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United States Patent (19) (11) 4,357,330 Fleming, Jr

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United States Patent (19) (11) 4,357,330 Fleming, Jr United States Patent (19) (11) 4,357,330 Fleming, Jr. et al. 45) Nov. 2, 1982 54 PHARMACEUTICAL COMPOSITIONS OTHER PUBLICATIONS 75) Inventors: James S. Fleming, Jr., Manlius; Thrombosis Res. 15:373-388 (1979). Joseph P. Buyniski, Syracuse, both J. Lab. Clin. Med. 95 (2): 241-257 (1980). of N.Y. A. Scriatabine et al., Platelets & Thrombosis, Baltimore 73) Assignee: Bristol-Myers Company, New York, University Park Press, 1974, pp. 247-262. N.Y. British J. Eng. Path, 58:474-477 (1977). (21) Appl. No.: 288,639 Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-David M. Morse 22 Filed: Jul. 30, 1981 57 ABSTRACT (51) Int. Cl............................................. A61K 31/625 Supra-additive blood platelet antiaggregation activity is 52 U.S. Cl. ......- - - - - - - - as so as . see sea as so ess sess so so 424/232 observed with anagrelide in combination with those 58) Field of Search ........................................ 424/232 non-steroidal anti-inflammatory agents which are inhib 56) References Cited itors of platelet cyclooxygenase. The supra-additive effects of such combinations make possible new compo U.S. PATENT DOCUMENTS sitions and methods for both therapeutic and prophylac 4,080,447 3/1978 Amselem moir 424/230 tic treatment of thrombosis and other disorders associ FOREIGN PATENT DOCUMENTS ated with bloodplatelet aggregation. 239.0957 5/1978 France . 5 Claims, 6 Drawing Figures 4,357,330 1. 2 prostaglandin I2) with respect to ADP-or collagen PHARMACEUTICAL COMPOSITIONS induced aggregation. 3. Br. J. Exp. Path. 58: 474–477 (1977) discloses an in BACKGROUND OF THE INVENTION vivo supra-additive effect between acetylsalicylic acid 1. Field of the Invention and the antithrombotic agent SH 1117 with respect to This invention is directed toward improved methods ADP-induced aggregation. and compositions for inhibiting blood platelet aggrega 4. J. Lab. Clin. Med. 95(2): 241-257 (1980) discloses tion. that anagrelide potentiates the inhibitory effect of pros 2. Description of the Prior Art taglandin E1 on platelet function and the prostaglandin A number of non-steroidal anti-inflammatory agents 10 El-induced elevation of cylic 3',5'-adenosine mono such as acetylsalicylic acid (aspirin), zomepirac, ibu phosphate (cAMP) basic level. profen, naproxen, sulfinpyrazone, phenylbutazone and 5. U.S. Pat. No. 4,080,447 discloses the supra-additive interaction of acetylsalicylic acid and ticlopidine with indomethacin have been found to be inhibitors of blood respect to blood platelet antiaggregation activity. platelet aggregation. The presumed mechanism of ac 15 tion of such agents is inhibition of the blood platelet 6. U.S. Pat. No. 4,206,214 discloses that a combina cyclooxygenase enzyme which ultimately leads to inhi tion of dipyridamole and sulfinpyrazone exhibits a su bition of collagen-induced platelet aggregation. Aspirin pra-additive antithrombotic effect. 7. French Pat. No. 2,390,959 (Farmdoc 14511B/08) and sulfinpyrazone have been evaluated clinically for discloses inter alia the supra-additive antiaggregation the prevention of stroke and heart attack and aspirin has 20 been approved for prevention of transient cerebral isch activity of acetylsalicylic acid and dipyridamole. emic attacks and stroke. 8. Acta Univ. Carol. Med. Monogr. 72: 199-210 dis Anagrelide having the chemical name 6,7-dichloro closes in vitro supra-additive interaction with certain 1,5-dihydroimidazo2, 1-bduinazolin-2(3H)-one and the combinations of five drugs, i.e. metergoline, dipyrida structural formula mole, acetylsalicylic acid, nimergoline and 5-adenosyl 25 methionine. SUMMARY OF THE INVENTION It has now been found according to the present inven tion that supra-additive blood platelet antiaggregation 30 activity is observed with anagrelide in combination Cl with those non-steroidal anti-inflammatory agents Cl which are inhibitors of platelet cyclooxygenase. The supra-additive effects of such combinations demon has been recently reported to be a potent inhibitor of strated by both in vitro and in vivo tests make possible platelet aggregation induced by a variety of aggregating 35 new compositions and methods for both therapeutic agents. This potent activity has been observed in vitro and prophylactic treatment of thrombosis and other in platelet rich plasma, ex vivo following oral dosing in disorders associated with blood platelet aggregation. animals and in several in vivo animal models following oral administration. Anagrelide has also been shown to BRIEF DESCRIPTION OF THE DRAWINGS inhibit aggregation when administered orally to man FIG. 1 is an isobolographic analysis showing the (Circulation 62: III-277, 1980). Anagrelide appears to be supra-additive platelet antiaggregation activities of sev uniquely different from the non-steroidal anti-inflamma eral mixtures of anagrelide and acetylsalicylic acid. tory agents in that it produces a broad spectrum effect, FIG. 2 is an isobolographic analysis showing the i.e. it blocks not only collagen-induced release and ag 45 supra-additive platelet antiaggregation activities of sev gregation and the second wave of ADP (adenosine eral mixtures of anagrelide and ibuprofen. diphosphate)-induced aggregation but also the first FIG. 3 is an isobolographic analysis showing the phase of ADP-induced aggregation as well as aggrega supra-additive platelet antiaggregation activities of sev tion induced by thrombin, arachidonic acid and antigen eral mixtures of anagrelide and naproxen. antibody complex (Thrombosis Research 15: 373-388, 50 FIG. 4 is an isobolographic analysis showing the 1979). Recent studies indicate that anagrelide acts in supra-additive platelet antiaggregation activities of sev part by selective inhibition of blood platelet low Kn eral mixtures of anagrelide and Zomepirac. cyclic AMP (adenosine monophosphate) phosphodies FIG. 5 is an isobolographic analysis showing the terase (J. Lab. Clin. Med. 95(2): 241-257, 1980). supra-additive platelet antiaggregation activities of sev Certain blood platelet antiaggregation agents have 55 eral mixtures of anagrelide and sulfinpyrazone. been found to exhibit a supra-additive interaction when FIG. 6 shows the supra-additive interaction of combined. Representative of such supra-additive com anagrelide and acetylsalicylic acid on biolasar-induced binations are the following: thrombosis in the microcirculation of the rabbit ear 1. Platelets and Thrombosis, A. Scriabine and S. chamber. Sherry (Eds.), Baltimore, University Park Press, 1974, 60 pg. 247-262 at p. 256 discloses that a combination of DETAILED DESCRIPTION OF THE acetylsalicyclic acid and prostaglandin E1 exhibited INVENTION supra-additive interaction against both collagen-and In one aspect the present invention relates to a ADP-induced platelet aggregation. method for inhibiting blood platelet aggregation which 2. Fed. proc. 38(3):419 (1979) reports that supra-addi 65 comprises orally administering to a mammal in need of tive interaction is exhibited between combinations of such treatment, either simultaneously or sequentially, anagrelide and prostaglandin I2 and combinations of anagrelide and a non-steroidal anti-inflammatory agent anagrelide and prostaglandin I2-S (the 6,9-thia analog of capable of inhibiting blood platelet cyclooxygenase. 4,357,330 3 4. In another aspect the present invention relates to oral acid which along with its salts (including the sodium pharmaceutical compositions comprising, as active in salt which is preferred) is described in U.S. Pat. No. gredient, anagrelide and a non-steroidal anti-inflamma 3,904,682. Phenylbutazone is the generic name for 4 tory agent capable of inhibiting blood platelet cycloox butyl-1,2-diphenyl-3,5-pyrazolidinedione which is dis ygenase, said compositions providing an enhanced (su closed in U.S. Pat. No. 2,562,830. Ibuprofen is the ge pra-additive) inhibitory activity on blood piatelet aggre neric name for 2-(4-isobutylphenyl)-propionic acid gation. which is disclosed in U.S. Pat. No. 3,385,886. Zomepi We have surprisingly discovered that when anagre rac is the generic name for 5-(p-chlorobenzoyl)-1,4- lide and a non-steroidal anti-inflammatory agent capa dimethylpyrrole-2-acetic acid which along with its salts . ble of inhibiting blood platelet cyclooxygenase are ad 10 (including the sodium salt which is preferred) is dis ministered together to a mammal, most preferably a closed in U.S. Pat. No. 3,752,826. human patient, a strong supra-additive inhibitory activ In practicing the present invention, the anagrelide ity on blood platelet aggregation is produced, whereby and non-steroidal anti-inflammatory agent are prefera the antiaggregation effects of the combination are bly administered orally. In prepared solid oral dosage greater than the sum of the effects produced by each 15 forms, any of the usual pharmaceutical granulating component acting alone. This unexpected supra-addi agents, lubricants, binders, disintegrating agents, tive interaction makes possible extremely potent antiag starches, sugars or the like may be used to prepare such gregative activity for prophylactic and therapeutic dosage forms as tablets, capsules or powders. For liquid treatment of thrombosis and other disorders associated oral preparations, one may utilize water, glycols, oils, with platelet aggregation. Alternatively, the supra-addi 20 alcohols or the like, along with coloring agents, preser tive effect allows the dosage of anagrelide which would vatives, flavors or the like, to prepare solutions, elixers, normally be required for achievement of a certain
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