IE43778B1 - Solid solutions of ergot alkaloids in polymers - Google Patents
Solid solutions of ergot alkaloids in polymersInfo
- Publication number
- IE43778B1 IE43778B1 IE2282/76A IE228276A IE43778B1 IE 43778 B1 IE43778 B1 IE 43778B1 IE 2282/76 A IE2282/76 A IE 2282/76A IE 228276 A IE228276 A IE 228276A IE 43778 B1 IE43778 B1 IE 43778B1
- Authority
- IE
- Ireland
- Prior art keywords
- composition
- polymer
- molecular weight
- solid
- weight
- Prior art date
Links
- 229920000642 polymer Polymers 0.000 title claims description 29
- 229960003133 ergot alkaloid Drugs 0.000 title claims description 17
- 239000006104 solid solution Substances 0.000 title claims description 17
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 11
- 239000003381 stabilizer Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 230000008020 evaporation Effects 0.000 claims description 6
- 229920001515 polyalkylene glycol Polymers 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 210000004051 gastric juice Anatomy 0.000 claims description 3
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000008180 pharmaceutical surfactant Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229920006324 polyoxymethylene Polymers 0.000 claims 1
- 230000000063 preceeding effect Effects 0.000 claims 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000011343 solid material Substances 0.000 abstract 2
- 229930015720 peptide alkaloid Natural products 0.000 abstract 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229960004704 dihydroergotamine Drugs 0.000 description 3
- 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 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- -1 methanesulphonic Chemical class 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 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
- 239000004150 EU approved colour Substances 0.000 description 1
- BGHDUTQZGWOQIA-VQSKNWBGSA-N Ergovaline Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)C(C)C)C)C2)=C3C2=CNC3=C1 BGHDUTQZGWOQIA-VQSKNWBGSA-N 0.000 description 1
- LFPHMXIOQBBTSS-UHFFFAOYSA-N Galetin Natural products C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 LFPHMXIOQBBTSS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 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
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- YDOTUXAWKBPQJW-UHFFFAOYSA-N alpha-Ergocryptinine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-UHFFFAOYSA-N 0.000 description 1
- YDOTUXAWKBPQJW-NSLWYYNWSA-N alpha-ergocryptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-NSLWYYNWSA-N 0.000 description 1
- 229950001817 alpha-ergocryptine Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine 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]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- BGHDUTQZGWOQIA-RKUMIMICSA-N ergovaline Natural products O=C(N[C@@]1(C)C(=O)N2[C@H](C(C)C)C(=O)N3[C@@H]([C@]2(O)O1)CCC3)[C@@H]1C=C2[C@H](N(C)C1)Cc1c3c([nH]c1)cccc23 BGHDUTQZGWOQIA-RKUMIMICSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 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
- A61K31/33—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a process for the preparation of a solid material composed of ergot peptide alkaloids, their hydrogenated forms or their salts and polyvinylpyrrolidone. The solid material obtained according to the invention can be used for the preparation of pharmaceutical compositions.
Description
This invention relates to new pharmaceutical compositions of ergot Ikaloids.
The invention provides pharmaceutical compositions comprising a solid olution of one or more ergot alkaloids in a pharmaceutically acceptable olid polymer which is soluble or swellable in gastric juices.
In the term ergot alkaloids is included naturally occuring ergot Ikaloids for example ergotamine, ergocryptine ergocrypine and rgocornine: their synthetic derivatives, for example ergovaline; their ydrogenated forms, for example dihydroergotamine, and the salts of any f these. Suitable salts are those derived from pharmaceutically acceptable cids, for example organic acids such as methanesulphonic, tartaric and aieic acids or inorganic acids such as hydrochloric acid.
Preferably the polymer is a polyalkylene glycol, polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate or a mixture of these, f mixtures of polymers are used, the proportion of different polymers n the mixture is not critical; preferably, however, equal quantities of no or three different polymers may be present. In the case of mixtures, ne or more of the polymers may be a liquid, for example a low molecular sight polyalkylene glycol, provided that the resulting mixture of Jlymers is a solid. 1 »*' 1., <· Tg Suitable polyalkylene glycols include polyethylene glycol and polypropylene glycol and their copolymers having a molecular weight of 200 to 20,000, preferably 4000 to 15,000, more preferably 6000 to 13,000.
By polyvinylpyrrolidone is meant uncrosslinked poly (N-vinyl)pyrrolidone, suitably of molecular weight between 10,000 and 100,000 preferably 11,500 to 40,000, more preferably 20,000 to 30,000. The copolymer of vinyl pyrrolidone and vinyl acetate preferably contains 60% by weight vinylpyrrolidone and 40% by weight vinyl acetate and preferably has a molecular weight of £30,000 to 100,000, more preferably 40,000 to 90,000.
IQ The solid solution of ergot alkaloid in polymer may also contain certain additional pharmaceutically acceptable ingredients, particularly surfactants such as sodium lauryl sulphate or polyethylene glycol fatty acid esters, preferably polyethylene glycol stearate; and stabilisers such as acids, preferably methanesulphonic acid, maleic acid and tartaric acid, to adjust the pH of the composition. The preferred pH range for the composition is pH 4-6, preferably pH 4-5.
In the solid solution, the proportion by weight of ergot alkaloid to solid polymer together with surfactant and/or stabilizer, if present, may lie between 0.1:99.9 and 50:50, preferably between 5:95 and 15:85. Where surfactants and/or stabilisers are present, the proportion stabilizer in the ergot alkaloid is suitably from 1:45 to 10:1.
The solid solution of the invention is a true solid solution of the ergot alkaloid in the polymer: that is, it consists of only one solid phase.
The invention also provides a process for the perparation of pharmaceutical compositions comprising the step of working up one or more ergot alkaloids into a solid solution in a pharmaceutically acceptable solid polymer which is soluble or swellable in gastric juices, preferably consisting of a polyalkylene glycol, polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, or a mixture of these. The solid solution may be used without further admixture, or may be compounded in known manner with one or more conventional pharmaceutically acceptable excipients, and optionally with additional active ingredients.
Preferably, the solid solution is obtained to dissolving the ergot 35 alkaloid, the polymer and optionally any surfactant and/or stabiliser in a common solvent and evaporating to dryness the clear solution so obtained. Suitable solvents include lower alcohols, having from 1 to 4 carbon atoms, 778 for example ethanol and methanol. The solids are suitably dissolved by stirring with the solvent at a temperature of from 30 to 70°C, preferably 40-60°C, and the solvent may be removed by evaporation under vacuum at the same temperature. In the preparation of the solution it is also possible to add only a part of the polymer and the surfactant and/or stabilizer, if any, and to add the remainder during the evaporation of the solvent. The resulting clear solution is left to solidify at room temperature (15-22°C) and the solid solution may then be ground to a fine powder and dried, suitably under vacuum at 30°C, to remove all traces of the solvent.
The solid solution may be used in the preparation of galenic forms such as tablets and capsules. For this purpose it may be compounded with conventional excipients for example binding agents, lubricants, fillers and disintegrants, as well as colouring agents, sweeteners and flavouring agents.
In the preparation of tablets calcium carbonate, sodium carbonate, lactose, starch and talc may be used as fillers: starch and alginic acid as granulating and disintegrating agents; starch and galetin as binding agents and magnesium stearate, stearic acid and talc as lubricants. Common pharmaceutical retarding agents such as waxes, fats, cellulose derivatives and other polymers may also be used. The tablets may be uncoated or coated in known manner.
In the preparation of soft gelatin capsules, the solid solution is compounded in known manner for example with a mixture of glycerol, sorbitol and water together with preservative and optionally colouring matter. For filling hard gelatin capsules, the solid solution may be used along or compounded in known manner with pharmaceutically acceptable diluents or carriers.
The pharmaceutical compositions according to the present invention have the advantageous property of giving increased absorption of the ergot alkaloids into the bloodstream of the recipient, thereby enchancing the known pharmacological properties of the ergot alkaloids.
The following Examples illustrate the invention: EXAMPLE 1 34.6 g Dihydroergotamine methane sulphonate, 195.4 g polyvinylpyrrolidone (av. mol. wt. 25,000) and 500 ml methanol are charged into a 41 round-bottomed flask, which is then attached to a 4377s EXAMPLE 1 rotary evaporator. The flask is rotated at a bath temperature of 60°C, until the flask contents reach 60°C, by which time a clear solution is obtained.
The bath temperature is maintained at 60°C and the pressure is reduced to approx, 250 Torr, Methanol is removed by evaporation until the residue has a syrupy consistency. The residue is decanted into an evaporating basin and left to solidify for two hours at room temperature. The solid residue is dried in a vacuum oven at 30°C, 1 Torr for 12 hours, ground to a find powder and dried again.
EXAMPLE 2 34.6 a Dihydroergotamine methanesulphonate, 193.2 g polyvinylpyrrolidone (av. mol. wt. 25,000) 2.26 g polyethylene glycol ¢1800) stearate and 500 g methanol are charged into a 41 round-bottomed flask. The procedure of Example 1 is repeated to obtain a dry powdered mixture.
EXAMPLE 3 Tablet Composition The following ingredients are compounded together in conventional manner and formed into tablets in a tabletting press: parts by weight Solid mixture of Example 1: 16 Lactose 104 corn starch 15 talc 12 cellulose powder 32 silicon dioxide 0 EXAMPLE 4 Composition for Soft Gelatin Capsules The following ingredients are compounded together in conventional manner and the mixture used to fill soft gelatin capsules: 7 8 EXAMPLE 4 parts by Solid mixture of Example 1: weight 16.3 Glycerol 9 Polyethylene glycol 400 74.7 EXAMPLE 5 Composition for Hard Gelatin Capsules The following ingredients are compounded together in conventional manner and the mixture used to fill hard gelatin capsules: parts by weight Solid mixture of Example 1: 16.3 Silicon dioxide 0.7 corn starch 13 lactose 65 EXAMPLE 6-8 Example 3-5 are repeated using the solid mixture of Example 2. 3 7 7 8
Claims (24)
1. A pharmaceutical composition comprising a solid solution of one or more ergot alkaloids, as herein defined, in a pharmaceutically acceptable solid polymer which is soluble or swellable in gastric juices, optionally together with a pharmaceutically acceptable surfactant and/or stabiliser, the proportion by weight of ergot alkaloid to solid polymer together with surfactant and/or stabiliser, if present, being from 0.1:99.9 to 50:5o said composition being capable of giving increased absorption of ergot alkaloid into the bloodstream of the recipient.
2. A composition as claimed in Claim 1 in which the polymer is a polyalkylene glycol, uncrosslinked poly(N-vinyl)pyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, or a mixture of these.
3. A composition as claimed in Claim 2 in which the polymer is polyethylene glycol, polymethylene glycol or a copolymer of these, having a molecular weight of 200 to 20.000.
4. A composition as claimed in Claim 3 in which the polymer has a molecular weight of from 4000 to 15,000.
5. A composition as claimed in Claim 4 in which the polymer has a molecular weight of from 6000 to 13,000.
6. A composition as claimed in Claim 2 in which the polymer is uncrosslinked poly(N-vinyl)pyrrolidone of molecular weight from 11,500 to 40,000.
7. A composition as claimed in Claim 6 in which the polymer has a molecular weight of from 20,000 to 30,000.
8. A composition as claimed in Claim 2 in which the polymer is a copolymer of vinylpyrrolidone and vinyl acetate, having a molecular weight of from 30,000 to 100,000.
9. A composition as claimed in Claim 8 which the polymer has a molecular weight of from 40,000 to 90,000.
10. A composition as claimed in any one of Claims 2, 8 or 9, in which the polymer is a copolymer of 60% by weight vinylpyrrolidone and 40% by weight vinyl acetate.
11. A composition as claimed in any one of the preceding claims in which the solid solution contains a pharmaceutically acceptable surfactant and/or stabiliser in addition to the ergot alkaloid and the solid polymer.
12. A composition as claimed in Claim 11 in which the proportion by 437 78 weight of the surfactant and/or stabiliser to the ergot alkaloid is from 1:45 to 10:1.
13. A composition as claimed in any one of the preceeding claims in which, in the solid solution, the proportion by weight of ergot alkalRid to solid polymer together with surfactant and/or stabiliser, if present, is from 5:95 to 15:85.
14. A composition as claimed in any one of the preceding claims comprising the solid solution in association with one or more conventional pharmaceutically acceptable excipients.
15. A composition as claimed in any one of the preceding claims, in the form of a tablet.
16. A composition as claimed in any one of Claims 1-14, in the form of a capsule.
17. A pharmaceutical composition substantially as described in any one of the Examples.
18. A process for the production of a pharmaceutical composition comprising the step of dissolving one or more ergot alkaloids and a pharmaceutically acceptable solid polymer selected from polyalkylene glycols, uncrosslinked po!y-(N-vinyl)pyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, or mixtures of these in a common solvent which is then removed by evaporation to give a solid solution of the ergot alkaloid in the polymer.
19. A process as claimed in Claim 18 in which the solvent is a lower alcohol having from 1-4 carbon atoms.
20. A process as claimed in Claim 19 in which the solvent is methanol.
21. A process as claimed in any one of Claims 18-20 in which the solution and evaporation steps are carried out at a temperature between 10 and 60°C.
22. A process as claimed in any one of Claims 18-21 in which the 'esidue from evaporation of the solvent is solidified, ground to a powder md dried.
23. A process as claimed in any one of Claims 18-22 in which the olid solution is compounded in known manner with one or more harmaceutically acceptable excipients and formed into tablets or apsules. 4 3 7 7 8
24. A pharmaceutical composition whenever produced by the process of any one of Claims 18-23.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2546577A DE2546577B2 (en) | 1975-10-17 | 1975-10-17 | Solid substances made from polyvinylpyrrolidone and ergot alkaloids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE43778L IE43778L (en) | 1977-04-17 |
| IE43778B1 true IE43778B1 (en) | 1981-05-20 |
Family
ID=5959411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2282/76A IE43778B1 (en) | 1975-10-17 | 1976-10-15 | Solid solutions of ergot alkaloids in polymers |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS5854122B2 (en) |
| AT (1) | AT362510B (en) |
| AU (1) | AU508628B2 (en) |
| BE (1) | BE847368A (en) |
| CA (1) | CA1079641A (en) |
| CH (1) | CH643737A5 (en) |
| CS (1) | CS199647B2 (en) |
| DE (1) | DE2546577B2 (en) |
| DK (1) | DK146194C (en) |
| ES (1) | ES452420A1 (en) |
| FI (1) | FI762875A (en) |
| FR (1) | FR2327764A1 (en) |
| GB (1) | GB1560406A (en) |
| GR (1) | GR61268B (en) |
| HK (1) | HK3183A (en) |
| HU (1) | HU172533B (en) |
| IE (1) | IE43778B1 (en) |
| IL (1) | IL50686A (en) |
| MY (1) | MY8400063A (en) |
| NL (1) | NL184558C (en) |
| NO (1) | NO144468C (en) |
| NZ (1) | NZ182341A (en) |
| PH (1) | PH14513A (en) |
| PT (1) | PT65719B (en) |
| SE (1) | SE430379B (en) |
| SG (1) | SG63082G (en) |
| SU (1) | SU1165223A3 (en) |
| ZA (1) | ZA766166B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1572226A (en) * | 1977-11-03 | 1980-07-30 | Hoechst Uk Ltd | Pharmaceutical preparations in solid unit dosage form |
| FI793888A (en) * | 1978-12-21 | 1980-06-22 | Sandoz Ag | GALENISKA BLANDNINGAR |
| US4411882A (en) | 1978-12-21 | 1983-10-25 | Sandoz Ltd. | Galenical compositions |
| FR2454804B1 (en) * | 1979-04-26 | 1986-11-21 | Sanofi Sa | DIHYDROERGOTOXIN-BASED MEDICINAL PRODUCT AND PROCESS FOR PREPARING THE SAME |
| US4366145A (en) * | 1981-06-24 | 1982-12-28 | Sandoz, Inc. | Soft gelatin capsule with a liquid ergot alkaloid center fill solution and method of preparation |
| US4898729A (en) * | 1983-12-09 | 1990-02-06 | Euroceltique, S.A. | Treatment of hypertension, compounds and compositions for antihypertension and diuresis |
| NL194389C (en) * | 1984-06-14 | 2002-03-04 | Novartis Ag | Process for preparing a solid dispersion of a pharmaceutically active agent that has low water solubility in a solid matrix of a water-soluble polyalkylene glycol as a carrier. |
| EP0277092B1 (en) * | 1987-01-14 | 1992-01-29 | Ciba-Geigy Ag | Therapeutic system for slightly soluble active ingredients |
| FR2610827B1 (en) * | 1987-02-18 | 1991-09-13 | Pf Medicament | DIHYDROERGOTAMINE (D.H.E.) TABLET OF THE HYDROPHILIC MATRIX TYPE AND MANUFACTURING METHOD THEREOF |
| US5064656A (en) * | 1989-11-14 | 1991-11-12 | Dr. Gergely & Co. | Uncoated pharmaceutical reaction tablet |
| DE4401646A1 (en) * | 1994-01-21 | 1995-07-27 | Krewel Werke Gmbh | Optimally releasing kava extracts |
| US6524832B1 (en) | 1994-02-04 | 2003-02-25 | Arch Development Corporation | DNA damaging agents in combination with tyrosine kinase inhibitors |
| ES2214757T3 (en) * | 1997-12-22 | 2004-09-16 | Schering Corporation | COMPOSITION OF MOLECULAR DISPERSION WITH IMPROVED BIODISPONIBILITY. |
| US6632455B2 (en) | 1997-12-22 | 2003-10-14 | Schering Corporation | Molecular dispersion composition with enhanced bioavailability |
| US6316462B1 (en) | 1999-04-09 | 2001-11-13 | Schering Corporation | Methods of inducing cancer cell death and tumor regression |
| PT1235574E (en) * | 1999-12-03 | 2005-05-31 | Polichem Sa | METHODS FOR PREPARING PHARMACEUTICAL COMPOSITIONS OF SUSTAINED LIBERTACAO OF DAILY ALCALOIDS HAVING AN IMPROVED BIODISPONIBILITY AND COMPOSITIONS SO OBTAINED |
| US7771746B2 (en) | 1999-12-03 | 2010-08-10 | Polichem Sa | Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof |
| US7135436B2 (en) | 2003-05-05 | 2006-11-14 | J.F. Daley International, Ltd. | Solid algicide, preparation and usage in recirculating water |
| US20060141038A1 (en) * | 2003-06-27 | 2006-06-29 | Bioprogress S. P. A. | Composite product obtainable by cogrinding of a active principle with a copolymer n-vinyl-2 pyrrolidone/vinyl-acetate |
| CA2987867C (en) | 2015-06-09 | 2023-06-27 | Capsugel Belgium Nv | Formulations to achieve rapid dissolution of drug from spray-dried dispersions in capsules |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1175430A (en) * | 1966-04-07 | 1969-12-23 | Sandoz Ltd | Pharmaceutical Compositions containing Ergot Alkaloids |
-
1975
- 1975-10-17 DE DE2546577A patent/DE2546577B2/en not_active Withdrawn
-
1976
- 1976-10-01 CH CH1244876A patent/CH643737A5/en not_active IP Right Cessation
- 1976-10-08 FI FI762875A patent/FI762875A/fi not_active Application Discontinuation
- 1976-10-08 SE SE7611189A patent/SE430379B/en not_active IP Right Cessation
- 1976-10-08 NO NO763446A patent/NO144468C/en unknown
- 1976-10-08 DK DK454176A patent/DK146194C/en not_active IP Right Cessation
- 1976-10-13 NL NLAANVRAGE7611295,A patent/NL184558C/en not_active IP Right Cessation
- 1976-10-14 PH PH19008A patent/PH14513A/en unknown
- 1976-10-14 CA CA263,423A patent/CA1079641A/en not_active Expired
- 1976-10-14 FR FR7630866A patent/FR2327764A1/en active Granted
- 1976-10-15 CS CS766685A patent/CS199647B2/en unknown
- 1976-10-15 ES ES452420A patent/ES452420A1/en not_active Expired
- 1976-10-15 AT AT767976A patent/AT362510B/en not_active IP Right Cessation
- 1976-10-15 GB GB42907/76A patent/GB1560406A/en not_active Expired
- 1976-10-15 NZ NZ182341A patent/NZ182341A/en unknown
- 1976-10-15 PT PT65719A patent/PT65719B/en unknown
- 1976-10-15 HU HU76SA00002985A patent/HU172533B/en not_active IP Right Cessation
- 1976-10-15 BE BE171578A patent/BE847368A/en not_active IP Right Cessation
- 1976-10-15 AU AU18754/76A patent/AU508628B2/en not_active Expired
- 1976-10-15 IE IE2282/76A patent/IE43778B1/en not_active IP Right Cessation
- 1976-10-15 SU SU762412401A patent/SU1165223A3/en active
- 1976-10-15 ZA ZA00766166A patent/ZA766166B/en unknown
- 1976-10-15 IL IL50686A patent/IL50686A/en unknown
- 1976-10-16 GR GR51952A patent/GR61268B/en unknown
- 1976-10-16 JP JP51123463A patent/JPS5854122B2/en not_active Expired
-
1982
- 1982-12-23 SG SG630/82A patent/SG63082G/en unknown
-
1983
- 1983-01-20 HK HK31/83A patent/HK3183A/en unknown
-
1984
- 1984-12-30 MY MY63/84A patent/MY8400063A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |