CN101146537A - Therapeutic agent for thrombosis - Google Patents

Abstract

Disclosed is a therapeutic agent for thrombosis, particularly a therapeutic agent for thrombosis effective with respect to both blood coagulation inhibition and thrombolysis. A therapeutic agent for thrombosis comprising a pitavastatin and aspirin.

Description

Therapeutic agent for thrombosis

Technical field

The present invention relates to a kind of therapeutic agent for thrombosis, particularly a kind of no matter to suppressing blood coagulation still to all effective therapeutic agent for thrombosis of thrombus.

Background technology

In thrombosis, because the reduction effect or the combined effect separately of the raising of the blood coagulation function that platelet aggregation hyperfunctioning, thrombin activation cause and thromboembolism function, form thrombosis in arteries or in the vein blood vessel, poor circulation takes place thereupon.The ischemia that the result causes makes the oxygen in the tip tissue that comprises brain, heart and other internal organs and the minimizings such as supply of nutrition, very easily causes the disease incidence of fatal symptoms such as cerebral infarction, myocardial infarction.Therefore, think that in the illness in above-mentioned field, the treatment of thrombosis is extremely important.

Now, in the treatment of thrombosis, use various medicaments.Treatment mainly concentrates on the anti-platelet agents that aspirin, ticlopidine, eicosapentaenoic acid (EPA), dipyridamole, hydrochloric acid dilazep etc. is suppressed platelet aggregation, and the anticoagulant of factor anticoagulant such as warfarin, heparin, Low molecular heparin, argatroban etc. carries out separately or merges administration.

Anti-platelet agents such as aspirin are by suppressing hematoblastic coagulation function, and reducing with the platelet aggregation is the focus that the caused blood of inducement continues to solidify, and the damage location that is suppressed at blood vessel forms thrombosis and blood clot.On the other hand, because platelet has the function that prevents from angiorrbagia simultaneously, will reduce and physiologically prevent hemorrhage function so excessively suppress hematoblastic coagulation function, thereby as a rule, when using anti-platelet agents treatment thrombosis, be difficult to guarantee sufficient dosage.

And anti-platelet agents such as aspirin do not show the effect of direct resisting blood coagulation, therefore as a rule, only use anti-platelet agents that the thrombosis patient is difficult to produce sufficient anti thrombotic action.In addition, known when using aspirin, heavy dose of administration of aspirin will produce aspirin side effect (Aspirin Dilemma).Promptly; know; the generation that suppresses physiological digestive tube mucous membrane protection material because of aspirin causes serious the intestines and stomach damage; bring out the damage of blood circulation because of suppressing physiological generation with material of vasorelaxation action; therefore, do not recommend to increase the method for aspirin dosage.Also be the reason in view of this respect, the aspirin that is difficult to thrombosis is treated needed abundant amount carries out administration.On the other hand, the administration of anticoagulant high dose also may bring the hemorrhage side effect of Denging, so as a rule, the anticoagulant that is difficult to thrombosis is treated needed abundant amount carries out administration.Therefore, in thrombosis treatment, under many circumstances, it is useful that anti-platelet agents such as an amount of aspirin and an amount of anticoagulant are merged administration.

Yet, though these situations all can still have the problem that increases bleeding tendency in different separately dosages by the formation of the anti-tampon of different separately mechanism.

As a kind of new therapeutic agent for thrombosis, the therapeutic agent for thrombosis of the merging administration of a kind of HMG-CoA of employing reductase inhibitor and aspirin is disclosed in patent documentation 1.Known HMG-CoA reductase inhibitor has the effect of very strong inhibition HMG-CoA reductase, and as the medicament that reduces cholesterol in the blood of great use, but it does not but get the nod as therapeutic agent for thrombosis.In addition, in above-mentioned communique, the action effect that does not have this merging administration of concrete record to produce, its degree is also not clear.And, also not about the record of the action effect that produces as the merging administration of the Pitavastatin class (patent documentation 2,3) of one of HMG-CoA reductase inhibitor and aspirin.

Patent documentation 1: the international pamphlet that discloses No. 98/11896

Patent documentation 2: No. 5856336 communique of United States Patent (USP)

Patent documentation 3: Japanese patent laid-open 1-279866 communique

Summary of the invention

Therefore, the object of the present invention is to provide a kind of few side effects and blood coagulation suppress and thromboembolism two aspect all effective therapeutic agent for thrombosis.

The present inventor has In view of the foregoing carried out deep research, discovery is under the situation that is used in combination Pitavastatin class and aspirin, than merging the situation of using other HMG-CoA reductase inhibitor and aspirin, can obtain significantly excellent blood coagulation inhibitory action and thromboembolism facilitation, treatment to thrombosis is very effective, thereby has finished the present invention.

That is, the invention provides a kind of therapeutic agent for thrombosis, it is characterized in that containing Pitavastatin class and aspirin.

In addition, the invention provides a kind of Pitavastatin class and the aspirin using method in making therapeutic agent for thrombosis.

The present invention also provides a kind of Therapeutic Method of thrombosis, it is characterized in that, Pitavastatin class and aspirin are merged administration.

The effect of invention

Use therapeutic agent for thrombosis of the present invention, by the resisting blood coagulation effect of excellence and the dual function of thromboembolism facilitation, demonstrate the anti thrombotic action when obviously being better than merging the HMG-CoA reductase inhibitor that uses other and aspirin, for hypertension, vasospasm, arteriosclerosis, diabetes, surgical operation, blood stasis etc. independent or concurrent with the treatment of thrombosis effective.In addition, the merging administration of Pitavastatin class and aspirin demonstrates very strong anti thrombotic action than aspirin is individually dosed, therefore, not only can avoid high dose aspirin administration, but also can reduce the side effect that aspirin self has by the common dosage that reduces aspirin with side effect.

Description of drawings

The figure of whole blood clotting time (r+k value) the prolongation effect (resisting blood coagulation effect) of thromboelastograph (thromboelastograph) mensuration that Fig. 1 is produced for the merging administration of expression by Pitavastatin Calcium (representing with Pitavastatin) and aspirin.

Fig. 2 forms the sketch map that ability (MA) suppresses effect (thromboembolism facilitation) for the maximum blood clot that the merging administration of representing Pitavastatin Calcium (representing with Pitavastatin) and aspirin is produced.

The specific embodiment

Employed Pitavastatin class comprises Pitavastatin ((3R among the present invention, 5S, 6E)-and 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid): No. 5856336 communique of United States Patent (USP), Japanese patent laid-open 1-279866 communique), the lactone ring organizator and the salt thereof of Pitavastatin, also comprise these chemical compounds hydrate, with the solvate that can be used as the received solvent of pharmaceuticals.As Pitavastatin salt, can enumerate alkali metal salts such as sodium salt, potassium salt; Alkali earth metal salt such as calcium salt, magnesium salt; And organic amine salt such as phenethylamine salt or ammonium salt etc.Wherein,, be preferably Pitavastatin salt, be preferably calcium salt especially as the Pitavastatin class.

The Pitavastatin class can be according to the method manufacturing of being put down in writing in No. 5856336 communique of United States Patent (USP), the Japanese patent laid-open 1-279866 communique.

The aspirin that uses among the present invention is aspirin, can be easy to obtain as commercially available product.In addition, this aspirin also can form salt with for example sodium, calcium, ammonium.

The present invention is by merging administration with Pitavastatin class and aspirin, as described later shown in the embodiment, in Cavia porcellus, than Pitavastatin class or the individually dosed situation of aspirin, have the prolongation effect (resisting blood coagulation effect) of blood coagulation time and the inhibitory action (thromboembolism facilitation) that maximum blood clot forms.

Therefore, therapeutic agent for thrombosis of the present invention, for based on diseases such as hypertension, vasospasm, arteriosclerosis, diabetes, surgical operation, blood stasis independent or concurrent with blood vessel injury and the treatment of the thrombosis of falling ill is effective.

The Pitavastatin class in the therapeutic agent for thrombosis of the present invention and the occupation mode of aspirin are not particularly limited, and both the administration respectively of each preparation also can be can be used as the unitary agent administration.In addition, both administrations simultaneously, administration respectively also can set interval.The administration number of times of each composition also can be different.

Under situation as the unitary agent administration, the match ratio of Pitavastatin class and aspirin by quality ratio, preferred range is 1: 2.5～1: 300, most preferred scope is 1: 2.5～1: 150.

In addition, Pitavastatin class and aspirin can with make unitary agent after acceptable diluent, the mixed with excipients on the galenic pharmacy, perhaps also two kinds of medicines can be made preparation respectively and use as medicine box.Two kinds of medicines are being made respectively under the situation of preparation, and two kinds of preparations also can adopt different dosage forms.

As the administering mode of medicine of the present invention, can enumerate with oral administrations such as tablet, capsule, granule, powder, liquor, syrups.

Preparation is except that effective ingredient, according to the dosage form that medicine adopted, pharmaceutically acceptable excipient, disintegrating agent, bonding agent, lubricant, diluent, buffer agent, isotonic agent, antiseptic, lubricant, emulsifying agent, dispersant, stabilizing agent, solubilizing agent etc. suitably can be mixed, dilute or dissolve, according to the conventional method manufacturing.

In the present invention, can suitably select the dosage of Pitavastatin class and aspirin according to patient's body weight, age, sex, symptom etc.Under common adult's situation, dosage every day of Pitavastatin class is 1～100mg, is preferably 1～50mg, more preferably 1～20mg; Dosage every day of aspirin is 10～300mg, is preferably 10～100mg.In addition, can administration every day 1 time, but also divide administration more than 2 times every day.

Embodiment

Below enumerating embodiment is described more specifically the present invention.But the present invention is not limited to these embodiment.

Embodiment 1

The merging administration of aspirin and Pitavastatin Calcium forms the effect of ability (MA) (thromboembolism facilitation) to whole blood clotting time (r+k value) (resisting blood coagulation effect) and maximum blood clot

When (following the 1st～4) measures aspirin and Pitavastatin Calcium carried out administration in accordance with the following methods, whole blood clotting time (r+k value) and maximum blood clot are formed the effect that ability (MA) is produced, in the 5th, show its result (r, reaction time: response time; K, clotting time: clotting time; MA, Maximal Amplitude: amplitude peak).

1. test animal and feeding environment

It is male guinea pig (Japanese SLC Co., Ltd.) that the Hartley in 6 ages in week is used in test.In whole experimental session, raise keep the light and shade cycle (forms by indoor light become clear during: the morning 7 points～afternoons 7 point), in the receptacle of 23 ± 3 ℃ of temperature, humidity 55 ± 15%, and make it freely absorb solid feed (RC4; Oriental Yeast Co., Ltd.) and tap water.

2. medicine modulation

Pitavastatin Calcium or aspirin are suspended in sodium carboxymethyl cellulose (rock well chemical drugs (the strain)) aqueous solution of 0.5 quality %, concentration are modulated to the suspension of 1mg/mL～10mg/mL respectively.In addition, because Pitavastatin Calcium contains the moisture of 9.43 quality %, thus press 1.1 times quality weighing of dosage, to carry out revisal.Suspension is put to the shading bottle cold preservation (4 ℃) preserve, this is modulated and carried out 1 time in per 7 days.

3. test method

24 Cavia porcelluss are divided into following 4 groups (every group 6 examples), that is, contrast (not administration) group, Pitavastatin Calcium individually dosed (3mg/kg) group, aspirin individually dosed (100mg/kg) group, and Pitavastatin Calcium (3mg/kg) and aspirin (100mg/kg) merging administration group.Two kinds of medicines 1 time on the 1st (point in afternoons 4) are oral administration 14 days repeatedly; Matched group carries out oral administration with the aqueous solution of the Carboxymethyl cellulose sodium of 0.5 quality % with 1mL/kg.Each group uses thromboelastograph (Helige society) to measure whole blood clotting time (r+k value) and maximum blood clot formation ability (MA) all from last administration fasting Mining blood after 18 hours.

4. data processing method

Result of the test is represented with the mean+SD of each group.

5. result of the test

Shown in Fig. 1 and table 1 (Pitavastatin Calcium is represented with Pitavastatin), in individually dosed group of individually dosed group of Pitavastatin Calcium and aspirin, whole blood clotting time (r+k value) is only by slight prolong (110% and 109%).Relative therewith, merge in the administration group at Pitavastatin Calcium and aspirin, than each individually dosed group, whole blood clotting time (r+k value) significantly prolongs (122%), and its effect is collaborative (B ü rgi formula).

That is, merge the product (122%〉110% * 109%=120%) of the effect of administration greater than individually dosed effect separately.

In addition, shown in Fig. 2 and table 2 (Pitavastatin Calcium is represented with Pitavastatin), in individually dosed group of individually dosed group of Pitavastatin Calcium and aspirin, maximum blood clot forms ability (MA) only by slight suppress (99% and 98%).Relative therewith, merge in the administration group at Pitavastatin Calcium and aspirin, than each individually dosed group, maximum blood clot forms ability (MA) and is then significantly suppressed (88%), and its effect is collaborative (B ü rgi formula).

That is, merge the product (88%＜99% * 98%=97%) of the effect of administration greater than individually dosed effect separately.

Therefore, can confirm: the merging administration of aspirin and Pitavastatin class, individually dosed than each medicament used in blood coagulation inhibitory action and these two of thromboembolism facilitations, demonstrates extremely strong anti thrombotic action.

[table 1]

Whole blood clotting time when Pitavastatin and aspirin merge administration

Dosage			Whole blood clotting time
					Pitavastatin	Aspirin	The example number	The r+k value (minute)	Relative value (%)
0mg/kg	0mg/kg	6	11.6±4.5	100
					3mg/kg	0mg/kg	6	12.8±2.4	10
0mg/kg	100mg/kg	6	12.7±1.6	109
					3mg/kg	100mg/kg	5	14.2±3.3*	122

(all results represent with mean+SD that all synergy is represented with *.)

[table 2]

Maximum blood clot when Pitavastatin and aspirin merge administration forms ability

Dosage			Maximum blood clot forms ability
					Pitavastatin	Aspirin	The example number	MA(mm)	Relative value (%)
0mg/kg	0mg/kg	6	72.5±8.6	100
					3mg/kg	0mg/kg	6	71.8±5.0	99
0mg/kg	100mg/kg	6	71.0±3.1	98
					3mg/kg	100mg/kg	5	63.9±6.0*	88

(all results all represent with mean+SD.Synergy is represented with *.)

Comparative example 1～3

The merging administration of aspirin and atorvastatin, simvastatin or pravastatin forms the effect of ability (MA) to whole blood clotting time (r+k value) and maximum blood clot

Use replaces Pitavastatin Calcium as the atorvastatin hydrate of calcium of one of representative HMG-CoA reductase inhibitor (No. 4681893 communique of United States Patent (USP) and No. 5273995 communique, Japanese patent laid-open 3-58967 communique), simvastatin (No. 4444784 communique of United States Patent (USP)) or pravastatin sodium (No. 4346227 communique of United States Patent (USP)), experimentize according to the method identical, and measure it whole blood clotting time (r+k value) and maximum blood clot are formed the effect that ability (MA) is produced with embodiment 1.In addition, the dosage of atorvastatin hydrate of calcium, simvastatin and pravastatin sodium is carried out according to 15mg/kg respectively.The result is illustrated in table 3～8.

Shown in table 3 and table 4 (atorvastatin calcium is represented with atorvastatin), merge in the administration group at atorvastatin hydrate of calcium and aspirin, do not observe prolongation effect to whole blood clotting time (r+k value).In addition, do not observe the merging administration forms ability (MA) to maximum blood clot inhibitory action yet.That is, the merging administration of atorvastatin hydrate of calcium and aspirin does not all obtain confirming to the potentiation of blood coagulation inhibitory action and these two effects of thromboembolism facilitation.

[table 3]

Whole blood clotting time when atorvastatin and aspirin merge administration

Dosage			Whole blood clotting time
					Atorvastatin	Aspirin	The example number	The r+k value (minute)	Relative value (%)
0mg/kg	0mg/kg	6	11.4±3.7	100
					15mg/kg	0mg/kg	6	12.6±3.8	111
0mg/kg	100mg/kg	5	9.5±2.4	83
					15mg/kg	100mg/kg	6	11.9±2.3	104

(all results all represent with mean+SD.)

[table 4]

Maximum blood clot when atorvastatin and aspirin merge administration forms ability

Dosage			Maximum blood clot forms ability
					Atorvastatin	Aspirin	The example number	MA(mm)	Relative value (%)
0mg/kg	0mg/kg	6	70.2±3.2	100
					15mg/kg	0mg/kg	6	71.4±2.4	102
0mg/kg	100mg/kg	5	70.9±3.0	101
					15mg/kg	100mg/kg	6	72.3±3.6	103

(all results all represent with mean+SD.)

Shown in table 5 and table 6, merge under the situation of administration at simvastatin and aspirin, do not observe influence to whole blood clotting time (table 5) and maximum blood clot formation ability (table 6).In addition, merge under the situation of administration, also do not observe influence whole blood clotting time (table 7) and maximum blood clot formation ability (table 8) at pravastatin sodium (representing) and aspirin with pravastatin.That is, no matter the merging administration of simvastatin and aspirin still is the merging administration of pravastatin sodium and aspirin, does not all demonstrate the prolongation effect (anticoagulation) of whole blood clotting time and the inhibitory action (thrombolytic effect) that maximum blood clot forms ability.

[table 5]

Whole blood clotting time when simvastatin and aspirin merge administration

Dosage			Whole blood clotting time
					Simvastatin	Aspirin	The example number	The r+k value (minute)	Relative value (%)
0mg/kg	0mg/kg	6	11.3±2.6	100
					15mg/kg	0mg/kg	5	10.6±1.1	94
0mg/kg	100mg/kg	6	10.2±2.7	90
					15mg/kg	100mg/kg	6	10.5±1.7	93

(all results all represent with mean+SD.)

[table 6]

Maximum blood clot when simvastatin and aspirin merge administration forms ability

Dosage			Maximum blood clot forms ability
					Simvastatin	Aspirin	The example number	MA(mm)	Relative value (%)
0mg/kg	0mg/kg	6	65.2±3.2	100
					15mg/kg	0mg/kg	5	65.2±2.1	100
0mg/kg	100mg/kg	6	66.0±2.7	101
					15mg/kg	100mg/kg	6	66.3±1.6	102

(all results all represent with mean+SD.)

[table 7]

Whole blood clotting time when pravastatin and aspirin merge administration

Dosage			Whole blood clotting time
					Pravastatin	Aspirin	The example number	The r+k value (minute)	Relative value (%)
0mg/kg	0mg/kg	6	11.3±2.6	100
					15mg/kg	0mg/kg	6	10.1±1.7	89
0mg/kg	100mg/kg	6	10.2±2.7	90
					| 15mg/kg	100mg/kg	6	9.4±1.8	83

(all results all represent with mean+SD.)

[table 8]

Maximum blood clot when pravastatin and aspirin merge administration forms ability

Dosage			Maximum blood clot forms ability
					Pravastatin	A department woods	The example number	MA(mm)	Relative value (%)
0mg/kg	0mg/kg	6	65.2±3.2	100
					15mg/kg	0mg/kg	6	67.3±2.5	103
0mg/kg	100mg/kg	6	66.0±2.7	101
					15mg/kg	100mg/kg	6	66.7±7.4	102

(all results all represent with mean+SD.)

Confirm to have only the merging administration of Pitavastatin and aspirin just to demonstrate the prolongation effect (anticoagulation) of collaborative whole blood clotting time and the inhibitory action (thrombolytic effect) that maximum blood clot forms ability according to The above results.

Claims (9)

1. therapeutic agent for thrombosis is characterized in that:

Contain Pitavastatin class and aspirin.

2. therapeutic agent for thrombosis as claimed in claim 1 is characterized in that:

The Pitavastatin class is a Pitavastatin Calcium.

3. therapeutic agent for thrombosis as claimed in claim 1 or 2 is characterized in that:

Being combined with mass ratio is the Pitavastatin class and the aspirin of 1: 2.5～1: 300 scope.

4. Pitavastatin class and the aspirin use in therapeutic agent for thrombosis is made.

5. use as claimed in claim 4 is characterized in that:

The Pitavastatin class is a Pitavastatin Calcium.

6. use as claimed in claim 4 is characterized in that:

The fit quality ratio is the Pitavastatin class and the aspirin of 1: 2.5～1: 300 scope.

7. the Therapeutic Method of a thrombosis is characterized in that:

Pitavastatin class and aspirin are merged administration.

8. the Therapeutic Method of thrombosis as claimed in claim 7 is characterized in that:

The Pitavastatin class is a Pitavastatin Calcium.

9. as the Therapeutic Method of claim 7 or 8 described thrombosiss, it is characterized in that:

To be combined with mass ratio and be 1: 2.5～1: 300 the Pitavastatin class of scope and the preparation of aspirin and carry out administration.

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