: a) a pharmacologically acceptable alcohol or a mixture thereof, and b) water, at a temperature of 15 to 25°C, the water content of the solvent being regulated so that the prepared solution may have a dielectric constant between 30 and 46 and the concentration of water therein may be from 15 to 403 by weight.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772735587 DE2735587A1 (en) | 1977-08-06 | 1977-08-06 | STABLE SOLUTIONS AND METHOD FOR THEIR PRODUCTION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE781598L IE781598L (en) | 1979-02-06 |
| IE47791B1 true IE47791B1 (en) | 1984-06-27 |
Family
ID=6015843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1598/78A IE47791B1 (en) | 1977-08-06 | 1978-08-04 | Stable solutions of hydrogenated ergopeptide alkaloids |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS5428811A (en) |
| AT (1) | AT364463B (en) |
| AU (1) | AU525725B2 (en) |
| BE (1) | BE869560R (en) |
| CA (1) | CA1111348A (en) |
| CH (1) | CH635347A5 (en) |
| CS (1) | CS203199B2 (en) |
| DE (1) | DE2735587A1 (en) |
| DK (1) | DK337678A (en) |
| FI (1) | FI782341A (en) |
| FR (1) | FR2399248A2 (en) |
| GB (1) | GB1596948A (en) |
| GR (1) | GR72791B (en) |
| IE (1) | IE47791B1 (en) |
| IL (1) | IL55285A (en) |
| IT (1) | IT1202759B (en) |
| NL (1) | NL7808122A (en) |
| NO (1) | NO147901C (en) |
| NZ (1) | NZ188073A (en) |
| PT (1) | PT68386A (en) |
| SE (1) | SE444114B (en) |
| YU (1) | YU188378A (en) |
| ZA (1) | ZA784435B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2930369A1 (en) * | 1979-07-26 | 1981-02-05 | Rentschler Arzneimittel | MEDICINE SOLUTIONS |
| 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 |
| DE3227122A1 (en) * | 1982-07-20 | 1984-01-26 | Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim | STABLE SOLUTIONS OF MOTHER CORNAL CALOIDS |
| IT1200609B (en) * | 1985-04-04 | 1989-01-27 | Poli Ind Chimica Spa | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CEREBROVASCULAR TURBES AND THE ELDERLY BRAIN |
| GB8629781D0 (en) * | 1986-12-12 | 1987-01-21 | Glaxo Group Ltd | Pharmaceutical compositions |
| ATE269056T1 (en) | 1999-03-26 | 2004-07-15 | Pozen Inc | HIGHLY EFFECTIVE MEDICINAL COMPOSITIONS CONTAINING DIHYDROERGOTAMIN |
| DE102007014947B4 (en) | 2007-03-23 | 2010-05-27 | Axxonis Pharma Ag | Stabilized aqueous solutions of ergoline compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3749779A (en) * | 1970-08-27 | 1973-07-31 | American Home Prod | Stable solutions of sodium diphenylhydantoin |
-
1977
- 1977-08-06 DE DE19772735587 patent/DE2735587A1/en not_active Withdrawn
-
1978
- 1978-05-30 GB GB23758/78A patent/GB1596948A/en not_active Expired
- 1978-07-24 CH CH796478A patent/CH635347A5/en not_active IP Right Cessation
- 1978-07-27 FI FI782341A patent/FI782341A/en not_active Application Discontinuation
- 1978-07-28 SE SE7808210A patent/SE444114B/en unknown
- 1978-07-28 DK DK337678A patent/DK337678A/en not_active Application Discontinuation
- 1978-07-28 NO NO782605A patent/NO147901C/en unknown
- 1978-08-02 IT IT26407/78A patent/IT1202759B/en active
- 1978-08-02 NL NL787808122A patent/NL7808122A/en not_active Application Discontinuation
- 1978-08-03 YU YU01883/78A patent/YU188378A/en unknown
- 1978-08-04 IL IL55285A patent/IL55285A/en unknown
- 1978-08-04 AU AU38676/78A patent/AU525725B2/en not_active Expired
- 1978-08-04 CS CS785139A patent/CS203199B2/en unknown
- 1978-08-04 ZA ZA784435A patent/ZA784435B/en unknown
- 1978-08-04 IE IE1598/78A patent/IE47791B1/en unknown
- 1978-08-04 FR FR7823160A patent/FR2399248A2/en active Granted
- 1978-08-04 NZ NZ188073A patent/NZ188073A/en unknown
- 1978-08-04 PT PT68386A patent/PT68386A/en unknown
- 1978-08-04 GR GR56936A patent/GR72791B/el unknown
- 1978-08-04 BE BE78189738A patent/BE869560R/en not_active IP Right Cessation
- 1978-08-04 CA CA308,775A patent/CA1111348A/en not_active Expired
- 1978-08-04 AT AT0567378A patent/AT364463B/en not_active IP Right Cessation
- 1978-08-05 JP JP9576378A patent/JPS5428811A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ATA567378A (en) | 1981-03-15 |
| AT364463B (en) | 1981-10-27 |
| IE781598L (en) | 1979-02-06 |
| IL55285A0 (en) | 1978-10-31 |
| DK337678A (en) | 1979-02-07 |
| SE7808210L (en) | 1979-02-07 |
| IL55285A (en) | 1981-09-13 |
| NZ188073A (en) | 1980-12-19 |
| SE444114B (en) | 1986-03-24 |
| FR2399248B2 (en) | 1980-07-18 |
| FR2399248A2 (en) | 1979-03-02 |
| FI782341A (en) | 1979-02-07 |
| IT1202759B (en) | 1989-02-09 |
| CS203199B2 (en) | 1981-02-27 |
| YU188378A (en) | 1984-02-29 |
| CA1111348A (en) | 1981-10-27 |
| NL7808122A (en) | 1979-02-08 |
| DE2735587A1 (en) | 1979-02-15 |
| ZA784435B (en) | 1980-03-26 |
| NO782605L (en) | 1979-02-07 |
| JPS5428811A (en) | 1979-03-03 |
| CH635347A5 (en) | 1983-03-31 |
| GR72791B (en) | 1983-12-05 |
| AU525725B2 (en) | 1982-11-25 |
| NO147901C (en) | 1983-07-06 |
| IT7826407A0 (en) | 1978-08-02 |
| PT68386A (en) | 1978-09-01 |
| NO147901B (en) | 1983-03-28 |
| BE869560R (en) | 1979-02-05 |
| GB1596948A (en) | 1981-09-03 |
| AU3867678A (en) | 1980-02-07 |
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