Note: Descriptions are shown in the official language in which they were submitted.
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WO 97/37641 PCT/US97/05800
TITLE OF THE ~VENTION
ORAL COATED ACTIVE DRUGS
BACKGROUND OF THE ~NVENTION
The present invention relates to a coated solid active drug
composition having releasability of the active drug in the small or large
intestine or, more particularly, to a coated solid fibrinogen receptor
antagonist composition which, when orally admini~tered, passes
unaffected through the stomach but is disintegrated when it reaches the
10 small or large intestine so as to release the therapeutically active drug
contained therein only in the small or large intestine.
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
15 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 occlu.sive
20 thrombus formation in the lumen of the blood vessel.
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 translllmin~l coronary angioplasty
25 (PTCA). Available drugs, such as aspirin and ticlopidine, have shown
efficacy in syndromes involving vascular occlusion, presumably due to
sustained inhibition of platelet function. However, the inhibitory effects
of aspirin and ticlopidine are dependent upon the agonist which activates
the platelet. For example, aspirin is effective in blocking platelet
30 aggregation induced by agonists such as collagen that are dependent upon
the cylooxygenase pathway. It is, however, less effective against
concentrations of thrombin which can act by cyclooxygenase independent
pathways. Likewise, ticlopidine's inhibitory effect~s can be overcome by
combinations of agonists. Thus, an efficaciou.s inhibitor of platelet
_ . ,
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aggregation that acts independently of the agonist and the pathway
activating the platelet could be an important therapeutic advance
providing greater efficacy than aspirin or ticlopidine in a broader
spectrum of thrombotic events.
S The final obligatory step in platelet aggregation is the
binding of fibrinogen to an activated membrane-bound glycoprotein
complex, GP IIb/IIIa (a~ 3). 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 results 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/ma 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.
Orally active agents include SC54684, which is a prodrug
(i.e., it requires biotransformation in vivo to its active form) with high
oral bioavailability and RO43-8857, GRl44053, and DMP728, which are
themselves the active inhibitors (Cook et al. ibid.; and Cox et al. ibid.).
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 all of them retain the basic charge relations of
the RGD sequence with a positive charge separated from a negative
charge by approximately 10-20 A (Cook et al. ibid.; and Cox et al. ibid.).
Acad. ibid.).
Oral fibrinogen receptor antagonists are readily absorbed
when a patient consumes them on an empty stomach. However, it has
been recently observed that absorption and bioavailability of oral
fibrinogen receptor antagonists, when taken with food, may be reduced
by the presence of food in the stomach.
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Food is digested in the stomach, by mixing with digestive
aids such as secreted acid and digestive enzymes, to form a material
referred to as chyme. Chyme is a thick semifluid mass of partly digested
food that is passed from the stomach to the duodenum
The present invention provides a mean.s for allowing the
active drug to remain in the stomach in the presence of food. By this
means, food is converted in the stomach to chyme and emptied into the
duodenum prior to transfer of the active drug into the duodenum. The
active drug is transferred to the duodenum only after food has first been
converted into chyme and passed into the duodenum. The active drug is
thus released in the intestine following food digestion, thereby preventing
food interaction.
SUMMARY OF THE rNVENTION
The invention is an oral, coated pharmaceutical composition
suitable for administration to a patient . The coated compositions
comprise an active drug, suitable solid oral dosage form pharmaceutical
excipients, and a suitable protective enteric coating surrounding the
active drug and pharmaceutical excipients. The suitable coating prevents
release from the composition of active drug while the coated composition
is located in the stomach, and provides for release of the active drug
following transfer of the composition from the stomach to the intestine.
The compositions have sufficient effective diameter to prevent gastric
emptying of the composition from the stomach into the duodenurn until
gastric emptying of chyme from the stomach is completed.
The compositions are specifically designed to prevent
interaction of the active drug with food. While the compositions remain
in the stomach, food is converted in the stomach to chyme and then
transported to the duodenum. Only after gastric emptying of the chyme
does the composition leave the stomach and enter the duodenum. The
active drug is then released from the coated composition into the
intestine.
The compositions include a coated medicament having
releasability of the active drug only in the intestine having an inner core
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and an outer coating, wherein the inner core comprise.s active drug and
one or more suitable pharmaceutically acceptable excipients, and wherein
the outer coating does not substantially dissolve in the stomach and does
substantially dissolve in the intestine.
The invention also includes a method for preventing
interaction between food and an active drug whose absorption is affected
by the presence of food, which comprises a~lrninistering to the patient an
oral, coated pharmaceutical composition of the invention which releases
the active drug into the intestine after food has been digested.
The active drug can be a fibrinogen receptor antagonist
suitable for ~ ninistration to a patient in need of therapy for inhibiting
platelet aggregation. The coated compositions of the invention thus may
comprise an inhibitor of fibrinogen binding to the GP IIb/IIIa receptor,
suitable solid oral dosage form pharmaceutical excipients, and a suitable
protective enteric coating surrounding the inhibitor and pharmaceutical
excipients. The suitable coating prevents release from the composition of
the fibrinogen receptor antagonist while the coated composition is located
in the stomach, and provides for release of the fibrinogen receptor
antagonist following transfer of the composition from the stomach to the
intestine. This only occurs after the food has been digested and
elimin~ted from the stomach.
The invention also includes the use of a composition of the
invention in the manufacture of a medicament for reducing the risk of
acute coronary ischemic syndrome in patients at risk to acute coronary
ischemic syndrome, in a m~mm~l.
The compositions are particularly useful for reducing the
risk of acute coronary ischemic syndrome in patients at risk to acute
coronary ischemic syndrome. The compositions minimi7e the risk
associated with oral fibrinogen receptor antagonists that interact with
food, and provide a safer means for treating patients in need of fibrinogen
receptor antagonists.
The invention also includes a composition in the
manufacture of a medicament for preventing, in a patient, interaction
. .
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between food and an active drug, the absorption rate of which drug is
substantially affected by the coinciding presence of food in the stomach.
DETAILED DESCRIPTION OF THE lNVENTION
S The invention is an oral drug dosage unit, for ~lministration
to a patient, having active drug, and an effective diameter and surface
composition sufficient for the unit to be transported from the stomach
into the duodenum following substantially complete emptying of chyme
from the stomach into the duodenum and prior to release of active drug
from the unit, wherein the active drug has an absorption rate that is
affected by the coinciding presence of food in the stomach, the effective
diameter of the unit prevents gastric emptying of the unit prior to gastric
emptying of chyme, and the surface composition is an enteric coating
which prevents release of the active drug in the stomach and allows
release of the active drug in the intestine.
Active drugs having food interaction are those where drug
absorption is affected by the presence of food, to such an extent that the
medicinal benefit ordinarily provided by the drug (in the absence of food)
is detrimentally altered.
Compositions within the scope of the invention, having
releasability of the active drug only in the intestine, have an inner core
and an outer enteric coating, wherein the inner core comprises an active
drug and one or more suitable pharmaceutically acceptable excipients,
and wherein the outer coating does not substantially dissolve in the
stomach and does substantially dissolve in the intestine.
The invention also includes a method for preventing, in a
patient, interaction between food and an active drug, the absorption rate
of which drug is substantially affected by the coinciding presence of food
in the stomach, which comprises administering to the patient an oral drug
dosage unit having the active drug, an effective diameter sufficient for the
unit to be transported from the stomach into the duodenum following
substantially complete emptying of chyme from the stomach into the
duodenum and prior to relea~se of active drug from the unit, and an enteric
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- 6 -
coating .surface composition which retains the active drug in the stomach
and relea~ses the active drug in the inte.stine.
In the compositions of the invention, the coating which
delays release of the active drug is insoluble in pH environments such as
5 those in the stomach, e.g. less than 4, but soluble in pH environment.s
such as those in the intestine, e.g. about 5.5. or greater.
The effective diameter of the pharmaceutical composition of
the invention is between about 3 mm and 20 mm, preferably between
about 6 and 15 mm, e.g. 7, 8, 9, lO, l 1, 12, 13, and 14 mm. "Effective
lO diameter" for purposes of this invention refers to the dimension of the
composition that is presented to the opening between the stomach and the
duodenum and which limits entry of the composition into the duodenum.
For example, the effective diameter of a spheroid is the diameter of the
spheroid. The effective diameter of a tablet is the diameter of the tablet
15 face. The effective diameter of a cylindrical capsule is the diameter of
the narrow dimension of the cylinder.
The compositions of the present invention may be prepared
in any of a number of ways as long as the objective of preventing release
of the active drug in the stomach and providing for release of the active
20 drug in the intestine is achieved. Such compositions are prepared with
enteric coatings that are insoluble in gastric juices but readily soluble on
passage into the intestine.
Compositions of the invention may also be prepared by
mixing the active drug with an excipient, and coating the mixture with a
25 thin polymer film. For example, the active drug is mixed with
microcrystalline cellulose to form a spheroid which is then coated with a
film of hydroxypropyl methyl cellulose phthalate which may or may not
contain a plasticizer which prevent.s any relea.se of the drug in the
stomach. When the composition reaches the intestine, the active drug is
30 released.
Compositions of the invention may also be prepared by
- mixing the active drug and an acid such as fumeric or tartaric acid which
is compressed into a tablet or capsule shape and coated with lacquers that
are insoluble in gastric juices and soluble in intestinal juices.
..... . .
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Compositions of the invention may also be prepared by mixing the active
drug with materials for forming a gel capsule, inserting drug particles into
a capsule, or inserting a liquid drug formulation into a capsule, which
capsules are then coated with lacquers that are in.soluble in gastric juices
5 and soluble in intestinal juices. These lacquers include copolymers of
acrylic acid and methacrylic acid esters. The acidic matrix prevents
quick dissolution early and yet promotes the drugs' bioavailability further
downstream in the digestive tract.
Compositions of the invention may also be prepared by
10 coating a solid dosage form of the active drug 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 coating 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 phth~ te, hydroxypropyl methyl cellulose hexahydrophthalate,
shellac, cellulose acetate, cellulose acetate phthalate, polyvinyl acetate
20 phthalate, carboxymethyl ethyl cellulose, methacrylic acid copolymers,
methacrylic ester copolymers and the like. A commercially available
enteric coating system (Sureteric YAE-6-18107), which contains
polyvinyl acetate phthalate, talc, polyethylene glycol, titanium dioxide,
sodium bicarbonate, triethyl citrate, purified stearic acid, sodium alginate,
25 and colloidal silicon dioxide, may be used.
In general, solid dosage forms comprising the active drug
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
30 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.
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Some pans have a cylindrical shape, are rotated horizontally,
and have at lea~t some regions of the walls perforated by small holes or
~lots. This design permits 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 air. 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.
Active drugs useful in the pre.sent invention include
fibrinogen receptor antagonists such as those described in United States
Patents 5,470,849, 5,463,011, 5,455,243, 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,
5,33~,7235,334,596, 5,321,034, 5,318,899,5,312,923, 5,294,616,
5,292,756, 5,281,5~5 5,272,158, 5,264,420,5,260,307, 5,239,113 (e.g.
Ethyl 3-L[4-~4-(aminoiminomethyl)phenyl]amino]-1,4-
dioxobutyl3amino]-4-pentynoate), 5,227,490, 5,206,373, 4,703,036 (e.g.
N-Methyl-D-phenylalanyl-N-[(l S)- 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 -piperidinyl)- 1 -
(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glyci~e), (R)-methyl-3-[[[3-[4-
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WO 97/37641 PCT/US97/05800
(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]acetyl lamino]-N-
(butoxycarbonyl)-L-alanine monoacetate, EP 333 356, and WO 9422820.
They are described as useful for inhibiting fibrinogen binding and
inhibiting clot formation.
S Glycoprotein IIb/ma receptor antagonists and their
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, c}avulanate,
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, mucate,
napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate,
succinate, t~nn~te, tartrate, teoclate, tosylate, triethiodide, valerate.
Pharmaceutically effective amounts of the glycoprotein
IIb/IIIa receptor antagonists are suitable for use in the compositions and
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 ~nim~l that
is being sought by a researcher or clinician.
The methods of the present invention are useful in
combination with procedures for treating patients 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).
In accordance with the invention, glycoprotein IIb/IIIa
receptor antagonists can be ~flministered to the patient in one oral
composition, such as a tablet or capsule, or in several oral compositions.
Suitable oral compositions include tablets, compressed
capsules, gel capsules cont~ining drug integrated into the gel matrix
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- 10-
forming the gel capsule, gel cap,sules containing drug particles, or gel
capsules containing liquid drug composition (each of which may include
sustained release or tirned release formulations), which are coated with an
enteric coating. The coated composition may be a tablet comprising the
5 active drug with other excipients and an enteric coat, a non-tablet solid
complex comprising the active drug with other excipients and an enteric
coat contained in a capsule (e.g. wherein the non-tablet solid complex is
loaded into the capsule) which is coated with an enteric coat, or other
form, with the condition being that the active drug is protected from
10 release in the stomach but not from release in the intestine.
The active drug may be ~-lmini.stered to patients where
prevention of thrombosis by inhibition of binding of fibrinogen to the
platelet membrane glycoprotein complex IIb/IIIa receptor is desired.
Such ~mini~tration is useful in surgery on peripheral arteries (arterial
15 grafts, carotid endarterectomy) 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.
The aggregated platelets may form thrombi and thromboemboli. The
active drugs may be administered to these surgical patients to prevent the
20 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 reocclusion
after angioplasty or coronary artery bypass procedures. The methods
25 may also be used to prevent myocardial infarction.
The dosage regimen utilizing the active drug 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
30 the patient; and the particular compound or salt thereof employed. An
ordinarily skilled physician or veterinarian can readily determine and
~ prescribe the effective amount of the drug re~uired to prevent, counter, or
arrest the progress of the condition.
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Oral dosages of active drug 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
5 between 0.1 mg and 500 g, preferably between 1.0 mg and 250 g, most
preferably between 1.0 mg and 150 g, e.g. l mg, 50 mg, 100 mg, 150 mg,
250 mg, or 500 mg. Oral ~clministration may be in one or divided doses
of two, three, or four times daily.
The active drug can be ~ ini.~tered in admixture with
10 suitable pharmaceutical diluents, excipients or carriers (collectively
referred to herein as "carrier" materials) suitably selected with respect to
the intended form of ~lmini.~tration, that is, oral tablets, capsules, and the
like, and consistent with convention pharmaceutical practices.
For instance, for oral ~(lmini~tration in the forrn of a tablet or
15 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, microcrystalline cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the
like. Moreover, when desired or necessary, suitable binders, lubricants,
20 disintegrating 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
25 forms include sodium oleate, sodium stearate, magnesium stearate,
stearic acid, sodium benzoate, sodium acetate, sodium chloride and the
like. Disintegrants include, without limitation, starch and derivatives
thereof, microcrystalline cellulose, methyl cellulose, agar, bentonite,
croscarmellose sodium, xanthan gum and the like.
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Therapeutic Treatment
The compositions are useful for treating patients where
inhibition of human or mamm~lian platelet aggregation or adhesion is
desired. They are useful in surgery on peripheral arteries (arterial grafts,
S 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 forrnation of thrombi
and thromboemboli. Methods of the invention may be used to prevent
the formation of thrombi and thromboemboli.
The present invention is demonstrated in a study of patients
with acute coronary ischemic syndromes 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
15 considerable higher morbidity than procedures perforrned in patients with
stable coronary disease. All patients receive heparin (a standard PTCA
regimen, weight adjusted in lighter patients) and aspirin. Heparin is
discontinued after completion of the procedure and sheaths removed
when the heparin-effect has dissipated. The compositions are
20 administered to patients who are evaluated at 30 days for acute coronary
ischemic syndrome and the need for follow-up intervention associated
with acute coronary ischemic syndrome, including coronary artery bypass
grafting, repeat percutaneous intervention for acute ischemia, and
insertion of a coronary endovascular stent.
EXAMPLE 1
gp IIb/IIIa anta~onist treatment (oral)
Patients with acute coronary ischemic syndromes receive
30 coronary revascularization with angioplasty. A,spirin is ~lmini.stered in a
dose of 325 mg at least two hours before angioplasty, and daily
thereafter. Heparin is given intravenously in an initial bolus dose of
10,000 to 12,000 units followed by incremental bolus doses of up to 3000
units at 15-minute intervals, but no more than 20,000 units is given
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WO 97/37641 PCT/US97/05800
during the procedure. The goal is to keep the activated clotting time
between 300 and 350 seconds during the operation. Heparin i,s continued
by constant infusion for at least 12 hours to maintain the activated partial-
thromboplastin time at 1.5 to 2.5 times the control value. Aspirin is
5 required at discharge in a dose of 325 mg per day.
Patients receive an oral tablet, as prepared in Example 2,
containing 15 mg of the fibrinogen receptor gp IIb/IIIa antagonist 2(S)-
[(p-Toluenesulfonyl)amino]-3-[[l 5,6,7,8-tetrahydro-4-oxo-5-[2-
(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a] [1,4]diazepin-2-yl]carbonyl]-
10 amino]propionic acid (compound 1 - 1), described in WO 94/18981.
Patients are monitored 30 days following initiation of the
fibrinogen receptor gp IIb/IIIa antagonist infusion, and show reduction in
acute coronary ischemic syndrome after 30 days.
EXAMPLE 2
Tablet Preparation
Coated tablets containing 15 mg of the fibrinogen receptor
gp IIb/IIIa antagonist 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-
tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-L 1,5-
a][1,4]diazepin-2-yl]carbonyl]-amino]propionic acid (compound 1-1) are
prepared as illustrated below:
Tablet for doses containing 15 mg of the
gp IIb/IIIa receptor antagonist
Ingredient mg
1-1 15.0
Microcrystalline cellulose 42.2
Dicalcium phosphate 42.2
Croscarmellose sodium 0.1
Magnesium stearate 0.5
Hydroxypropyl methyl 10
cellulose phth~l~te
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- 14-
Compound 1-1, microcry~talline cellulose, dicalcium
pho~phate and croscarmellose sodium are mixed and then lubricated with
magnesium stearate and the resulting mixture is then compressed into
tablets having diameter of ~ mm. The tablets are coated in a coating pan
5 with hydroxypropyl methyl cellulose phthalate in a coating amount of 10
mg per tablet.
EXAMPLE 3
10 Tablet Preparation
Coated tablets containing 15 mg of the fibrinogen receptor
gp IIb/IIIa antagonist 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,~-
tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[ 1 ,5-
a][1,4]diazepin-2-yl~carbonyl~-amino]propionic acid (compound 1-1) are
15 prepared as illustrated below:
Tablet for doses containing 15 m~ of the
~p IIbmIa receptor antagonist
Ingredient ~g
1-1 15.0
Microcrystalline cellulose 200.0
Modified food corn starch 8.5
Magnesium stearate 1.5
Hydroxypropyl methyl 20.0
cellulose phthalate
Compound 1-1, microcrystalline cellulose, and a portion of
the corn starch are mixed and granulated into lO~o corn starch paste. The
resulting granulation is sieved, dried and blended with the remainder of
25 the corn starch and the magnesium stearate. The resulting granulation is
then compressed into tablets having diameter of 8 mm. The tablets are
coated in a coating pan with hydroxypropyl methyl cellulose phthalate in
a coating amount of 20 mg per tablet.
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WO 97/37641 PCT/US97/05800
EXAMPLE 4
Cap~sule Preparation
Capsules containing the fibrinogen receptor gp IIb/IIIa
5 antagonist 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 (compound 1-1) are prepared as
illustrated below:
In~redient ~g
1-1 15.0
Microcrystalline cellulose 42.2
Dicalcium phosphate 42.2
Croscarmellose sodium 0.1
Magnesium stearate 0.5
Hydroxypropyl methyl 10
cellulose phth~l~te
Compound 1-1, microcrystalline cellulose, disodium
phosphate and croscarmellose sodium are mixed in a blender. The
resulting mixture is granulated and dried prior to milling. Milled
15 granule.s are lubricated and filled into a standard ph~ ceutical capsule,
having a narrow dimension of 4 mrn, which is then coated with
hydroxypropyl methyl cellulose phth~l~te.
EXAMPLE 5
Tablet Preparation
Tablets containing the fibrinogen receptor gp IIb/IIIa
- antagonist 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,~-tetrahydro-4-
oxo-5-[2-(piperidin-4-yl)ethyl] -4H-pyrazolo-[ 1 ,5-a] [ 1 ,4]diazepin-2-
25 yl]carbonyl]-amino]propionic acid (compound I -1 ) are prepared as
illustrated below.
CA 022~1022 1998-10-06
WO 97/37641 PCT/US97/05800
- 16-
Tablet core components
In~redient m~
1-1 1.0
Microcrystalline cellulose 146.42
Calcium phosphate diba,sic 146.42
Croscarmellose sodium 4.5
Magnesium stearate 1.5
Compound 1-1, microcrystalline cellulose, calcium
phosphate dibasic, croscarmellose sodium were combined in a
conventional manner to form the core tablet. Tablets were then coated
with a pre-coat solution of 2.4 mg hydroxypropylmethylcellulose, 2.4 mg
hydroxypropylcellulose, 0.96 mg titanium dioxide, and 60 microliters of
water. After the pre-coat solution was applied, the enteric coat was added
The enteric coat was made using Colorcon's Sureteric TAE-
6-1~107 aqueous based enteric coating system. A 15% solution of
Sureteric was made by suspending the powder in water. Dow Corning's
antifoam AF emulsion was added to prevent foaming (weight equal to
0.334% of the weight of the Sureteric in the suspension). The solution
was added until a 10% weight gain (based on core tablet weight of 300
mg) was achieved.
EXAMPLE 6
The tablet prepared in Example S was prepared. After the
enteric coating wa.s applied, an additional pre-coat solution of 2.4 mg
hydroxypropylmethylcellulose, 2.4 mg hydroxypropylcellulose, 0.96 mg
titanium dioxide, and 60 microliters of water was added to achieve a 3%
weight gain.
