CA1079194A - Pharmaceutical composition for the prophylactic treatment of thrombosis - Google Patents
Pharmaceutical composition for the prophylactic treatment of thrombosisInfo
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- CA1079194A CA1079194A CA267,029A CA267029A CA1079194A CA 1079194 A CA1079194 A CA 1079194A CA 267029 A CA267029 A CA 267029A CA 1079194 A CA1079194 A CA 1079194A
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Abstract
PHARMACEUTICAL COMPOSITION FOR THE PROPHYLACTIC TREATMENT
OF THROMBOSIS
Abstract of the Disclosure The invention provides novel pharmaceutical compositions useful in the treatment of thrombosis in mammals, comprising a mixture of dihydroergotamine or a related ergot alkaloid and heparin.
OF THROMBOSIS
Abstract of the Disclosure The invention provides novel pharmaceutical compositions useful in the treatment of thrombosis in mammals, comprising a mixture of dihydroergotamine or a related ergot alkaloid and heparin.
Description
1~'7~19'~ 118-3346 OF THROMBOSIS
This invention relates to new pharmaceutical compositions containing compounds of formula I:
C-N~..., N
HN
in which R is hydrogen or alkyl having from 1 to 4 carbon atoms,other than t. butyl Rl is methyl, ethyl or isopropyl, R2 ls ~sopropyl, sec.- butyl, isobutyl or benzyl and X is hydrogen or methoxy.
The lnvention provides a pharmaceutical composition comprising a mixture of a compound of formula I and heparin~ in which the proportion of the compound of formula I (in mg.) to heparin is from 1:500 to 1:70,000, in association with a pharmacologically acceptable diluent or carrier.
By the terms "compounds of formula I~ and ~heparin~
are included pharmacologically acceptable salts of th`ese compounds~ A pharmacologically acceptable salt is one which does not have substantially higher toxicity than 1~'79~9~
This invention relates to new pharmaceutical compositions containing compounds of formula I:
C-N~..., N
HN
in which R is hydrogen or alkyl having from 1 to 4 carbon atoms,other than t. butyl Rl is methyl, ethyl or isopropyl, R2 ls ~sopropyl, sec.- butyl, isobutyl or benzyl and X is hydrogen or methoxy.
The lnvention provides a pharmaceutical composition comprising a mixture of a compound of formula I and heparin~ in which the proportion of the compound of formula I (in mg.) to heparin is from 1:500 to 1:70,000, in association with a pharmacologically acceptable diluent or carrier.
By the terms "compounds of formula I~ and ~heparin~
are included pharmacologically acceptable salts of th`ese compounds~ A pharmacologically acceptable salt is one which does not have substantially higher toxicity than 1~'79~9~
- 2 - 118-3346 the corresponding free acid or base. Examples of such salts are the methanesulfonate, maleate and tartrate salts of compounds of formula I, and the sodium, potassium and calcium salts of heparin.
Preferred compounds of formula I are dihydroergot-amine, in which R = methyl, Rl = methyl, R2 = benzyl and X = hydrogen; 6-nor-6-isopropyl-9,10-dihydro-2'~-methyl-5'~-benzylergopeptin and dihydroergovaline, especially dihydroergotamine.
Pharmacologically acceptable diluents and carriers include polymers for example polyvinyl pyrrolidone and or~3anic esters, particularly es,ers of C10 - C24 fatty acids, including natural plant oils.
The proportion of compound of formuia I (in mg) to h~parin (in international units, I.U.) is suitably 1:500 to 1:70,000, preferably 1:2000 to 1:20,000.
The invention also provides a process for the preparation of a pharmaceutical composition according ~o the invention, characterised by mixiny a compound of formula I and heparin together with a pharmaceutically acceptable diluent or carrier.
Preferred processes according to the inver.tion are:
a) working up a compound of formula I with a pharmaceutically acceptable polymer, prefera~ly 10'7919'~
~ 3 ~ 118-3346 polyvinylpyrrolidone, to obtain a solid material which is then mixed with heparin, b) suspending a compound of formula I together with heparin in a pharmaceutically acceptable organic liquid, preferably an organic ester, or c) freeze dr~ing, separately or together, a solution of a compound of formula I and a solution of heparin, and, if separately, mixing together the freeze-dried products.
Process a) is preferably carried out by mixing the compound of formula I t~gether with polyvinylpyrrolidone in the form of an uncrosslinked poly-N-vinyl-2-pyrrolidolle of average molecular ~eight fro~ 10,000 to 100,000, pre-ferably from 11,500 to 40,000, particularly 25,000, op~ionally together ~ith pharmacologic211y acceptable additives. Such additives may inc]ude surfactants, forexample polyethylene glycol fatty acid esters, particu-larly polyethylene glycol stearate, as well as stabilizing additives for example acids, particularly metharesulphonic acid, ma eic acid and tartaric acid, to mai~tain a pH
of less than 7, preferably 4-~. The proportion of compound of formula I in the total mixture together ~ith the optional additives, is suitably from 0.1 to 5~ preferabiy from 0.5 to 1.0~ by weight.
~' `
1~)'79~9~
The mixture is then worked up so as to obtain a dry homogeneous material, for example by dissolving in a suitable solvent, and evaporating the solution. Suitable solvents include alcohols having from 1 to 4 carbon atoms, for example methanol and ethanol. The mixture may suitably be dissolved at an elevated temperature, preferably from 30 to 80C, more preferably from 40 to 70C. After complete solution, the solvent may be evaporated under the above conditions of temp~rature; preferably initially under atmospheric pressure and finally under vacuum.
Optionally, only a part of the polyvinylpyrrolidone and/or the further additives may be added to the compound of formula I before the solution is pr~pared, and the addition of the remainder may take place during the evaporation s~age. ~e solid residue obtained by complete r~moval of the solvent and cooling to room tempera.ure ~15-25C) may be ground to a fine powder in conventional manner and dried for example in vacuo for 12 hour at 30C.
The dried product is then mixed with the corres-ponding quantity of heparin, to give a solid product which may be dissolved in sterile ~istilled wa'er to provide an injectable solution. Preferably this ir,jectable solution will be isotonic and buffered to a physiologically acceptable pH. In order to accomplish this, the solid product is preferably mixed with sodium chloride and/or sodium hydrogen phosphate in guantity sufficient to give 1~79~9~
~ 5 ~ 118-3346 an isotonic solution of pH 7-7.5 when dissolved in the volume of water required to give the desired concen-tration of active ingredients.
Process b) may be carried out by suspending the compound of formula I together with heparin in an organic ester, suitably isopropyl myristate, isopropyl palmitate, ethyl oleate, olive oil, peanut oil, sesame oil and other cor~on plant oils, or mixtures of these.
For a mixture of from 0.1 to 2 mg compound of formula I and 1000 to 70no I.~. heparin, a quantity of from 0.3 to 10 ml of organic ester may be used. Preferably a mixture of 0.5 mg dihydroergota~.ine methanesulfonate and 5000 I.U. sodium heparin is suspended in 1 ml isopropyl Inyristate. The suspension is preferably pre-pared by stirring st room temperature tlS-25DC).
In process c) the solvent used in the solutions to be freeze-dried is preferably water and freeze-drying is carried out in conventional manner. The process may be carried out by freeze drying an aqueous soluticn of a compound of formula I, preferably in the form of an acid addition salt, and mixing the finely dispersed dried product with the product of freeze-drying an a~ueous solution of heparin, preferably in al~ali metal salt form.
Alternatively and preferably, a common solution containing both heparin ~nd a compo~nd of formula I may be prepared and freeze-dried to give an intimate mixture of tne active co~ponents. ~ further preferred procedure r~ ~
1~ .
~,.
10'7~9~
is to prepare the two solutions separatel~, to to pass them alternately into the freeze-drying apparatus so that alternate thin layers of compound of foxmula I and of heparin are built up on the collecting surface. The product is then collected and homogenised.
The solid mixture may then be dissolved in sterile distilled water to provide an injectable solution. As described above under process a), the solid mixture pre-ferahly contains salts such as sodium chloride and/or sodium phosphate so that the resulting injec~able solution will be i~otonic ~nd buffered to a physiological pH value.
The mixtuxe may also conta~n other a~juvant~, for ~xar~le polyvinyl pyrrolidone. Such salts ard other adiuvants .,ay be incorporated by mixing with the freeze-dried soljd product lS or, preferably, by dissolving in the solution or solutions prior to free7e drying.
The pllarmaceutical composi~ions according to the invention have surprisingly good ar.';ithromhotic proper-ties, as shown by the ~1 5 _ fibrinogen uptake test of K.H. Frey et al (Med. Klin. 70 (1~75) pp 1553-155~), in which radiation from I125 - fibrinogen, which is selec-tively concentrated in thrombotic material in leg vein~, is measured externally in human patients.
In this test, patients under~oing major surgery, for example total hip replacement, receive 100 ~ci of I - fihrino~en parenterally the ~ay before surgery and their legs are scanned for I125 radlation each day for 1~'79191~
between 2 and 3 weeks thereafter. The fibrinogen injection is repeated after 8-10 days 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 1970, 1, 540). neep vein thrombosis (~VT) is diagnosed if the counts at any site differ by 20~ or ~ore from those at an adjacent point on the same leg or the same position on the opposite ley, and if this difference persists or increasos in the subsequent 24 hours. The incidence or DVT in patients receiving prophylaxis by administration of a compound of formula I in conjunction with heparin is compared with that of control groups receiving heparin prophylaxis or no propllylaxis.
The compositions are therefore indicated for anti-thrombo1ic use, particularly in prophy]axis of post-operative thrombosis in mammals. A suitable indicated daily dosage is from 0.2 to 4 mg f preferably from 0.5 to 2 mg compound of formula I and from 2000 to 14,000 I.U., preferably from 4000 to 10,000 I.U. heparin. This daily dosage may suitably be administered in divided dosages of from 0.5 to 2 mg, preferably 0.125 to 1 mg compound of formula I and from 500 to 7,000 I.U., preferably from 1000 to 5000 I.U. heparin, t~lO to fcur times daily.
Particularly preferred is a mixture of 0.5 mg dihvdro-ergotamine methanQsulfonate and 50Q0 I.U. sodium heparin, administered thrice daily.
1~ 791~ 118-334G
The active ingredients may also be admini.stered separate].y, and may be supplied for this purpose in separate containers in the same package (twin-pack) with instructions for concomitant administration.
The compositions themselves, or galenic preparati.ons thereof such as sterile injectable solutions, may suitabl.y be packaged in unit dosaye forms, for example ampules of sterile injectable suspension containing a unit dosage of the active ingredients.
The following Examples illustrate the invent.ion;
~07919'~
g EY~ ~LE 1: Dry mixture to make up injectable solution Dihydroergotamine methanesulfonate (4.0 g) and 476 g polyvinyl pyrrolidone (average MW 25,00Q) is added to 1600 ml methanol in a 4 1 flask. The flask is connected to a rotary evaporator, and rotated in a bath at 60~C until the flask contents reach approximately 60C.
A clear solution is obtzined.
The solvent is then evaporated under reduced pressure (ca. 250 Torr) at a bath temperature of 60C, until the residue in the flask has a syrupy consistency.
The residue is transferred to an evaporating dish and left to starld for two hours at room temperature. The solid residue is dried in a vacuum oven at 30C, ca. 1 Torr for 12 hours, then milled and redried.
Tl~e dried residue (480 g) is then mixed under aseptic conditions with a quantity of sodium heparin corresponding to 40,000,000 I.U., 8 g disodium hydrogen phosphate di-hydrate and 72 g sodium chloride, specially purified. The mixture is then made up in bottles of unit dosage sealed with a pierceable septum, each bott~e conta~ning 105 mg of the dry mixture, comprising 0.5 mg dihydroergotamine methanesulfonate and 5000 I.U. sodium heparin.
In use, the septum is pierced by the needle of a syringe containing 1 ml of sterile distilled ~ater whîch is injected into the hottle. When the solid miY~ture 1~'7~19'~
has dissolved, the solution is withdrawn into the ss~ringe and administered parenterally.
EXAMPLE 2: Suspension -Dihydroer~otamine methanesulfonate (0.5 g) and a quant.ty of sodi~ heparin corresponding to 5,000,000 I.U.
are dispersed in 1 1 OL sterile filtered isopropyl myristate by stirxing under aseptic conditions. Ampoules of 1 ml capacity are then filled with the suspension.
EXAM~LE 3: Freeze dried mixture to make ~ in~ectahle solut_on a) A quantity of sodium heparin coxres~onding to 5,000,000 I.U., together with disodium hydrogen phosphate (1 g) and sodiurn chloride (9 g) is dissolved in 50Q ml of water suitable for injection.
b) Dihydroergotamine methanesulphonate (0.5 y~ an~
polyvinylpyrxolidone (59.5 g) are dissolved in 500 ml of water suitabLe for injection.
c) The solutions prepared ~ccording to a) and b) are mixed togetller ar.d sterile filtered. The filtrate is used to fi11 ampoules undex sterile conditions, each ampoule containing 1 ml of the con~i~led solution. The unsealed am~oules are then sub,ecte~d to freeze drying until all the water is removed. Finally the ampoules are sealed with a pierceable septum as in Example 1.
lO'Z~9~ 118-3346 E,Y~IPLES 4, 5, 6:
Examples 1, 2 and 3 are repeated using in place of dihydroergotamine methanesulfonate an equivalent quan~
tity of 6-nor-6-isopropyl-9,10-dihydro-2'~-methyl-5--benzylergopeptin methanesulfonate.
EX~P~ES 7, 8, 9:
Examples 1, 2 and 3 are repeated using instead of dihydroergotamine methanesulfonate an e~uivalent quantity of dihydroergovaline methanesulfonate.
9i9~
SUPPLEMENTARY DISCLOS~RÉ
A particularly useful composition according to the invention is one in wh~ch the ratio of compound of formula I
(in mg) to heparin (in I.U.) is 1:5000. By the use of such a composltion, preferably ~n unit dosage form containing 0.5 mg of compound of formula I (preferably dihydroergo-tamine) and 2500 I.U. heparin, administered 2 to 4 times daily, the advantageous antithrombotic properties are retained while side effects attrlbutable to hepar~n are reduced.
~ he preferred diluent or carrier is uncrosslin~ed poly-N-vlnyl-2-pyrrolldone havlng an average molecular welght of from 2000 to l00,000, preferably 2000 to 40,000.
All ratios glven above are calculated on the basls that the compound of formula I i5 ln free base form.
The followlng Examples are part of the Supplementary Disclosure:
10'79~9~
., .
EXAMP~E l~ Drv mlxture to ma~e up ln~ectable solutlon Dlhydroergotamlne methanesulfonate ~4.6 g, corres-pondlng to 4.0 g free base) and 476 g polyvlnyl pyrrolldone (average MW 2000) is added to 1600 ml mèthanol ln a 4 1 fla~k.
~he flask i8 connected to a rotary evaporator, and rotated ln a bath st 60C untll the flask contents reach approxlmately 60C. A clear ~olutlon 18 obtalned.
The solvent 18 then evaporated under reduced pre~sure (ca. 250 Torr) at a bath temperature of 60C, untll the re~ldue ln the fla~k ha~ ~ ~yrupy consl~tency. The resldue 1~ tran~ferred to an evaporatlng dlsh and left to stand for two hours at room temperature. The solld re~ldue 19 drled ln a vacuum oven at 30C, ca. 1 Torr for 12 hours, then milled and redrled.
The drled r~sldue (480 g) 1~ then mlxed under a~eptlc condltlons wlth a quantity of sodlum heparln correspondlng to 20,000,000 I.U., 8 g dl~odlum hydrogen phosphate dihydrate and 72 g sodlum chlorlde, speclally purlfled. The mlxture 1~ then made up ln bottles of unlt dosage ~ealed wlth a plerceable septum, each bottle contalnlng 90 mg of the dry mlxture, compr~slng 0.5 mg dlhydroergotamlne (as methane-~ulfonate) and 2500 I.U. ~odlum heparln.
In u~e, the septum 18 plerced by the needle o~ a ~yr~nqo cont~lnlng 1 ml of ~terlle dl~tllled water whlch 19 ln~ected lnto the bottle. When the solld mlxture has dls~olved, the ~olution 18 withdrawn lnto the syr~nge and admlnlstered parenterally.
1079~94 EXAMPLE 11: SusE~ension Dihydroergotamine methanesulfonate (0.57 mg. corres-ponding to 0.5 mg free base) and a quantity of sodium heparin corresponding to 2,500,000 I.U. are dispersed in 1 1 of sterile filtered isopropyl myristate by stirring under aseptic conditions. Ampoules of 1 ml capacity are then filled with the suspension.
EXAMPLE 12: Freeze dried mixture to make up injectable solution a~ A quantity of sodium heparin corresponding to 2,500,000 I.~., together with disodium hydrogen phospate (1 g) and sodium chloride (9 g) is dissolved in 500 ml of water suitable for injection.
b) Dihydroergotamine methanesulfonate (0.57 g,corres-ponding to 0.5 g free base) and polyvinylpyrrolidone (59.5g) are dissolved in 500 ml of water suitable for injection.
c) The solutlons prepared according to a) and b) are mixed together and sterile filtered. The filtrate is used to fill ampoules under sterile conditions, each ampoule contain-ing 1 ml of the combined solution. The unsealed ampoules are then subjected to freeze drying until all the water is removed. Finally the ampoules are sealed with a pierceable septum as in Example 10.
EXAMPLE 13, 14 15:
Examples 10, 11 and 12 are repeated using in place of dihydroergotamine methanesulfonate an equivalent quantity of 6-nor-6-isopropyl-9,10-dihydro-2' -methyl-5-a-benzylergo-peptin methanesulfonate.
107919~
EXAMPLES 16, 17, 18:
Examples 10, 11 and 12 are repeated using instead of dihydroergotamine methanesulfonate an equivalent quantity of dihydroergovaline methanesulfonate.
Preferred compounds of formula I are dihydroergot-amine, in which R = methyl, Rl = methyl, R2 = benzyl and X = hydrogen; 6-nor-6-isopropyl-9,10-dihydro-2'~-methyl-5'~-benzylergopeptin and dihydroergovaline, especially dihydroergotamine.
Pharmacologically acceptable diluents and carriers include polymers for example polyvinyl pyrrolidone and or~3anic esters, particularly es,ers of C10 - C24 fatty acids, including natural plant oils.
The proportion of compound of formuia I (in mg) to h~parin (in international units, I.U.) is suitably 1:500 to 1:70,000, preferably 1:2000 to 1:20,000.
The invention also provides a process for the preparation of a pharmaceutical composition according ~o the invention, characterised by mixiny a compound of formula I and heparin together with a pharmaceutically acceptable diluent or carrier.
Preferred processes according to the inver.tion are:
a) working up a compound of formula I with a pharmaceutically acceptable polymer, prefera~ly 10'7919'~
~ 3 ~ 118-3346 polyvinylpyrrolidone, to obtain a solid material which is then mixed with heparin, b) suspending a compound of formula I together with heparin in a pharmaceutically acceptable organic liquid, preferably an organic ester, or c) freeze dr~ing, separately or together, a solution of a compound of formula I and a solution of heparin, and, if separately, mixing together the freeze-dried products.
Process a) is preferably carried out by mixing the compound of formula I t~gether with polyvinylpyrrolidone in the form of an uncrosslinked poly-N-vinyl-2-pyrrolidolle of average molecular ~eight fro~ 10,000 to 100,000, pre-ferably from 11,500 to 40,000, particularly 25,000, op~ionally together ~ith pharmacologic211y acceptable additives. Such additives may inc]ude surfactants, forexample polyethylene glycol fatty acid esters, particu-larly polyethylene glycol stearate, as well as stabilizing additives for example acids, particularly metharesulphonic acid, ma eic acid and tartaric acid, to mai~tain a pH
of less than 7, preferably 4-~. The proportion of compound of formula I in the total mixture together ~ith the optional additives, is suitably from 0.1 to 5~ preferabiy from 0.5 to 1.0~ by weight.
~' `
1~)'79~9~
The mixture is then worked up so as to obtain a dry homogeneous material, for example by dissolving in a suitable solvent, and evaporating the solution. Suitable solvents include alcohols having from 1 to 4 carbon atoms, for example methanol and ethanol. The mixture may suitably be dissolved at an elevated temperature, preferably from 30 to 80C, more preferably from 40 to 70C. After complete solution, the solvent may be evaporated under the above conditions of temp~rature; preferably initially under atmospheric pressure and finally under vacuum.
Optionally, only a part of the polyvinylpyrrolidone and/or the further additives may be added to the compound of formula I before the solution is pr~pared, and the addition of the remainder may take place during the evaporation s~age. ~e solid residue obtained by complete r~moval of the solvent and cooling to room tempera.ure ~15-25C) may be ground to a fine powder in conventional manner and dried for example in vacuo for 12 hour at 30C.
The dried product is then mixed with the corres-ponding quantity of heparin, to give a solid product which may be dissolved in sterile ~istilled wa'er to provide an injectable solution. Preferably this ir,jectable solution will be isotonic and buffered to a physiologically acceptable pH. In order to accomplish this, the solid product is preferably mixed with sodium chloride and/or sodium hydrogen phosphate in guantity sufficient to give 1~79~9~
~ 5 ~ 118-3346 an isotonic solution of pH 7-7.5 when dissolved in the volume of water required to give the desired concen-tration of active ingredients.
Process b) may be carried out by suspending the compound of formula I together with heparin in an organic ester, suitably isopropyl myristate, isopropyl palmitate, ethyl oleate, olive oil, peanut oil, sesame oil and other cor~on plant oils, or mixtures of these.
For a mixture of from 0.1 to 2 mg compound of formula I and 1000 to 70no I.~. heparin, a quantity of from 0.3 to 10 ml of organic ester may be used. Preferably a mixture of 0.5 mg dihydroergota~.ine methanesulfonate and 5000 I.U. sodium heparin is suspended in 1 ml isopropyl Inyristate. The suspension is preferably pre-pared by stirring st room temperature tlS-25DC).
In process c) the solvent used in the solutions to be freeze-dried is preferably water and freeze-drying is carried out in conventional manner. The process may be carried out by freeze drying an aqueous soluticn of a compound of formula I, preferably in the form of an acid addition salt, and mixing the finely dispersed dried product with the product of freeze-drying an a~ueous solution of heparin, preferably in al~ali metal salt form.
Alternatively and preferably, a common solution containing both heparin ~nd a compo~nd of formula I may be prepared and freeze-dried to give an intimate mixture of tne active co~ponents. ~ further preferred procedure r~ ~
1~ .
~,.
10'7~9~
is to prepare the two solutions separatel~, to to pass them alternately into the freeze-drying apparatus so that alternate thin layers of compound of foxmula I and of heparin are built up on the collecting surface. The product is then collected and homogenised.
The solid mixture may then be dissolved in sterile distilled water to provide an injectable solution. As described above under process a), the solid mixture pre-ferahly contains salts such as sodium chloride and/or sodium phosphate so that the resulting injec~able solution will be i~otonic ~nd buffered to a physiological pH value.
The mixtuxe may also conta~n other a~juvant~, for ~xar~le polyvinyl pyrrolidone. Such salts ard other adiuvants .,ay be incorporated by mixing with the freeze-dried soljd product lS or, preferably, by dissolving in the solution or solutions prior to free7e drying.
The pllarmaceutical composi~ions according to the invention have surprisingly good ar.';ithromhotic proper-ties, as shown by the ~1 5 _ fibrinogen uptake test of K.H. Frey et al (Med. Klin. 70 (1~75) pp 1553-155~), in which radiation from I125 - fibrinogen, which is selec-tively concentrated in thrombotic material in leg vein~, is measured externally in human patients.
In this test, patients under~oing major surgery, for example total hip replacement, receive 100 ~ci of I - fihrino~en parenterally the ~ay before surgery and their legs are scanned for I125 radlation each day for 1~'79191~
between 2 and 3 weeks thereafter. The fibrinogen injection is repeated after 8-10 days 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 1970, 1, 540). neep vein thrombosis (~VT) is diagnosed if the counts at any site differ by 20~ or ~ore from those at an adjacent point on the same leg or the same position on the opposite ley, and if this difference persists or increasos in the subsequent 24 hours. The incidence or DVT in patients receiving prophylaxis by administration of a compound of formula I in conjunction with heparin is compared with that of control groups receiving heparin prophylaxis or no propllylaxis.
The compositions are therefore indicated for anti-thrombo1ic use, particularly in prophy]axis of post-operative thrombosis in mammals. A suitable indicated daily dosage is from 0.2 to 4 mg f preferably from 0.5 to 2 mg compound of formula I and from 2000 to 14,000 I.U., preferably from 4000 to 10,000 I.U. heparin. This daily dosage may suitably be administered in divided dosages of from 0.5 to 2 mg, preferably 0.125 to 1 mg compound of formula I and from 500 to 7,000 I.U., preferably from 1000 to 5000 I.U. heparin, t~lO to fcur times daily.
Particularly preferred is a mixture of 0.5 mg dihvdro-ergotamine methanQsulfonate and 50Q0 I.U. sodium heparin, administered thrice daily.
1~ 791~ 118-334G
The active ingredients may also be admini.stered separate].y, and may be supplied for this purpose in separate containers in the same package (twin-pack) with instructions for concomitant administration.
The compositions themselves, or galenic preparati.ons thereof such as sterile injectable solutions, may suitabl.y be packaged in unit dosaye forms, for example ampules of sterile injectable suspension containing a unit dosage of the active ingredients.
The following Examples illustrate the invent.ion;
~07919'~
g EY~ ~LE 1: Dry mixture to make up injectable solution Dihydroergotamine methanesulfonate (4.0 g) and 476 g polyvinyl pyrrolidone (average MW 25,00Q) is added to 1600 ml methanol in a 4 1 flask. The flask is connected to a rotary evaporator, and rotated in a bath at 60~C until the flask contents reach approximately 60C.
A clear solution is obtzined.
The solvent is then evaporated under reduced pressure (ca. 250 Torr) at a bath temperature of 60C, until the residue in the flask has a syrupy consistency.
The residue is transferred to an evaporating dish and left to starld for two hours at room temperature. The solid residue is dried in a vacuum oven at 30C, ca. 1 Torr for 12 hours, then milled and redried.
Tl~e dried residue (480 g) is then mixed under aseptic conditions with a quantity of sodium heparin corresponding to 40,000,000 I.U., 8 g disodium hydrogen phosphate di-hydrate and 72 g sodium chloride, specially purified. The mixture is then made up in bottles of unit dosage sealed with a pierceable septum, each bott~e conta~ning 105 mg of the dry mixture, comprising 0.5 mg dihydroergotamine methanesulfonate and 5000 I.U. sodium heparin.
In use, the septum is pierced by the needle of a syringe containing 1 ml of sterile distilled ~ater whîch is injected into the hottle. When the solid miY~ture 1~'7~19'~
has dissolved, the solution is withdrawn into the ss~ringe and administered parenterally.
EXAMPLE 2: Suspension -Dihydroer~otamine methanesulfonate (0.5 g) and a quant.ty of sodi~ heparin corresponding to 5,000,000 I.U.
are dispersed in 1 1 OL sterile filtered isopropyl myristate by stirxing under aseptic conditions. Ampoules of 1 ml capacity are then filled with the suspension.
EXAM~LE 3: Freeze dried mixture to make ~ in~ectahle solut_on a) A quantity of sodium heparin coxres~onding to 5,000,000 I.U., together with disodium hydrogen phosphate (1 g) and sodiurn chloride (9 g) is dissolved in 50Q ml of water suitable for injection.
b) Dihydroergotamine methanesulphonate (0.5 y~ an~
polyvinylpyrxolidone (59.5 g) are dissolved in 500 ml of water suitabLe for injection.
c) The solutions prepared ~ccording to a) and b) are mixed togetller ar.d sterile filtered. The filtrate is used to fi11 ampoules undex sterile conditions, each ampoule containing 1 ml of the con~i~led solution. The unsealed am~oules are then sub,ecte~d to freeze drying until all the water is removed. Finally the ampoules are sealed with a pierceable septum as in Example 1.
lO'Z~9~ 118-3346 E,Y~IPLES 4, 5, 6:
Examples 1, 2 and 3 are repeated using in place of dihydroergotamine methanesulfonate an equivalent quan~
tity of 6-nor-6-isopropyl-9,10-dihydro-2'~-methyl-5--benzylergopeptin methanesulfonate.
EX~P~ES 7, 8, 9:
Examples 1, 2 and 3 are repeated using instead of dihydroergotamine methanesulfonate an e~uivalent quantity of dihydroergovaline methanesulfonate.
9i9~
SUPPLEMENTARY DISCLOS~RÉ
A particularly useful composition according to the invention is one in wh~ch the ratio of compound of formula I
(in mg) to heparin (in I.U.) is 1:5000. By the use of such a composltion, preferably ~n unit dosage form containing 0.5 mg of compound of formula I (preferably dihydroergo-tamine) and 2500 I.U. heparin, administered 2 to 4 times daily, the advantageous antithrombotic properties are retained while side effects attrlbutable to hepar~n are reduced.
~ he preferred diluent or carrier is uncrosslin~ed poly-N-vlnyl-2-pyrrolldone havlng an average molecular welght of from 2000 to l00,000, preferably 2000 to 40,000.
All ratios glven above are calculated on the basls that the compound of formula I i5 ln free base form.
The followlng Examples are part of the Supplementary Disclosure:
10'79~9~
., .
EXAMP~E l~ Drv mlxture to ma~e up ln~ectable solutlon Dlhydroergotamlne methanesulfonate ~4.6 g, corres-pondlng to 4.0 g free base) and 476 g polyvlnyl pyrrolldone (average MW 2000) is added to 1600 ml mèthanol ln a 4 1 fla~k.
~he flask i8 connected to a rotary evaporator, and rotated ln a bath st 60C untll the flask contents reach approxlmately 60C. A clear ~olutlon 18 obtalned.
The solvent 18 then evaporated under reduced pre~sure (ca. 250 Torr) at a bath temperature of 60C, untll the re~ldue ln the fla~k ha~ ~ ~yrupy consl~tency. The resldue 1~ tran~ferred to an evaporatlng dlsh and left to stand for two hours at room temperature. The solld re~ldue 19 drled ln a vacuum oven at 30C, ca. 1 Torr for 12 hours, then milled and redrled.
The drled r~sldue (480 g) 1~ then mlxed under a~eptlc condltlons wlth a quantity of sodlum heparln correspondlng to 20,000,000 I.U., 8 g dl~odlum hydrogen phosphate dihydrate and 72 g sodlum chlorlde, speclally purlfled. The mlxture 1~ then made up ln bottles of unlt dosage ~ealed wlth a plerceable septum, each bottle contalnlng 90 mg of the dry mlxture, compr~slng 0.5 mg dlhydroergotamlne (as methane-~ulfonate) and 2500 I.U. ~odlum heparln.
In u~e, the septum 18 plerced by the needle o~ a ~yr~nqo cont~lnlng 1 ml of ~terlle dl~tllled water whlch 19 ln~ected lnto the bottle. When the solld mlxture has dls~olved, the ~olution 18 withdrawn lnto the syr~nge and admlnlstered parenterally.
1079~94 EXAMPLE 11: SusE~ension Dihydroergotamine methanesulfonate (0.57 mg. corres-ponding to 0.5 mg free base) and a quantity of sodium heparin corresponding to 2,500,000 I.U. are dispersed in 1 1 of sterile filtered isopropyl myristate by stirring under aseptic conditions. Ampoules of 1 ml capacity are then filled with the suspension.
EXAMPLE 12: Freeze dried mixture to make up injectable solution a~ A quantity of sodium heparin corresponding to 2,500,000 I.~., together with disodium hydrogen phospate (1 g) and sodium chloride (9 g) is dissolved in 500 ml of water suitable for injection.
b) Dihydroergotamine methanesulfonate (0.57 g,corres-ponding to 0.5 g free base) and polyvinylpyrrolidone (59.5g) are dissolved in 500 ml of water suitable for injection.
c) The solutlons prepared according to a) and b) are mixed together and sterile filtered. The filtrate is used to fill ampoules under sterile conditions, each ampoule contain-ing 1 ml of the combined solution. The unsealed ampoules are then subjected to freeze drying until all the water is removed. Finally the ampoules are sealed with a pierceable septum as in Example 10.
EXAMPLE 13, 14 15:
Examples 10, 11 and 12 are repeated using in place of dihydroergotamine methanesulfonate an equivalent quantity of 6-nor-6-isopropyl-9,10-dihydro-2' -methyl-5-a-benzylergo-peptin methanesulfonate.
107919~
EXAMPLES 16, 17, 18:
Examples 10, 11 and 12 are repeated using instead of dihydroergotamine methanesulfonate an equivalent quantity of dihydroergovaline methanesulfonate.
Claims (23)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition comprising a mixture of a compound of formula I
I
in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl R1 is methyl, ethyl or isopropyl, R2 is isopropyl, sec.- butyl, isobutyl or benzyl, and X is hydrogen or methoxy, and heparin, in which the proportion of the compound of formula I
(in mg.) to heparin (in international units) is from 1:500 to 1:70,000, in association with a pharmaceutically acceptable diluent or carrier.
I
in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, other than t-butyl R1 is methyl, ethyl or isopropyl, R2 is isopropyl, sec.- butyl, isobutyl or benzyl, and X is hydrogen or methoxy, and heparin, in which the proportion of the compound of formula I
(in mg.) to heparin (in international units) is from 1:500 to 1:70,000, in association with a pharmaceutically acceptable diluent or carrier.
2. A pharmaceutical composition according to Claim 1, in which the compound of formula I is dihydroergotamine.
3. A pharmaceutical composition according to Claim 1 in which the said proportion is from 1:2000 to 1:20,000.
4. A pharmaceutical composition according to Claim 1 in which the pharmacologically acceptable diluent or carrier is uncrosslinked poly-N-vinyl-2-pyrrolidone of average molecular weight from 10,000 to 100,000.
5. A pharmaceutical composition according to Claim 4 in which the polyvinylpyrrolidone has an average molecular weight of from 11,500 to 40,000.
6. A pharmaceutical composition according to Claim 4 in which the proportion of compound of formula I to polyvinyl-pyrrolidone is from 0.1% to 5% by weight.
7. A pharmaceutical composition according to Claim 6 in which the said proportion is from 0.5% to 1.0% by weight.
8. A pharmaceutical composition according to Claim 4 in the form of a solid mixture containing sodium chloride and/or sodium phosphate.
9. A pharmaceutical composition according to Claim 1 in which the pharmacologically acceptable diluent or carrier is an organic ester.
10. A pharmaceutical composition according to Claim 9 in which the organic ester is isopropyl myristate.
11. A pharmaceutical composition according to Claim 9 which contains from 0.1 to 2 mg of compound of formula I and 1000 to 7000 I.U. of heparin in from 0.3 to 10 ml of organic ester.
12. A pharmaceutical composition according to Claim 9 in the form of a sterile injectable suspension.
13. A pharmaceutical composition according to Claim 1, containing a mixture of freeze-dried compound of formula I
and freeze-dried heparin.
and freeze-dried heparin.
14. A pharmaceutical composition according to Claim 13, in the form of a solid mixture containing sodium chloride and/or sodium phosphate.
15. A pharmaceutical composition according to Claim 1 in which the parmacologically acceptable diluent or carrier comprises water.
16. A pharmaceutical composition according to Claim 15 in the form of a sterile injectable solution.
17. A pharmaceutical composition according to Claim 1 in unit dosage form, containing from 0.05 to 2 mg of compound of formula I and from 500 to 7,000 I.U. heparin per unit.
18. A pharmaceutical composition in unit dosage form according to Claim 17, containing from 0.125 to 1 mg of compound of formula I and from 1000 to 5000 I.U. heparin per unit.
19. A method for the preparation of a pharmaceutical composition according to Claim 4, characterised by dissolving a compound of formula I together with polyvinylpyrrolidone in a solvent which is evaporated to give a solid material which is then mixed with heparin.
Claims Supported by Supplementary Disclosure
Claims Supported by Supplementary Disclosure
20. A pharmaceutical composition as claimed in claim 1 in which the proportion of compound of formula I (in mg.) to heparin (in International Units) is 1:5000.
21. A pharmaceutical composition as claimed in claim 20 in which the compound of formula I is dihydroergotamine.
22. A pharmaceutical composition as claimed in claim 20 in which the pharmaceutically acceptable diluent or carrier is poly-N-vinyl-2-pyrrolidone having an average molecular weight of from 2000 to 100,000.
23. A pharmaceutical composition as claimed in any one of claims 20, 21 or 22 in unit dosage form containing 0.5 mg of the compound of formula I and 2500 I.U. heparin per unit.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2554533A DE2554533C3 (en) | 1975-12-04 | 1975-12-04 | Use of dihydroergotamine and heparin |
| DE19762625403 DE2625403A1 (en) | 1976-06-05 | 1976-06-05 | Antithrombotic association of medicaments - contains heparin and an ergoline-(8)-carboxylic acid peptidic amide esp. dihydroergotamine opt. with polyvinyl pyrrolidone |
| DE19782809618 DE2809618A1 (en) | 1978-03-06 | 1978-03-06 | NEW THERAPEUTIC PREPARATION AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1079194A true CA1079194A (en) | 1980-06-10 |
Family
ID=27186649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA267,029A Expired CA1079194A (en) | 1975-12-04 | 1976-12-02 | Pharmaceutical composition for the prophylactic treatment of thrombosis |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1079194A (en) |
-
1976
- 1976-12-02 CA CA267,029A patent/CA1079194A/en not_active Expired
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