Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
PLATELET AGGREGATION INHIBITION USING LOW MOLECULAR
WEIGHT HEPARIN IN COMBINATION WITH A GP IIb/IIIa
ANTAGONIST
BACKGROUND OF THE INVENTION
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 angiopiasty, 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.
The final obligatory step in platelet aggregation is the
binding of fibrinogen to an activated membrane-bound glycoprotein
complex, GP IIb/IIIa (all~ig). Platelet activators such as thrombin,
collagen, epinephrine or ADP, are generated as an outgrowth of tissue
damage. During activation, GP IIb/IIIa undergoes changes in
conformation that result in exposure of occult binding sites for
fibrinogen. There are six putative recognition sites within fibrinogen for
GP IIb/IIIa and thus fibrinogen can potentially act as a hexavalent
ligand to crossing GP IIb/IIIa molecules on adjacent platelets. A
deficiency in either fibrinogen or GP IIb/IIIa prevents normal platelet
aggregation regardless of the agonist used to activate the platelets. Since
the binding of fibrinogen to its platelet receptor is an obligatory
component of normal aggregation, GP IIb/IIIa is an attractive target for
an antithrombotic agent.
Results from clinical trials of GP IIb/IIIa inhibitors
support this hypothesis. The monoclonal antibody 7E3, which blocks the
GP ITb/IIIa receptor, has been shown to be an effective therapy for the
high risk angioplasty population. It is used as an adjunct to
percutaneous transluminal coronary angioplasty or atherectomy for the
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prevention of acute cardiac ischemic complications in patients at high
risk for abrupt closure of the treated coronary vessel.
A study reported in The New n land ~lou_rnpl of ~~~";,"~o
vol. ,~, No. 14, pp. 956-961 (1994) showed a decrease from 12.8% to g.3%
in the combined endpoints of death, non-fatal MI and need for urgent
revascularization with fibrinogen receptor blockade. This benefit was at
the expense of some additional risk of bleeding, with the need for
transfusion increasing from 3% to 6%, and the incidence of patients with
decreased hematocrit increasing from 7% to 15%. 7E3 was added to the
standard regime of heparin and aspirin thus leaving few hemostatic
control mechanisms intact. The clinical benefats of this drug could be
seen at 6 months.
Many other studies have shown that blocking the
GPIIb/IIIa receptor will stop platelet aggregation induced by all of the
agonists and thus prevent thrombus formation but leave platelet
adhesion relatively intact. The 7E3 monoclonal antibody is described in
Coller g~,, gnn. NY Acad ci lggl; ,~: 193-213; and Coller ~
Olin Invest. 1985; ~: 101-108. Others have used agents based on the RGD
sequence, including snake venom proteins, small peptides, and
peptidomimetics (Cook . Drugs of F,~t"r lgg4; ~: 135-159; and Cox
g~,. Medicinal R.paparch R ~~i~P~=~,~ lgg4.; ,~: 195-22$). Integrilin is a
cyclic peptide that is based on the KGD sequence in the snake venom
protein barbourin (Cook g~. ; and Cox g,~. ~,), It inhibits
ligand binding to GPIIb/IIIa but has very little effect on ligand binding
~ av(13. Among the non-peptide compounds are RO 44-9883 and MK-383,
which are administered intravenously, and are also selective for
GPIIb/iIIa (Cook . .; ,~d Cox g~. ~,). Orally active agents
include SC54684, a prodrug with high oral bioavailability, and 8043-
8857, GR144053, and DMP728, which are themselves the active inhibitors
(Cook g~,; and Cox g,~. ~,), Literally thousands of other
compounds have been synthesized in an attempt to obtain optimal
potency, metabolic stability, receptor specificity, and favorable
intravascular survival. Despite variations in these compounds, virtually
of all of them retain the basic charge relations of the RGD sequence with
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a positive charge separated from a negative charge by approximately 10-
20 ~ (Cook g~. ~.; and Cox g,~j. ~. ).
The results of the 7E3 study support the hypothesis that
blockade of GPIIb/IIIa receptors is more effective than aspirin in
preventing platelet thrombi, even in the presence of heparin. They also
support the hypothesis that platelet-dependent thrombi frequently
contribute significantly to the development of ischemic complications
after PTCA, even when minor mechanical dissections are present.
Heparin is a commonly used anticoagulant.
Unfractionated heparin unpredictably binds electrostatically to proteins
in addition to tethering to tighten weak antithrombin IIIahrombin
interactions. Low molecular weight heparin tends to bind in a more
predictable pharmacodynamic fashion and is therefore more effective
than unfractionated heparin in reducing clot formation. Cohen g~., ~j
En~l ~g,~ lgg7; ,x:44?-52 compares low molecular weight heparin to
unfractionated heparin for treatment of unstable coronary artery
disease. Patients received 1 mg of enoxaparin (low molecular weight
heparin) per kg body weight subcutaneously twice daily, or continuous
intravenous unfractionated heparin at a dose adjusted according to the
activated partial-thromboplastin time, targeting the activated partial-
thromboplastin time at 55 to 85 seconds. All patients received 100 to 325
mg of oral aspirin daily. Results showed that antithrombotic therapy
with enoxaparin plus aspirin was more effective than unfractionated
heparin plus aspirin in reducing the incidence of ischemic events in
patients with unstable angina or non-(1-wave myocardial infarction in
the early phase. The benefit with enoxaparin was achieved with an
increase in minor but not major bleeding.
SUMMARY OF THE INVENTION
The invention is a method for inhibiting platelet
aggregation in a mammal comprising administering to the patient a
safe and therapeutically effective amount of a GPIIb/IIIa receptor
antagonist or a pharmaceutically acceptable salt thereof and a safe and
therapeutically effective amount of low molecular weight heparin. The
invention also is the use of a GPIIb/IIIa receptor antagonist or a
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pharmaceutically acceptable salt thereof, and a safe and therapeutically
effective amount of low molecular weight heparin, in the manufacture of
a medicament for inhibiting platelet aggregation in a mammal.
The invention is also a method for inhibiting platelet
aggregation in a mammal comprising administering to the patient a
safe and therapeutically effective amount of a GPIIb/IIIa receptor
antagonist or a pharmaceutically acceptable salt thereof, a safe and
therapeutically effective amount of low molecular weight heparin, and a
safe and therapeutically effective amount of aspirin.
DETAILED DESCRIPTION OF THE INVENTION
One example of the invention is a method for inhibiting
platelet aggregation in a mammal comprising administering to the
patient a safe and therapeutically effective amount of 2-S-(n-
butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid or
a pharmaceutically acceptable salt thereof (e.g. 2-S-(n-
butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid
hydrochloride, also called "tirofiban") and a safe and therapeutically
effective amount of iow molecular weight heparin. A further example of
the invention is the use of 2-S-(n-butylsulfonylamino)-3[4-(piperidin-4-
yl)butyloxyphenyl]propionic acid or a pharmaceutically acceptable salt
thereof, and a safe and therapeutically effective amount of low molecular
weight heparin, in the manufacture of a medicament for inhibiting
platelet aggregation in a mammal.
Another example of the invention is a method for inhibiting
platelet aggregation in a mammal comprising administering to the
patient a safe and therapeutically effective amount of 2-S-(n-
butylsulfonylanuno)-3[4-(piperidin-4-y1)butyloxyphenyl]propionic acid or
a pharmaceutically acceptable salt thereof (e.g. 2-S-(n-
butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic acid
hydrochloride), a safe and therapeutically effective amount of low
molecular weight heparin, and a safe and therapeutically effective
amount of aspirin.
The invention takes advantage of the reduced prolongation
of bleeding time experienced with, a GP IIb/IIIa receptor antagonist,
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e.g., 2-S-(n-butylsulfonylamino)-3[4-(piperidin-4-
yl)butyloxyphenyl)propionic acid or a pharmaceutically acceptable salt,
in combination with low molecular weight heparin, as compared to the
extended prolongation of bleeding time associated with the combination
of a GP IIb/IIIa receptor antagonist, e.g., 2-S-(n-butylsulfonylamino)-
3[4-(piperidin-4-yl)butyloxyphenyl]-propionic acid or a pharmaceutically
acceptable salt, in combination with unfractionated heparin.
Unless otherwise indicated, the following terms have the
designated meanings:
"Tirofiban" means 2-S-(n-butylsulfonylamino)-3[4-piperidin-
4-yl)butyloxyphenyl)propionic acid hydrochloride.
"Pharmaceutically acceptable salts" means non-toxic salts
of the compounds (which are generally prepared by reacting the free
acid with a suitable organic or inorganic base) 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, isothionate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, mutate, napsylate,
nitrate, oleate, oxalate, pamaote, palmitate, panthothenate,
phosphateJdiphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide,
valerate.
"Therapeutically 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.
"Mammal" includes, within its meaning, primates (e.g.
humans, monkeys, etc.), dogs, rabbits, and other species commonly
known to be mammals.
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The methods of the present invention are useful in
combination with procedures for treating patients with other
anticoagulants (e.g, thrombin inhibitors such as heparin, Factor Xa
inhibitors such as warfarin, tissue factor pathway inhibitors, or
thrombin receptor antagonists), thrombolytic agents (e.g. streptokinase
and tissue plasminogen activator), and platelet antiaggregation agents
(e.g. aspirin and dipyridamole).
The methods are suitable for patients where prevention of
thrombosis by inhibition of binding of fibrinogen to the platelet
membrane glycoprotein complex IIb/IIIa receptor is desired. Such
administration is useful in surgery on peripheral arteries (arterial
grafts, carotid endarterectomy) for treatment of peripheral vascular
disease, and in cardiovascular surgery where manipulation of arteries
and organs, and/or the interaction of platelets with artificial surfaces,
leads to platelet aggregation and consumption. Since aggregated
platelets may form thrombi and thromboemboli, the methods may be
used on these surgical patients to prevent the formation of thrombi and
thromboemboli. The GP IIb/IIIa receptor antagonists may also be
administered to treat stroke, carotid percutaneous transluminal
coronary revascularization, or carotid endarterectomy.
Applications of the methods include prevention of platelet
thrombosis, thromboembolism and reocclusion during and after
thrombolytic therapy and prevention of platelet thrombosis,
thromboembolism and reocclusion after angioplasty or coronary artery
bypass procedures, or to improve outcomes following stent implantation
(i.e., to prevent thromboembolism on device insertion). It may also be
used to treat patients with acute coronary ischemic syndromes
including unstable angina and subsequent myocardial infarction.
IOW mp~rmlar ~ei~rht hR.,~..:..
Compositions containing, procedures for making, and
methods for using law molecular weight heparin are described in
various patent publications, the contents of which are hereby
incorporated by reference, including US 4281108, US 4687765, US 5106734,
US 4977250, US 5576304, and EP 372 969. Commercially available low
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molecular weight heparin includes FRAGMINT"' (dalteparin sodium
injection, available from Pharmacia, Inc. (Columbus, OH)) and
LOVENOX~ (enoxaparin sodium injection, available from Rhone-
Poulenc Rorer Pharmaceuticals, Inc. (Coilegeville, PA), described in EP
040144).
FRAGMINT"' dalteparin sodium injection is a sterile low
molecular weight heparin produced through controlled nitrous acid
depolymerization of sodium heparin from porcine intestinal mucosa
followed by a chromatographic purification process. It is composed of
strongly acidic sulphated polysaccharide chains (oligosaccharide,
containing 2,5-anhydro-D-mannitol residues as end groups) with an
average molecular weight of 5000 and about 90°!0 of the material within
the range 2000-9000. It acts by enhancing the inhibition of Factor Ya and
thrombin by antithrombin. It is available in a strength of 2500 anti-
Factor Xa IU/0.2 mL. FRAGMINT"' is used for prophylagis against deep
vein thrombosis, which may lead to pulmonary embolism, in patients
undergoing abdominal surgery who are at risk for thromboembolic
complications, including those over 40 years of age, obese, undergoing
surgery under general anesthesia lasting longer than 30 minutes or .
who have additional risk factors such as malignancy or a history of deep
vein thrombosis or pulmonary embolism. Typically, for patients
undergoing abdominal surgery, between 1000 and 5000, e.g. 2500 IU
should be administered subcutaneously only, each day, and repeated
once each day for 5 to 10 days. Dosage adjustment and routine
monitoring of coagulation parameters are not required.
LOVENOX~ enoxaparin sodium injection is a sterile, low
molecular weight heparin produced by alkaline degradation of heparin
derived from porcine intestinal mucosa. Its structure is characterized
by a 2-O-sulfo-4-enepyranosuronic end group at the non-reducing end of
the chain. The substance is the sodium salt. The average molecular
weight is 4500. LOVENOX~ is used for prevention of deep vein
thrombosis, which may lead to pulmonary embolism, following hip or
knee replacement surgery. It contains 30 mg enoxaparin sodium in 0.3
mL of Water for Injection, and has an anti-Factor Xa activity of
approximately 3000 IU. In patients undergoing hip replacement, or
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treat~nnent for arterial thrombosis; the recommended dose of LOVENOX
Injection is 30 mg twice daily administered by subcutaneous injection
with the initial dose given within 12-24 hours post-operatively provided
hemostasis has been established. Treatment should be continued
throughout the period of post-operative care until the risk of deep vein
thrombosis has been diminished.
G, lvconrote~~/Tj,~a $n a~~nis s
Antagonists for the glycoprotein IIb/IIIa fibrinogen
receptor, along with their therapeutic use, have been described in United
States Patents 5,470,849, 5,463,011, 5,465,243, 5,451,578, 5,446,056,
5,441,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791, 5,393,760, 5,389,631,
5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,7235,334,596,
5,321,034, 5,318,899 (e.g. cyclic heptapeptides Mpr-(Acetimidyl-Lys)-Gly-
Asp-Trp-Phe-Cys-NH2, Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-
NH2, Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH2,and Mpr-
(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH2, wherein Mpr is
mercapto propionyl), 5,312,923, 5,294,616, 5,292,756 (e.g. 2-S-(n-
butylsulfonylamino)-3[4-(piperidin-4-yI)butyloxyphenyl]propionic acid
and 2-S-(n-butylsulfonylamino)-3[4-(piperidin-4-
yl)butyloxyphenyl]propionic acid hydrochloride), 5,281,585 5,272,158,
5,264,420, 5,260,307, 5,239,113 (e.g. Ethyl 3-[[4-[[4-
(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate),
5,227,490, 5,206,373, 4,703,036 (e.g. N-Methyl-D-phenylalanyl-N-[(1S)-1-
formyl-4-guanidinobutyl]-L-prolinamide), EP 505 868 (e.g. ((1-(2-((4-
(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropyl)-4-
piperidinyl)oxy)-(S)-acetic acid), WO 9311152 (e.g. N-(2-(2-(((3-
((aminoiminomethyl)amino)propyl)amino)-carbonyl)-1-piperidnyl)-1-
(cyclohexylmethyl)-2-oxoethyl~.(R,S)-glycine), EP 333 356 and WO
9422820, WO 95/14683, and WO 94/18981, all of which are herein
incorporated by reference, and wherein the scope of this invention
includes, but is not limited to, the use of each of the specifically disclosed
compounds therein. They are described as useful for inhibiting
fibrinogen binding and inhibiting clot formation.
In particular, the GP IIb/IIIa receptor antagonist is
selected from: [3(R)-[2-piperidin-4-yl)ethyl)-2-piperidone-1]acetyl-3(R)-
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methyl-b-alanine) described in United States Patent No. 5,281,585; 2(S~
[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-
yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propionic
acid described in WO 94/18981; 5-[(4-Piperidinyl)methoxy]-2-
indolecarbonyl-2(S)-phenylsulfonyl-amino-b-alanine described in WO
97/15568; and 2-S-(n-butylsulfonylamino)-3[4-piperidin-4-
yl)butyloxyphenyl)propionic acid hydrochloride (also known as tirofiban)
described in United States Patent 5,292,756; DMP 728, described in
Circulation.1996 ,;~:537-543, Cox g~j., Medicinal Res ar h Rp~~ p.ne
1994, x:195-228, and Cook g., Drugs of the FutnrP_ 1994
159, from DuPont Merck; DMP 754 ((R)-methyl-3-[[[3-[4- ~ '135
(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]acetyl]amino]-N
. (butoxycarbonyl)-L-alanine monoacetate, described in WO 95/14683) from
DuPont-Merck; 8044-9883 and 8043-8857, both described in Cook g~.,
, and Cox g~., i~',~, from Hoffman-LaRoche; xemlofiban (also
known as xemilofiban) from Searle/Sankyo, described in Circulation,
1995, 92 :2331; fradafiban from Boehringer Ingleheim/K. Thomae; SB
2144857 (from SmithKline Beecham); ZD2486 (from Zeneca); TAK 029,
described in J. Pharmacoloev and .Ynp,.~mant~l There»t;r.a 1996, ~
:502-510, from Takeda; orbofiban and SC-58635 from Searle; SC54684,
described in Cook g~., '1~',~, and Cox g~,., ~,~, from Searle; GR144053,
described in Thrombosis and Hema n~;~ lgg3, ~ :107I, Cook ., ~~
and Cox g~,., ~, from Glaxo; compound 109891 from Rhone Polenc
Rorer; and sibrafiban from Hoffman-LaRoche as described in EP 656348.
2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-
yl)butyloxyphenyl]propionic acid or pharmaceutically acceptable salts
thereof, including tirofiban, described in patent publication United
States Patent 5,292.756, the contents of which are hereby incorporated by
reference, are particularly useful in the present invention. They are
described as useful for inhibiting fibrinogen binding, platelet
aggregation, and clot formation.
Suitable intravenous compositions of GP IIb/IIIa receptor
antagonists, and compositions of low molecular weight heparin, include
bolus or extended infusion compositions. Such intravenous
compositions are well known to those of ordinary skill in the
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pharmaceutical arts. In accordance with the invention, for example, 2-
S-(n-butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic
acid or pharmaceutically acceptable salts thereof and low molecular
weight heparin can be administered to the patient together, e.g. in one
intravenous solution, or in two separate simultaneously administered
solutions. Intravenous administration of the GP IIb/IIIa receptor
antagonist and low molecular weight heparin, whether administered
together in one solution, or together in two separate solutions, involves
preparation of suitable infusion solutions according to procedures well
known in the art. Administrations in these various ways are suitable
for the present invention as long as the beneficial pharmaceutical effect
of the GP IIb/IIIa receptor antagonist and the low molecular weight
heparin are realized by the patient at substantially the same time. Such
beneficial effect is achieved when the target plasma level concentrations
of each active drug ordinarily achieved during independent usage of the
drugs are maintained at substantially the same time. Such target
plasma level concentrations are readily determined for each patient by
persons having ordinary skill in the art.
The dosage regimen utilizing the active drugs is selected in
accordance with a variety of factors including type, species, age, weight,
sex and medical condition of the patient; the severity of the condition to
be treated; the route of administration; the renal and hepatic function of
the patient; and the particular compound or salt thereof employed. An
ordinarily skilled physician or veterinarian can readily determine and
prescribe the therapeutically effective amount of the drug required to
prevent, counter, or arrest the progress of the condition.
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, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
Pharmaceutical practices.
Typically, suitable intravenous solutions of GP IIb/IIIa
receptor antagonists, e.g., 2-S-(n-butylsulfonylamino)-3-[4-(4-(piperidin-
4-yl)butyloxy)phenyl]propionic acid or pharmaceutically acceptable salts
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thereof, include pharmaceutically acceptable pH buffers (e.g. sodium
citrate), tonicity adjusting agents and other components providing a
storage stable and therapeutically effective intravenous solution.
Tonicity adjusting agents, including sodium chloride, are
used to adjust tonicity for osmotic pressure and prevent blood cell lysing.
These agents minimize pain and thrombophlebitis often experienced by
patients receiving intravenous administrations of pharmaceutical
compositions. The amount used is that which makes the formulation
isotonic with osmotic pressure of the biological system of the patient.
Expressed in osmolarity units, the preferred amount of tonicity
adjusting agent suitable for the present invention, e.g., sodium chloride,
is between about 50-500 milliosmoles, more preferably about 290
milliosmoles. In compositions of the invention, pharmaceutically
acceptable osmolarity can be achieved by formulating with an amount of
sodium chloride of between about 1.5 and 15 mg/ml, preferably about 9
mg/mi. Such osmolality can also be achieved by using an amount of
mannitol of between about 7 and 75 mg/ml, preferably about 50 mg/ml.
Other tonicity adjusting agents which can be used to adjust tonicity
include, but are not limited to, dextrose and other sugars.
The compositions are not limited to the GP IIb/IIIa receptor
antagonist, citrate buffer and tonicity adjusting agent, however, and
may also include other pharmaceutically acceptable diluents, excipients
or carriers. The formulations are suitable for long-term storage in glass
containers commonly used in the pharmaceutical industry, e.g., in
concentrated form in standard USP Type I borosilicate glass containers.
In general, the procedure for preparing GPIIb/IIIa
receptor antagonist compositions of the invention involves combining the
various ingredients in a mixing vessel, e.g., at room temperature. The
active ingredient (in salt or free base form), buffer sources (e.g., citric
acid and sodium citrate), and tonicity adjusting agent, are combined to
obtain an active ingredient concentration of between about 0.01 mg/ml
and 0.5 mg/ml.
In one procedure for preparing such compositions, a
substantial portion of the finished product amount of water (e.g.,
between about 60 and 100%) is introduced into a standard
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pharmaceutical mixing vessel. An amount of active ingredient suitable
for obtaining the desired finished product concentration is dissolved in
the water. Amounts of sodium citrate and citric acid suff cient to obtain
a finished citrate concentration of between about 2 and 20 mM, are
added. A pharmaceutically acceptable amount of tonicity adjusting
agent in the isotonic range, is added. Any remaining portion of water is
then added to achieve the desired final concentrations of ingredients.
The amount of water initially used in preparing the formulation, and
the amount of the remaining portion of water added at the end of the
procedure, does not affect the properties of the finished product. Such
amounts are a matter of choice for the skilled artisan, allowing for pH
adjustment during formulation.
Concentrated formulations of the compositions can be
diluted at the time of administration with a suitable diluent to obtain a
finished concentration, for example, of about 0.05 mg/ml, which is
suitable for transfer to an infusion bag and use by the patient in need of
the desired active ingredient.
Intravenously, the most preferred doses of 2-S-(n-
butylsulfonylamino)-3-[4-(4-(piperidin-4-yl)butyloxy)phenyl]propionic
acid hydrochloride will range from about 0.001 to about 2 ~,g/kg/minute
during a constant rate of infusion, e.g., 0.1, 0.15, 0.2, and 0.4
~g/kg/minute. In order to administer such amounts of tirofiban, an
intravenous composition having 0.05 mg/ml of active ingredient can be
administered at rates of 0.002, 0.003, 0.004 or 0.008 ml/kg/min,
respectively. Compositions of the invention containing higher
concentrations of active ingredients should be administered at
correspondingly lower rates.
Typically, for treating unstable angina pectoris or non-Q-
wave myocardial infarction, 2-S-(n-butylsulfonylamino)-3-[4-(4-
(piperidin-4-yl)butyloxy)phenyl]propionic acid hydrochloride (tirofiban)
is administered intravenously at an initial infusion rate of 0.4
~g/kg/minute for 30 minutes or as a bolus of 10 ~,g/kg over 3 minutes.
Upon completion of the initial infusion or bolus, tirofiban is continued at
a maintenance infusion rate of 0.10 ~.g/kg/minute. Administration may
be continued as needed, e.g. for 48 hours or more (through angiography,
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and 12 to 24 hours post-angioplasty). In patients in whom tirofiban is
initiated in the setting of angioplasty/atherectomy, tirofiban should be
administered intravenously as an initial bolus of 10 ~,g/kg administered
over 3 minutes followed by a maintenance infusion rate of 0.15
~g/kg/minute.
GP IIb/IIIa receptor antagonists which are orally active are
also suitable for purposes of the present method. Dosages of such
antagonists, when used for the indicated effects, will range between
about 0.005 mg per kg of body weight per day (mg/kg/day) to about 50
mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 0.005-
10 mg/kg/day. Suitable oral tablets contain between 0.5 mg and 5 g,
preferably between 0.5 mg and 2 g, most preferably between 0.5 mg and
lg, e.g. 50 mg, 150 mg, 250 mg, or 500 mg. Oral administration may be
in one or divided doses of two, three, or four times daily.
For oral administration in the form of a tablet or capsule,
the active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as lactose, starch,
sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium
phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral .
administration in liquid form, the oral drug components can be
combined with any oral, non-toxic, pharmaceutically acceptable inert
carrier such as ethanol, glycerol, water and the like. Moreover, when
desired or necessary, suitable binders, lubricants, distintegrating agents
and coloring agents can also be incorporated into the mixture. Suitable
binders include starch, gelatin, natural sugars such as glucose or beta-
lactose, corn-sweeteners, natural and synthetic gums such as acacia,
tragacanth or sodium alginate, carboxymethylcellulose, polyethylene
glycol, waxes and the like. Lubricants used in these dosage forms
include sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like. Disintegrators
include, without limitation, starch methyl cellulose, agar, bentonite,
xanthan gum and the like.
Oral compositions of the GP IIb/IIIa receptor antagonists
with enteric coatings may be prepared by mixing the antagonist with an
excipient to form a spheroid, and coating the spheroid with a thin
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polymer film. For example, the antagonist is mixed with non-water
swellable microcrystalline cellulose to form a spheroid which is then
coated with a film of hydroxypropyl methyl cellulose phthalate and or a
plasticizer which prevents any release of the antagonist in the stomach.
When the composition reaches the intestine, the antagonist is released.
The oral compositions may also be prepared by mixing the
antagonist with a wetting agent such as fatty acid esters, lecithin,
sucrose, mannitol or sorbitol and then spheronizing or granulating the
mixture into microgranules. These are then coated with a microporous
membrane polymer such as Eudragit ~ E30D (Rohm Pharma GmbH,
Weiterstadt, Germany), hydroxypropyl methyl cellulose phthalate and
other wetting agents, plasticizers and the like. The formulations are
enteric by nature and the antagonist does not become bioavailable until
the system reaches the intestine.
The compositions may also be prepared by mixing the
antagonist and an acid such as fumeric or tartaric acid which is
compressed into a spherical tablet and coated with lacquers that are
insoluble in gastric juices and soluble in intestinal juices. These
lacquers include copolymers of acrylic acid and methacrylic acid eaters:
The acidic matrix prevents quick dissolution early and yet promotes the
antagonist's bioavailability further downstream in the digestive tract.
The compositions may also be prepared by coating a solid
dosage form of the antagonist with hydroxypropyl methyl cellulose
phthalate or acidic succinyl and acetyl esters of hydroxypropyl methyl
cellulose. Triethylcitrate is added as a plasticizer which aids in the
binding of the coating material to the core pellet. The coatsng resists
dissolution in the stomach but completely dissolves in the small
intestine.
Suitable materials for providing enteric coatings include,
for example, hydroxypropyl methyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl
cellulose phthalate, hydroxypropyl methyl cellulose
hexahydrophthalate, shellac, cellulose acetate, cellulose acetate
phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose,
methacrylic acid copolymers, methacrylic ester copolymers and the like.
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In general, solid dosage forms comprising the antagonist
may be coated using conventional coating techniques such as
conventional pan coating techniques or column spray coating
techniques.
For example, coating pans, e.g. subglobular, pear shaped or
hexagonal pans, which are inclined are set to rotate at an appropriate
setting sufficient to allow uncoated tablets to be exposed to spray
solutions of the polymer used to form the coat. The pan is heated to a
sufficient temperature to allow the coat to dry soon after contact with the
outside of the tablet.
Some pans have a cylindrical shape, are rotated
horizontally, and have at least some regions of the walls perforated by
small holes or slots. This design peiznits a one-way air flow through the
pan. In other designs the flow of air is through the tablet bed and out
through the perforated wall of the pan. In others the air flows from the
perforated pan wall through the tablet bed into the central region, i.e.,
countercurrent to the coating spray direction. Still others permit either
co- or counter-current air flow to suit particular products.
The coating is sprayed in one of several methods. One
method relies entirely on hydraulic pressure to produce a spray when
material is forced through a nozzle (airless spraying). In another
method, atomization of the spray is assisted by turbulent jets of sir. This
method tends to produce a more easily controlled spray pattern and is
therefore better for small-scale operations, although both are capable of
giving the flat jet. profile preferred for pan operation.
The thickness of coating required on the granules depends
on the dissolution profile of the particular coating materials. The
coating can contain a plasticizer and possibly other coating additives
such as coloring agents, gloss producers, talc and/or magnesium
stearate.
The antagonists can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
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Antagonists may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules are
coupled. Antagonists may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include polyvinyl-
pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-
phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-
polyiysine substituted with palmitoyl residues. Furthermore,
antagonists may be coupled to a class of biodegradable polymers useful
in achieving controlled release of a drug, for example, polylactic acid,
polyglycolic acid, copolymers of polylactic and polyglycolic acid,
polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or
amphipathic block copolymers of hydrogels.
In ocular formulations such as eyedrops, from about 0.01-
5.0% (w/v) of antagonist can be employed, e.g., from about 0.01-2.0% (w/v)
of antagonist. Suitable eyedrop volume is, for example, 20, 30, 35, 50 or
100 mI. The objective is to administer a dose of between about 0.005-0.5
mg/kg per day to each eye, for a total dosage of between about 0.01-1.0
mg/kg/day, e.g. a dose of about 0.05 mg/kg per day to each eye, for a total
dosage of about 0.1 mg/kg/day. For example, the eyedrops can be used to
provide doses of 1 mg, 10 mg, or 50 mg. These dosage values are based
on known and presently understood pharmacology of the antagonist.
Dosage requirements are variable and must be individualized on the
basis of the disease and the response of the patient.
Suitable eyedrop formulations are those which are isotonic
and maintain sufficient contact with the eye surface to systemically
deliver the active agent to the patient. Such formulations
advantageously have a pH approximating neutrality and are non-
irritating to the eye, e.g. they do not induce tearing and consequential
flow of active agent out of the eye. Pharmaceutically acceptable carriers
are, for example, water, mixtures of water and water-miscible solvents
such as lower alkanols or arylalkanols, vegetable oils, polyalkylene
glycols, petroleum based jelly, ethyl cellulose, hydroxy ethyl cellulose,
ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl
myristate and other conventionally-employed non-toxic,
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pharmaceutically acceptable organic and inorganic carriers. The
pharmaceutical preparation may also contain non-toxic auxiliary
substances such as emulsifying, preserving, wetting agents, bodying
agents and the like, as for example, polyethylene glycols 200, 300, 400 and
600, carbowaxes 1000, 1500, 4000, 6000 and 10000, antibacterial
compounds, phenylmercuric salts known to have cold sterilizing
properties and which are non-injurious in use, thimerosal, methyl and
propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients
such as sodium chloride, sodium borate, sodium acetates, gluconate
buffers, and other conventional ingredients such as sorbitan
monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan
monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,
thiosorbitol, ethylenediamine tetraacetic acid, and the like.
Additionally, suitable ophthalmic vehicles can be used as carrier media
for the present purpose including conventional phosphate buffer vehicle
systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles,
isotonic sodium borate vehicles and the like.
In the procedure for making eyedrops, formulations are
rendered sterile by appropriate means, such as starting the preparation
procedure with sterile components and proceeding under sterile
conditions, irradiating or autoclaving the finished formulation, and the
like. Suitable anti mirxobial agents are also useful for maintaining
sterility of the eyedrop.
The ocular preparation may also be a solid insert such as
one which, after dispensing the antagonist, remains essentially intact,
or a bioerodible insert that is soluble in lacrimal fluids, or otherwise
disintegrates. For example, one may use a solid water soluble polymer
as the carrier for the antagonist. The polymer used to form the insert
may be any water soluble non-toxic polymer, for example, cellulose
derivatives such as methylcellulose, sodium carboxymethyl cellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl
cellulose, acrylates such as polyacrylic acid salts, ethylacrylates,
polyacrylamides, natural products such as gelatin, alginates, pectins,
tragacanth, karaya, chondrus, agar, acacia, starch derivatives such as
starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as
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well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl
pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized
carbopol, gellan gum and xanthan gum, and mixtures of said polymers.
The ocular preparation may also be an ointment which is
compounded, for example, by mixing finely milled powdered ingredients
with a small amount of white petrolatum and levigating or otherwise
mixing until a uniform distribution is achieved. The balance of white
petrolatum is added by geometric addition until the desired dosage form
is made.
The present invention is demonstrated in a study of patients
with acute coronary ischemic syndromes. Such patients may undergo
early coronary revascularization with percutaneous coronary
angioplasty or atherectomy. Acute coronary ischemic syndrome is
associated with unstable angina, nonfatal myocardial infarction, and
death, and subsequent follow-up procedures such as coronary artery
bypass grafting, repeat percutaneous intervention for acute ischemia,
and insertion of a coronary endovascular stent. 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. In
accordance with the methods of the invention, patients receive 2-S-(n-
butylsulfonylamino)-3-[4-(4-(piperidin-4-yl )butyloxy)phenyl)propionic
acid or pharmaceutically acceptable salts thereof with low molecular
weight heparin and optionally aspirin.
The following examples show that therapeutic levels of
unfractionated heparin combined with tirofiban elicit prolongation in
bleeding time that is greater than prolongation in bleeding time
resulting from administration of therapeutic levels of low molecular
weight heparin combined with tirofiban.
A patient is treated for unstable angina by intravenously
receiving tirofiban in an amount of 0.4 p,g/kg/min for 30 minutes
followed by 0.1 p.g/kg/min for 47.5-107.5 hours. During tirofiban therapy,
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LOVENOX~ enoxaparin is subcutaneously administered in an amount
of 1 mg/kg every 12 hours.
A patient is treated for non-Q wave myocardial infarction by
intravenously receiving tirofiban in an amount of 0.4 ~,g/kg/min for 30
minutes followed by 0.1 ~tg/kg/min for 47.5-107.5 hours. During tirofiban
therapy, LOVENOX~ enoxaparin is subcutaneously administered in an
amount of 1 mg/kg every 12 hours.
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In a dog, the effects of l~,g/kg/min tirofiban, a bolus dose of
700 pg/kg of low molecular weight heparin followed by intravenous
infusion of 7 ~,g/kg/min of low molecular weight heparin, and a bolus
dose of 5 mg/kg of aspirin, individually and in combination, on template
bleeding times, were measured after the initiation of infusions.
Bleeding time was measured using a SIMPLATE~ bleeding time device
(Organon Teknika Corporation, Durham, NC) to make incisions on the
mucous membrane of the inner, upper lip of the dog and were measured
for a maximum of 20 minutes. Activated partial thromboplastin times
(APTT, ex vivo measurement of intrinsic coagulation pathway in
plasma) and activated clotting times (ACT, ex vivo measurement of
intrinsic coagulation pathway in whole blood) were determined as an
indication of the function of the clotting factors. Following blood
collection and centrifugation, plasma for APTT determination was
removed and stored on ice for later assay. APTTs were determined
using an automated clot timer (ELECTRA 900, Medical Laboratory
Automation, Mt. Vernon, NY) and commercially available reagents
(American Dade, Aquada, Puerto Rico), ACTs were measured and
determined immediately using fresh, unanticoagulated whole blood
(ACT II, Medtronic HemoTec, Inc., Parker, Colorado). AntiXa activity
was determined using a colorimetric assay with the Stachrom~
Heparin kit (MLA Electra 900C). Whole blood platelet counts were
determined using an automated hematology analyzer (Biochem
Immunosystems, Allentown, PA. The concentration of tirofiban in dog
plasma was obtained by radioimmunoassay.
90 minutes following initiation of treatment, the three-way
combination of tirofiban, low molecular weight heparin and aspirin
(TLA) showed greater bleeding times than tirofiban + low molecular
weight heparin (TL) or aspirin + low molecular weight heparin (AL).
Results obtained by substituting unfractionated heparin (H) for low
molecular .weight heparin are compared below:
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TLA - 3.1 minutes
THA- 7.3 minutes
TL - 1.7 minutes
TH - 5.3 minutes
AL - 1.5 minutes
AH - 8.0 minutes
The study results indicate that use of low molecular weight
heparin in combination with tirofiban provides reduced prolongation of
bleeding time as compared to the use of unfractionated heparin in
combination with tirofiban.
Intravenous formulations
An intravenous dosage form of tirofiban is prepared as
follows:
Tirofiban 0.5-100.0 mg
Sodium Citrate 5-50mg
Citric Acid 1-l5mg
Sodium Chloride 1-8mg
Water for Injection (USP) q.s. to 1 L
Utilizing the above quantities, the active compound 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, Maryland, copyright 1994.
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Int~ave~r~ous formulations
A pharmaceutical composition was prepared at room
temperature using tirofiban, a citrate buffer, and sodium chloride, to
obtain a concentration of tirofiban of 0.25 mg/ml.
800 grams of water was introduced into a standard
pharmaceutical mixing vessel. 0.25 grams of tirofiban 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:
Ingredient
Tirofiban 0.25 mg/ml
citrate buffer 10 mM
sodium chloride 8 mg/ml
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.
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