U.S. patent application number 14/991326 was filed with the patent office on 2016-05-05 for method for inhibiting platelet aggregation.
The applicant listed for this patent is MEDICURE INTERNATIONAL INC.. Invention is credited to Peter M. DiBATTISTE, David J. SCHNEIDER.
Application Number | 20160120856 14/991326 |
Document ID | / |
Family ID | 29401623 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120856 |
Kind Code |
A1 |
DiBATTISTE; Peter M. ; et
al. |
May 5, 2016 |
METHOD FOR INHIBITING PLATELET AGGREGATION
Abstract
A method for inhibiting platelet aggregation in a patient in
need thereof, comprising 1) administering to the patient a bolus
injection of an active drug, in an amount of between about 25
.mu.g/kg, and 2) administering to the patient, after the bolus
injection, an intravenous infusion for a period of between about 12
hours and about 72 hours, of the active drug, in an amount of about
0.15 .mu.g/kg/min, wherein the active drug is tirofiban or a salt
thereof.
Inventors: |
DiBATTISTE; Peter M.;
(Chalfont, PA) ; SCHNEIDER; David J.; (Shelburne,
VT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEDICURE INTERNATIONAL INC. |
Holetown |
|
BB |
|
|
Family ID: |
29401623 |
Appl. No.: |
14/991326 |
Filed: |
January 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14086230 |
Nov 21, 2013 |
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14991326 |
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12820630 |
Jun 22, 2010 |
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14086230 |
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10909608 |
Aug 2, 2004 |
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12820630 |
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10427436 |
May 1, 2003 |
6770660 |
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10909608 |
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60380084 |
May 6, 2002 |
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Current U.S.
Class: |
514/331 |
Current CPC
Class: |
A61P 9/10 20180101; A61K
31/4465 20130101; A61K 9/0019 20130101; A61P 7/02 20180101; A61K
9/08 20130101 |
International
Class: |
A61K 31/4465 20060101
A61K031/4465; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for reducing the risk of thrombosis, thromboembolism or
reocclusion in a patient after surgery on peripheral arteries,
comprising administering to the patient a bolus injection of about
25 .mu.g/kg of tirofiban or salt thereof to inhibit platelet
aggregation.
2. The method of claim wherein the patient underwent peripheral
arterial intervention.
3. The method of claim 1 wherein the platelet aggregation occurs in
peripheral arteries.
4. The method of claim 1 wherein the bolus injection is at least 20
.mu.g/kg of tirofiban or salt thereof.
5. The method of claim 1, wherein the salt is tirofiban
hydrochloride.
6. The method of claim 1, further comprising administering to the
patient, after the bolus injection, an intravenous infusion for a
period of between about 12 hours and about 72 hours, of tirofiban
or salt thereof to inhibit platelet aggregation, in an amount of
about 0.15 .mu.g/kg/min.
7. The method of claim 6 wherein the intravenous infusion is about
12 hours.
8. A method of preventing platelet thrombosis, thromboembolism or
reocclusion after surgery on peripheral arteries in a patient
comprising administering to the patient a bolus injection of
tirofiban or salt thereof, in amounts sufficient to inhibit
platelet aggregation.
9. The method of claim 8 wherein the patient underwent peripheral
arterial intervention.
10. The method of claim 8 wherein the platelet aggregation occurs
in peripheral arteries.
11. The method of claim 8 wherein the bolus injection is at least
20 .mu.g/kg of tirofiban or salt thereof.
12. The method of claim 8, wherein the salt is tirofiban
hydrochloride.
13. The method of claim 8, further comprising administering to the
patient, after the bolus injection, an intravenous infusion for a
period of between about 12 hours and about 72 hours, of tirofiban
or salt thereof to inhibit platelet aggregation, in an amount of
about 0.15 .mu.g/kg/min.
14. The method of claim 8 wherein the intravenous infusion is about
12 hours.
15. A method of preventing myocardial infarction in a patient after
surgery on peripheral arteries in a patient comprising
administering to the patient a bolus injection of tirofiban or salt
thereof.
16. The method of claim 15 wherein the patient underwent peripheral
arterial intervention.
17. The method of claim 15 wherein the bolus injection is at least
20 .mu.g/kg of tirofiban or salt thereof.
18. The method of claim 15, wherein the salt is tirofiban
hydrochloride.
19. The method of claim 15, further comprising administering to the
patient, after the bolus injection, an intravenous infusion for a
period of between about 12 hours and about 72 hours, of tirofiban
or salt thereof to inhibit platelet aggregation, in an amount of
about 0.15 .mu.g/kg/min.
20. The method of claim 15 wherein the intravenous infusion is
about 12 hours.
Description
[0001] This application is a divisional of co-pending U.S.
application Ser. No. 14/086,230 filed Nov. 21, 2013, which is a
continuation of U.S. application Ser. No. 12/820,630, filed Jun.
22, 2010, which is a continuation of U.S. application Ser. No.
10/909,608, filed Aug. 2, 2004, which is a continuation of U.S.
application Ser. No. 10/427,436, filed May 1, 2003 (now U.S. Pat.
No. 6,770,660), which claims priority to U.S. Provisional
Application No. 60/380,084 filed May 6, 2002, the entire
disclosures of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Platelet activation and aggregation are involved in unstable
angina and acute myocardial infarction, in reocclusion following
thrombolytic therapy and angioplasty, in transient ischemic
attacks, and in a variety of other vaso-occlusive disorders. When a
blood vessel is damaged, either by acute intervention such as
angioplasty, or, more chronically, by the pathophysiological
processes of atherosclerosis, platelets are activated to adhere to
the disrupted surface and to each other. This activation, adherence
and aggregation may lead to occlusive thrombus formation in the
lumen of the blood vessel.
[0003] Antiplatelet therapy has been used in a wide variety of
cardiovascular disease states and in conjunction with
interventional therapy such as coronary artery or peripheral bypass
grafting, cardiac valve replacement, and percutaneous transluminal
coronary angioplasty. Inhibitors of the glycoprotein complex GP
IIb/IIIa, including abciximab, tirofiban, and eptifibatide, are
used intravenously to inhibit platelet aggregation. Platelet
aggregation inhibition results in reduced incidences or reduced
severity of adverse events such as death or damage to the heart.
Typical use of these inhibitors involves initial bolus injection
and subsequent sustained infusion, for a period of hours or
days.
[0004] Holmes et al., Coronary Artery Disease (2001) 12:245-253,
describe the efficacy of platelet aggregation inhibition induced by
treatment with tirofiban hydrochloride in patients with unstable
angina, non-ST-segment elevation myocardial infarction or
symtomatic coronary disease undergoing percutaneous coronary
intervention. Patients received either 0.4 .mu.g/kg/min over 30
minutes followed by 0.1 .mu.g/kg/min, or 10 .mu.g/kg bolus
injection followed by continuous infusion at 0.15 .mu.g/kg/min.
[0005] Neumann, et al., J. Am. Coll. Cardiol. (2001) vol. 37, pp.
1323-1328, describe antiplatelet effects if tirofiban hydrochloride
in patients undergoing intracoronary stent placement for
symptomatic coronary artery disease. Patients received 10 .mu.g/kg
bolus injection followed by continuous infusion at 0.15
.mu.g/kg/min for 72 hours.
[0006] Topol et al., N Engl J Med, (2001) vol. 344, pp. 1888-1894,
describe the use of tirofiban hydrochloride for the prevention of
ischemic events with percutaneous coronary revascularization.
Treated patients were those scheduled to undergo a coronary
stenting procedure of a newly stenotic or restenotic
atherosclerotic lesion in a native vessel or a bypass graft.
Patients received 10 pg/kg bolus injection followed by continuous
infusion at 0.15 .mu.g/kg/min for 18-24 hours.
[0007] Kabbani et al. The American Journal of Cardiology (2002)
vol. 89 pp. 647-650, describe the use of tirofiban hydrochloride in
patients having an acute coronary syndrome in whom a percutaneous
coronary intervention was mandated. Patients received 10 .mu.g/kg
bolus injection followed by continuous infusion at 0.15
.mu.g/kg/min for 18-24 hours. Results from the study show that the
average inhibition of maximal aggregation during the period of time
between 15 and 60 minutes following administration of the bolus
dose was between 61% and 66%.
[0008] In each of the above studies, patients were treated either
with no bolus dose of tirofiban hydrochloride or a 10 .mu.g/kg
bolus dose of tirofiban. The duration of continuous infusion was
between 18 and 72 hours. In no case was the bolus amount greater
than 10 .mu.g/kg.
[0009] We have now found that substantially more effective
inhibition of platelet aggregation can be obtained by
administering, to a patient in need thereof, a bolus dose of
tirofiban hydrochloride of about 25 .mu.g/kg. The increased bolus
dose greatly improves the overall platelet aggregation inhibitory
effect of tirofiban therapy, providing an aggregation inhibition of
greater than 90%, without the need to increase the concentration of
tirofiban hydrochloride solution delivered during the continuous
infusion phase of tirofiban therapy, and without the need to extend
the duration of the continuous infusion phase. Further, this
benefit is achieved in the absence of increased undesirable side
effects.
SUMMARY OF THE INVENTION
[0010] The invention is a method for inhibiting platelet
aggregation in a patient in need thereof, comprising 1)
administering to the patient a bolus injection of an active drug,
in an amount of about 25 .mu.g/kg, and 2) administering to the
patient, after the bolus injection, an intravenous infusion of an
active drug for a period of between about 12 hours and about 72
hours, in an amount of about 0.15 .mu.g/kg/min, wherein the active
drug is tirofiban or a salt thereof.
[0011] In a class of methods of the invention, the salt is
tirofiban hydrochloride. In a subclass of the class, the amount of
tirofiban hydrochloride in the bolus injection is 25 .mu.g/kg. In
another subclass of the class, the intravenous infusion is between
12 hours and 72 hours, e.g. between 18 hours and 72 hours.
[0012] The invention is also a method for reducing the risk of
acute coronary syndrome in a patient at risk to acute coronary
syndrome, comprising 1) administering to the patient a bolus
injection of an active drug, in an amount of between about 25
.mu.g/kg, and 2) administering to the patient, after the bolus
injection, an intravenous infusion for a period of between about 12
hours and about 72 hours, of the active drug, in an amount of about
0.15 .mu.g/kg/min, wherein the active drug is tirofiban or a salt
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Tirofiban hydrochloride, commercially available as
AGGRASTAT.RTM., is a non-peptide antagonist for the glycoprotein
IIb/IIIa fibrinogen receptor. Tirofiban hydrochloride is chemically
described as
N-(butylsulfonyl)-O-[4-(4-piperidinyl)butyl)]-L-tyrosine
monohydrochloride and structurally represented as
##STR00001##
Tirofiban hydrochloride is also referred to as
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic
acid hydrochloride, and is described in U.S. Pat. No.
5,292,756.
[0014] Tirofiban hydrochloride and related pharmaceutically
acceptable salts are useful in the present invention. The term
"pharmaceutically acceptable salts" means non-toxic salts of the
compounds which include, but are not limited to, acetate,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
clavulanate, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynapthoate, iodide, isethionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, mucate, napsylate,
nitrate, oleate, oxalate, pamaote, palmitate, panthothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, tannate, tartrate, teoclate, tosylate,
triethiodide, valerate.
[0015] Tirofiban, tirofiban hydrochloride, and other tirofiban
salts, are also collectively referred to hereinafter as "active
drug."
[0016] Pharmaceutically effective amounts of the active drug are
suitable for use in the methods of the present invention. The term
"pharmaceutically effective amount" means that amount of a drug or
pharmaceutical agent that will elicit the biological or medical
response of a tissue, system or animal that is being sought by a
researcher or clinician.
[0017] The methods of the present invention are useful in
combination with other procedures for treating candidate patients,
including procedures involving treatments with other anticoagulants
(e.g. heparin and warfarin), thrombolytic agents (e.g.
streptokinase and tissue plasminogen activator), and platelet
antiaggregation agents (e.g. aspirin and dipyridamole).
[0018] The dosage regimen utilizing the active drug is selected in
accordance with weight of the patient; an ordinarily skilled
physician or veterinarian can readily determine and prescribe the
effective amount of the drug required to prevent, counter, or
arrest the progress of the condition in accordance with the present
invention.
[0019] The active drug can be administered in admixture with
suitable pharmaceutical diluents, excipients or carriers
(collectively referred to herein as "carrier" materials) suitably
selected with respect to the intended form of administration and
consistent with conventional pharmaceutical practices.
[0020] The methods according to the present invention for
administering the active drug are useful for treating patients
where inhibition of human or mammalian platelet aggregation or
adhesion is desired. They are useful in surgery on peripheral
arteries (arterial grafts, carotid endaterectomy) and in
cardiovascular surgery where manipulation of arteries and organs,
and/or the interaction of platelets with artificial surfaces, leads
to platelet aggregation and potential formation of thrombi and
thromboemboli. Methods of the invention may be used to prevent the
formation of thrombi and thromboemboli. Other applications include
prevention of platelet thrombosis, thromboembolism and reocclusion
during and after thrombolytic therapy and prevention of platelet
thrombosis, thromboembolism and reocchision after angioplasty or
coronary artery bypass procedures. The methods may also be used to
prevent myocardial infarction.
[0021] The present invention is demonstrated in a study of patients
with acute coronary syndrome who are undergoing early coronary
revascularization with percutaneous coronary angioplasty or
atherectomy. Because of unstable plaque with thrombus, percutaneous
revascularization procedures in these patients carry with them
considerable higher morbidity than procedures performed in patients
with stable coronary disease. Patients are evaluated after
treatment for acute coronary syndrome and may require follow-up
intervention associated with acute coronary syndrome, including
coronary artery bypass grafting, repeat percutaneous intervention
for acute ischemia, and insertion of a coronary endovascular
stent.
EXAMPLE 1
Treatment of Acute Coronary Syndrome
[0022] Eligible patients included those with an acute coronary
syndrome in. whom a percutaneous coronary intervention was
clinically mandated. An acute coronary syndrome was defined by the
following criteria; ischemic symptoms plus either 0.5 mm of ST
segment depression on the ECG or an elevated troponin or creatine
kinase MB fraction. Exclusion criteria included treatment with an
antiplatelet agent other than aspirin in the previous 14 days,
thrornbolytic therapy within 24 hours, renal insufficiency
(creatinine greater than 2.5 mg/dl), and any contraindication to
treatment with a glycoprotein IIb-IIIa inhibitor.
[0023] Patients were treated with a 20 .mu.g/kg bolus of tirofiban
hydrochloride followed by a 0.15 .mu.g/kg/min infusion for 18-24
hours or a 25 .mu.g/kg bolus followed by the same infusion.
Enrollment of subjects in the panel with the 20 .mu.g/kg bolus
(n=15/pane)) was completed and the clinical effects and
pharmacodynamic properties were evaluated before subjects were
enrolled in the panel with the 25 .mu.g/kg bolus. Patients were
treated with aspirin (325 mg before the procedure and daily) and
unfractionated heparin (target activated clotting time 250
seconds). Clopidogrel (300 mg and then 75 mg daily) (commercially
available as PLAVIX.RTM.) was administered at least 45 minutes
after the start of tirofiban hydrochloride. All other medications
were administered at the discretion of the attending cardiologist.
Sheath removal was performed when the activated clotting time was
less than 175 seconds unless a closure device was used.
[0024] Blood samples were obtained from a venous catheter for
assessment of platelet function by light transmission aggregometry,
rapid platelet function analyzer and flow cytometry before
treatment and after 15, 30, 45, and 60 minutes. Blood was obtained
after 5 minutes for analysis by flow cytometry. Blood for light
transmission aggregometry and rapid platelet function analyzer was
anticoagulated with D-Phe-Pro-Arg-chloromethyl ketone (38 .mu.M) to
avoid potentially confounding effects of citrate on inhibitory
properties of tirofiban hydrochloride (Rebello et al., J. Thromb.
Thrombolysis (2000) vol. 9 pp. 23-28). Blood for flow cytometry was
anticoagulated with corn trypsin inhibitor, a specific inhibitor of
coagulation factor XIIa without effect on other coagulation factors
(Schneider et al., Circulation (1997) vol. 96 pp. 2877-83).
Aggregation (light transmission aggregometry) of platelets was
assessed in platelet rich plasma in response to 20 .mu.M adenosine
diphosphate (Chronolog). Maximal aggregation (ex vivo) after 4
minutes was determined. rapid platelet function analyzer was
performed in accordance with manufacturer specifications with
thrombin receptor agonist peptide cartridges. Assessment of the
capacity of platelets to bind fibrinogen was performed as
previously described (Holmes et al., Coron. Artery Dis. (2001) vol.
12 pp. 245-253; Kabbani et al., Circulation (2001) vol. 104 pp.
181-186). For flow cytometry, samples were processed and platelets
were fixed at each site.
[0025] The study was designed to identify a bolus dose of tirofiban
hydrochloride that inhibited platelet aggregation, on average, by
at least 90% with a lower 95% confidence interval of the extent of
inhibition of at least 85% at all times between 15 to 60 minutes
after onset of treatment. The occurrence of 3 major bleeding
episodes (as defined by the American College of Cardiology Task
force (Cannon et al. J. Am. Coll. Cardiol. (2001) vol. 38 pp.
2114-30) in each panel was a pre-specified criteria for termination
of the study.
[0026] The activated clotting time at the time of percutaneous
coronary intervention was 249.+-.24 seconds. No major bleeding
episode occurred with either the 20 .mu.g/kg or 25 .mu.g/kg
bolus.
[0027] The average extent of inhibition of platelet aggregation
assessed with light transmission aggregometry (20 .mu.M adenosine
diphosphate) ranged from 84% to 89% from 15 through 60 minutes
after the 20 .mu.g/kg bolus and from 92% to 95% after the 25
.mu.g/kg bolus of tirofiban (see Table 1).
TABLE-US-00001 TABLE 1 % Inhibition of platelet aggregation 15-60
minutes after bolus injection 10 .mu.g/kg 20 .mu.g/kg 25 .mu.g/kg
61-66% 84-89% 92-95%
[0028] The antiplatelet effects of the 20 and 25 .mu.g/kg bolus
were evaluated also by flow cytometric determination of the
capacity to bind fibrinogen in response to 1 .mu.M adenosine
diphosphate. The extent of inhibition was greater after onset of
treatment with the high bolus dose.
[0029] Light transmission aggregometry and rapid platelet function
analyzer were performed with D-Phe-Pro-Arg-chloromethyl ketone as
the anticoagulant and flow cytometry was performed with blood
anticoagulated with corn trypsin inhibitor. Citrate and other
chelators of calcium alter platelet reactivity and the inhibitory
properties of GP IIb-IIIa inhibitors (Rebello et al., J. Thromb.
Thrombolysis (2000) vol 9 pp. 23-28; Schneider et al. Circulation
(1997) vol. 96 pp. 2877-83). Accordingly, the evlauations were
performed with conditions that limit potentially confounding
influences of selected anticoagulants and simulate intense exposure
of platelets to multiple platelet agonists during thrombosis by
using high concentrations of adenosine diphosphate and thrombin
receptor agonist peptide.
[0030] The interval from 15 to 60 minutes after onset of treatment
is a critical period during which iatrogenic vessel injury is
induced and a thrombogenic object (intra-coronary stent) is
frequently introduced. The present invention identifies a dosage
range of tirofiban hydrochloride that achieves an average
inhibition of platelet aggregation of greater than 90% throughout
the first hour after treatment. This dosage entails an increase in
the bolus amount as compared to conventional bolus amounts (from 10
to 25 .mu.g/kg), but no change in the rate or duration of the
infusion.
EXAMPLE 2
Intravenous Formulations
[0031] An intravenous dosage form of
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic
acid hydrochloride (Active I) is prepared as follows:
TABLE-US-00002 Active I 0.5-10.0 mg Sodium Citrate 5-50 mg Citric
Acid 1-15 mg Sodium Chloride 1-8 mg Water for Injection (USP) q.s.
to 1 L
[0032] Utilizing the above quantities, Active I is dissolved at
room temperature in a previously prepared solution of sodium
chloride, citric acid, and sodium citrate in Water for Injection
(USP, see page 1636 of United States Pharmacopeia/National
Formulary for 1995, published by United States Pharmacopeial
Convention, Inc., Rockville, Md., copyright 1994).
EXAMPLE 3
[0033] Intravenous Formulations
[0034] A pharmaceutical composition was prepared at room
temperature using Active I, a citrate buffer, and sodium chloride,
to obtain a concentration of 0.25 mg/ml.
[0035] 800 grams of water was introduced into a standard
pharmaceutical mixing vessel. 0.25 grams of Active I was dissolved
in the water. 2.7 grams sodium citrate and 0.16 grams citric acid
were added to obtain a finished citrate concentration of 10 mM. 8
grams of sodium chloride was added. 200 grams of water was then
added to achieve the desired final concentrations of ingredients.
The resulting aqueous formulation had the following
concentrations:
TABLE-US-00003 Ingredient Amount Active I 0.25 mg/ml citrate buffer
10 mM sodium chloride 8 mg/ml
[0036] The finished concentrated formulation is stored in a
standard USP Type I borosilicate glass container at 30-40 degrees
C. Prior to compound administration, the concentrated formulation
is diluted in a 4:1 ratio resulting in a finished concentration of
0.05 mg/ml and transferred to an infusion bag.
* * * * *