NZ625998B2 - Methods for treating cardiovascular disorder - Google Patents
Methods for treating cardiovascular disorder Download PDFInfo
- Publication number
- NZ625998B2 NZ625998B2 NZ625998A NZ62599812A NZ625998B2 NZ 625998 B2 NZ625998 B2 NZ 625998B2 NZ 625998 A NZ625998 A NZ 625998A NZ 62599812 A NZ62599812 A NZ 62599812A NZ 625998 B2 NZ625998 B2 NZ 625998B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dosage form
- metoprolol
- tablet
- pharmaceutically acceptable
- pharmaceutical dosage
- Prior art date
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
pharmaceutical dosage form for treatment of cardiovascular disorders and suitable for once daily administration comprising a fixed dose combination of: (a) metoprolol or a pharmaceutically acceptable salt thereof in extended release form, (b) Clopidogrel or a pharmaceutically acceptable salt thereof, and (c) one or more rate controlling excipients. The dosage form exhibits a dissolution profile such that less than 6% of metoprolol or a pharmaceutically acceptable salt thereof is released within 1 hour, when the release rate is measured in USP Type 2 Dissolution apparatus in paddle type at 50 rpm using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium. of, and (c) one or more rate controlling excipients. The dosage form exhibits a dissolution profile such that less than 6% of metoprolol or a pharmaceutically acceptable salt thereof is released within 1 hour, when the release rate is measured in USP Type 2 Dissolution apparatus in paddle type at 50 rpm using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.
Description
METHODS FOR TREATING CARDIOVASCULAR DISORDER
Field of The Invention
The present invention relates to a once-a-day therapeutically synergistic
pharmaceutical dosage form for treatment of cardiovascular disorders, wherein
the dosage form comprises a fixed dose combination of metoprolol in extended
release form and one or more antiplatelet agent along with one or more rate
controlling excipients.
Background Of The Invention
"Cardiovascular disease or disorder" is intended to mean any cardiovascular
disease or disorder known in the art, including, but not limited to, congestive
heart failure, complications associated with diabetes mellitus,
hyperhomocysteinemia, hypercholesterolemia, atherosclerosis, inflammatory
heart disease, valvular heart disease, restenosis, hypertension ( e .g. pulmonary
hypertension, labile hypertension, idiopathic hypertension, low-renin
hypertension, salt-sensitive hypertension, low-renin, salt-sensitive hypertension,
thromboembolic pulmonary hypertension; pregnancy-induced hypertension;
renovascular hypertension; hypertension-dependent end-stage renal disease,
hypertension associated with cardiovascular surgical procedures, hypertension
with left ventricular hypertrophy, and the like) , diastolic dysfunction, coronary
artery disease, myocardial infarctions, cerebral infarctions, arteriosclerosis,
atherogenesis, cerebrovascular disease, angina (i ncluding chronic, stable,
unstable and variant ( P rinzmetal) angina pectoris), aneurysm, ischemic heart
disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet
aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-
vascular complications associated with the use of medical devices, vascular or
non-vascular wall damage, peripheral vascular disease, neointimal hyperplasia
following percutaneous transluminal coronary angiograph, vascular grafting,
coronary artery bypass surgery, thromboembolic events, post-angioplasty
restenosis, coronary plaque inflammation, embolism, stroke, shock, arrhythmia,
atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion
cerebrovascular incidents, and the like.
Many individuals at an elevated risk of suffering serious to life-threatening
cardiovascular events, such as myocardial infarction (h eart attack), cardiac
arrest, congestive heart failure, stroke, peripheral vascular disease and/or
claudication. And the risk factors for these are numerous and widespread
throughout the world. They include cigarette smoking, diabetes,
hypercholesterolemia (h igh serum cholesterol), hypertension, angina, systemic
lupus erythematosus, prior heart attacks or strokes, hemodialysis,
hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ
transplant, atherosclerosis, and others. There is a need for a safe and convenient
pharmaceutical formulation that would effectively reduce the risk of incurring a
cardiovascular event in individuals who have these risk factors.
Many individuals at an elevated risk of suffering serious to life-threatening
cardiovascular events, such as myocardial infarction ( h eart attack), cardiac
arrest, congestive heart failure, stroke, peripheral vascular disease and/or
claudication. And the risk factors for these are numerous and widespread
throughout the world. They include cigarette smoking, diabetes,
hypercholesterolemia (h igh serum cholesterol) , hypertension, angina, systemic
lupus erythematosus, prior heart attacks or strokes, hemodialysis,
hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ
transplant, atherosclerosis, and others. There is a need for a safe and convenient
pharmaceutical formulation that would effectively reduce the risk of incurring a
cardiovascular event in individuals who have these risk factors.
The treatments and drugs discovered or known in the art for cardiovascular
disease includes the beta-blockers, for example, atenolol, metoprolol, nadolol,
oxprenolol, pindolol, propranolol, timolol; Alpha blockers, for example, doxazosin,
phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline;
mixed alpha and beta blockers, for example, bucindolol, carvedilol and labetalol,
etc.
Beta-blocker, for example, metoprolol acts by blocking the adrenergic stimulation
of the heart and thus reduces the oxygen demand of the cardiac tissue.
Apparently, this explains their beneficial effects in angina pectoris and
cardioprotective action in myocardial infarction. In addition, beta-blockers
normalize blood pressure in a large proportion of patients with arterial
hypertension, which probably is due to an additional action on the control of
peripheral resistance to blood-flow.
Metoprolol ( Fo rmula I) is a beta1-selective (ca rdioselective) adrenoreceptor-
blocking agent. It is commercially available in two salt forms; one of them is
tartrate salt available as Lopressor tablets and the other is succinate salt
available as Toprol-XL tablets. The Toprol XL tablets contain 23.75, 47.5, 95 and
190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of
metoprolol tartrate, USP, respectively. Metoprolol is indicated in the treatment of
hypertension, heart failure and angina pectoris.
Formula I
Initial therapy with a diuretic or beta-blocker has been the usual first approach for
treating cardiovascular disorders. Several fixed dose combinations of anti-
hypertensive drugs are available in the market. One of the commercially
available cardiovascular drug combinations include Lopressor HCT® (M etoprolol
and Hydrochlorthiazide).
These cardiovascular combinations or individual drugs are also prescribed along
with other drugs such as cardioprotectant, platelet aggregation inhibitors,
anticoagulants, etc.
Anti-platelet drugs are class of pharmaceuticals that decrease platelet
aggregation and inhibit thrombus formation. They are widely used in primary and
secondary prevention of thrombotic cerebrovascular or cardiovascular disease.
Commonly used anti-platelet drugs include Cyclooxygenase inhibitors e.g.
Aspirin, Adenosine diphosphate ( A DP) receptor inhibitors e.g. Clopidogrel
® ® ® ®
( P lavix ); Prasugrel (E ffient ); Ticagrelor (B rilinta ); Ticlopidine (T iclid ) ;
Phosphodiesterase inhibitors e.g. Cilostazol (P letal ); Adenosine reuptake
inhibitors e.g. Dipyridamole (P ersantine ) , etc.
Aspirin suppress the production of prostaglandins and thromboxanes due to its
irreversible inactivation of the cyclooxygenase enzyme required for prostaglandin
and thromboxane synthesis. Low-dose, long-term aspirin use irreversibly blocks
the formation of thromboxane A2 in platelets, producing an inhibitory effect on
platelet aggregation. This antithrombotic property makes aspirin useful for
reducing the incidence of heart attacks.
Clopidogrel specifically and irreversibly inhibits the P2Y subtype of ADP
receptor, which is important in aggregation of platelets and cross-linking by the
protein fibrin. The blockade of this receptor inhibits platelet aggregation by
blocking activation of the glycoprotein IIb/IIIa pathway.
As per the World Heart Federation, hypertension is the single most important risk
factor for stroke. It causes about 50 percent of ischemic strokes and also
increases the risk of hemorrhagic stroke.
Hypertension places strain on all blood vessels, thus makes them weaken and
predisposes them to damage. In such situation heart also work harder to keep
blood circulating. Once the blood vessels are gets weaken, they are more likely
to block. This can cause an ischemic stroke or transient ischemic attacks. Less
often, hypertension is implicated in hemorrhagic strokes when a blood vessel in
the brain bursts and blood leaks into the brain.
Hence, for preventing the transient ischemic attacks, there is need for a fixed
dose combination comprising anti-hypertensive agents along with one or more
antiplatelet agent.
The drawback of using cardiovascular drugs alone, for example metoprolol, is
release of some prostaglandins in the body, which may occur shortly after
administration of metoprolol dosage. Generally, the production of prostaglandin
suppress with the anti-platelet agent such as aspirin, clopidogrel and the like or
combination thereof.
Hence, combinations of beta-blockers with anti-platelet agents are expected to
provide a better control over various cardiovascular diseases. The said
combinations can be given as two separate drugs administered separately at
same time or at different timings.
However, in the combination product, each component causes a proportional risk
reduction. The long-term benefits would be even larger, perhaps more than a 75
percent overall risk reduction, since risk is only partially reversed in the first one
to two years of blood pressure and cholesterol lowering treatment.
The problem associated with these fixed dose combination is that it does not
provide physician an option to modulate the dose of drugs within these fixed
dose combinations according to need of a patient.
Since cardiovascular disorders are often chronic in nature, complex drug regimen
involving several drugs has a negative impact on patient’s life leading to non-
compliance. Moreover multiple medication administration, complex drug regimen,
and frequent dose administration complicates the patient’s compliance. Further, it
becomes difficult for the physician to prescribe appropriate doses of different
drugs when used in combination.
U.S. Patent No. 4,847,265 and 4,529,596 disclose clopidogrel and German
Patent No. 218467 discloses aspirin.
Compositions comprising beta-adrenergic blockers and/or antiplatelet agent have
been suggested in the prior art.
U.S. Patent No. 5,156,849 discloses a capsule comprising atenolol, aspirin, and
a barrier around the atenolol to prevent interaction between the aspirin and
atenolol.
U.S. Patent application No. 2004/0198839A1 discloses a single dosage form of a
beta-blocker agents and a platelet aggregation. The application, however, neither
discloses conditions for formation of single dosage form nor its release profile,
which may be responsible for synergistic therapeutic effect in cardiovascular
patient.
U.S. Patent application No. 2010/0261684A1 discloses pharmaceutical
combination of aspirin or clopidogrel, metoprolol and nitroglycerin as sub-lingual
tablet.
The prior art references do not disclose fixed dose combination of metoprolol in
extended release form along and antiplatelet agent and use of such composition
for treating cardiovascular disease.
Metoprolol is a cardioselective beta-blocker that has been classified as a class I
substance according to the Biopharmaceutics Classification Scheme BCS,
meaning that it is highly soluble and highly permeable. The drug is readily and
completely absorbed throughout the whole intestinal tract but is subject to
extensive first pass metabolism resulting in incomplete bioavailability (a bout
50%). On the other hand, clopidogrel, a representative example in class of anti-
platelet drugs, is poorly water-soluble drug. Clopidogrel is largely protein bound
to albumin (9 4-98%) and undergoes extensive first pass metabolism in the liver
with a low bioavailability. Thus, formulating a once-a-day dosage form of highly
water soluble metoprolol in a fixed dose combination comprising an extended
release metoprolol and poorly water soluble clopidogrel is a challenging task for
a pharmacist.
None of the above mentioned prior arts completely provide a once-a-day fixed
dose formulation comprising an extended release metoprolol and anti-platelet
agent, which is safe and has an enhanced therapeutic effect over the existing
individual drug therapy. The combination disclosed in the prior arts also does not
address the uniform release and bioavailability related aspects of either
metoprolol or antiplatelet agents when formulated into a once-a-day dosage
form. Further, preparing a fixed dose combination comprising metoprolol in an
extended release dosage form was also a major challenge as it was difficult to
achieve the desired therapeutic release of the combination when combined into a
single unit dosage form. Therefore, there is the need for the development of new
dosage forms comprising an extended release metoprolol and antiplatelet agent,
which are safe and effective.
Summary Of The Invention
In one general aspect of the invention, there is provided a pharmaceutical
dosage form for treatment of cardiovascular disorders and suitable for once daily
administration comprising a fixed dose combination of: (a ) metoprolol or a
pharmaceutically acceptable salt thereof in extended release form, (b )
Clopidogrel or a pharmaceutically acceptable salt thereof, and (c ) one or more
rate controlling excipients; wherein the dosage form exhibits a dissolution profile
such that less than 6% of metoprolol or a pharmaceutically acceptable salt
thereof is released within 1 hour, when the release rate is measured in USP Type
2 Dissolution apparatus in paddle type at 50 rpm using 500 ml of pH 6.8
phosphate buffer at 37°C ± 0.5°C as dissolution medium.
In another general aspect of the invention, there is provided a once-a-day
pharmaceutical dosage form for treatment of cardiovascular disorders, wherein
the dosage form comprises a fixed dose combination of about 25mg to about
200mg of metoprolol or salt thereof and about 5mg to about 770mg of one or
more anti-platelet agents or salt thereof.
In another general aspect of the invention, the once-a-day pharmaceutical
dosage form exhibits immediate release of antiplatelet agent.
In another general aspect of the invention, the extended release metoprolol
component of the dosage form comprises water swellable or water insoluble inert
core coated with one or more rate controlling excipient.
In another general aspect of the invention, the water swellable core comprises
microcrystalline cellulose, hydroxypropyl methylcellulose, starch or mixtures
thereof.
In another general aspect of the invention, the water insoluble inert core
comprises silicon dioxide, glass particles, plastic resin particles or mixtures
thereof.
In another general aspect of the invention, the rate controlling excipient
comprises one or more polymeric rate controlling excipients, non-polymeric rate
controlling excipients, or mixtures thereof.
In another general aspect of the invention, the polymeric rate controlling excipient
is selected from the group consisting of one or more of cellulose derivatives;
polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives,
polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene
oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives;
or any combinations thereof and non-polymeric rate controlling excipient is
selected from the group consisting of fat, wax, fatty acid, fatty acid ester, long
chain monohydric alcohol or their ester or any combinations thereof.
In another general aspect of the invention, there is provided a pharmaceutical
dosage form for treatment of cardiovascular disorders suitable for once daily
administration comprising a fixed dose combination of metoprolol or salt thereof
in extended release form and one or more antiplatelet agents or salt thereof
along with one or more rate controlling excipients, wherein the composition
exhibits a dissolution profile such that less than 6% of metoprolol is released
within 1 hour; 30%-50% of metoprolol is released within 6 hours and at least 90%
of metoprolol is released after 20 hours when the release rate is measured in
Apparatus 2 (US P, Dissolution, paddle, 50 rpm) using 500 ml of pH 6.8
phosphate buffer at 37°C ± 0.5°C as dissolution medium.
In another general aspect of the invention, the pharmaceutical composition
comprises pharmaceutically acceptable excipients selected from one or more
diluents, binders, glidants, solubilizers, lubricants, disintegrants, colorants,
suspending agent, thickeners or taste masking agents.
In another general aspect of the invention, the pharmaceutical dosage form is in
the form of a tablet, a capsule, granules, a tablet in tablet, tablet/s in capsule,
granules in capsule, an orally disintegrating tablet, a bilayer tablet, a trilayer
tablet, an in-lay tablet, or suspension.
In another general aspect of the invention, there is provided a method of treating
one or more disorders selected from hypertension, congestive heart failure,
angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic
cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular
hypertrophy, cognitive dysfunction, and chronic heart failure, wherein the method
comprises administering a once-a-day pharmaceutical dosage form comprising a
fixed dose combination of metoprolol or its salt in extended release form and one
or more antiplatelet agents or salt thereof along with one or more rate controlling
excipients to a patient in need of said treatment.
Embodiments of the pharmaceutical composition may include one or more of the
following features. For example, the pharmaceutically acceptable excipients may
include diluents, disintegrants, binders, bulking agents, anti-adherents, anti-
oxidants, buffering agents, colorants, flavoring agents, coating agents,
plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents, and
the like known to the art used either alone or in combination thereof.
Detailed Description of the Invention
The present inventors while working on the development of pharmaceutical
composition comprising a fixed dose combination of an extended release
metoprolol with one or more anti-platelet agents, surprisingly found that the
pharmaceutical composition of the present invention provides a predictable and
uniform dissolution profile resulting in therapeutically effective release of drugs
for about 24 hours.
The present invention provides a once-a-day fixed dose therapeutically
synergistic pharmaceutical dosage form comprising an extended release
metoprolol and immediate release anti-platelet agents, which are not only safe
and effective medication for treatment of cardiovascular disease but is also found
to be synergistic with enhanced efficacy. This increased efficacy simplifies the
management of cardiovascular diseases.
The present inventors have now developed a once-a-day therapeutically
synergistic pharmaceutical dosage form comprising an extended release
metoprolol, anti-platelet agent and one or more rate controlling excipients, which
is safe and effective. From the preliminary studies, applicants have surprisingly
found that the combination therapy results in at least 5% reduction in risk of
stroke based on individual’s response when compared to monotherapy.
The term “metoprolol”, as used herein, refers to a metoprolol base, or any
pharmaceutically acceptable salt thereof. For the purpose of present invention
metoprolol salt could be metoprolol succinate or tartrate.
In further embodiment, the fixed dosage form of the present invention comprises
metoprolol succinate 23.75mg, 47.5mg, 95mg and 190mg equivalent to 25mg,
50mg, 100mg and 200 mg of metoprolol tartrate or equivalent to 9.75mg,
19.5mg, 39mg and 78mg of metoprolol base respectively.
The term “anti-platelet agents”, as used herein, refers to anti-platelet drug base,
or any pharmaceutically acceptable salt or ester thereof.
As used herein, the term "salt" refers to any pharmaceutically acceptable salt
(e .g., acid or base) of a compound of the present invention, which upon
administration to a subject is capable of providing a compound of this invention
or an active metabolite or residue thereof. As is known to those of skill in the art,
"salts" of the compounds of the present invention may be derived from inorganic
or organic acids and bases. Examples of acids include, but are not limited to,
hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric,
glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric,
methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene
sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not
in themselves pharmaceutically acceptable, may be employed in the preparation
of salts useful as intermediates in obtaining the compounds of the invention and
their pharmaceutically acceptable acid addition salts. Examples of bases include,
but are not limited to, alkali metals (e .g., sodium) hydroxides, alkaline earth
metals (e .g., magnesium), hydroxides, ammonia, and compounds of formula
NW4+, wherein W is C1-4 alkyl, and the like. Examples of salts include, but are
not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate,
dodecylsulfate, cyclopentanepropionate, ethanesulfonate, fumarate,
flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate,
maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, undecanoate, etc.
As used herein, the term "ester" refers to any pharmaceutically acceptable ester
of a compound of the present invention, which upon administration to a subject,
is capable of providing a compound of this invention or an active metabolite or
residue thereof. Representative examples of ester include medoxomil, cilexetil,
etc.
For the purpose of present invention, "once-a-day" means that the composition of
the present invention is administered only once over a twenty-four hour period
thereby providing therapeutically beneficial blood levels of the drug(s ).
The term "fixed dose combination", as used herein, refers to a combination of
two or more separate drug ingredients, combined in a single unit dosage form, in
defined doses.
The term “therapeutically synergistic”, as used herein, refers to a therapeutic
effect achieved by a fixed dose combination treatment that exceeds the optimal
effect achieved by monotherapy associated with the same drugs used in the
combination. For example, X is the therapeutic effect obtained by “A” drug and Y
is the therapeutic effect obtained by “B” drug on administration, thus when “A”
and “B” drugs are given together, then the expected therapeutic effect would be
“X+Y” but when the therapeutic effect achieved by co-administration of both the
drugs in a fixed dose combination exceeds “X+Y” i.e. “( X +Y)* Z”, wherein Z is
more than 1, the combination is said to be therapeutically synergistic.
The phrase “inert core,” as used herein, includes core that is water insoluble and
non-swellable.
The phrase “insoluble,” as used herein, refers to inert core, which does not
dissolve in water.
The phrase “non-swellable,” as used herein, refers to inert core having 20% or
less swelling after 24 hours.
The term 'inlayed tablet' as used herein refers to a type of a layered tablet in
which instead of the core tablet being completely surrounded by a coating, the
top surface is completely exposed.
The term 'inlayed in said layer' is used herein to mean that the tablet of
metoprolol may be present at any position in said layer.
The term “bioavailable” as used herein, includes, but is not limited to the rate and
extent to which the drug(s ) become bioavailable to the site of action after
administration.
The term "Cmax" is the highest plasma concentration of the drug attained within
the dosing interval.
The term "Tmax" is the time period, which elapses after administration of the
dosage form at which the plasma concentration of the drug attains the highest
plasma concentration of drug attained within the dosing interval.
The term "AUC " as used herein, means area under plasma concentration-time
curve from drug administration to last observed concentration at time’t’.
The term "AUC " as used herein, means area under the plasma concentration-
time curve extrapolated to infinite time.
The term "mean", when preceding a pharmacokinetic value (e .g. mean Tmax)
represents the mean value of the pharmacokinetic value taken from a population
of patients or healthy volunteers.
The present invention provides once-a-day therapeutically synergistic
pharmaceutical dosage form for treatment of cardiovascular disorders, wherein
the dosage form comprises a fixed dose combination of an extended release
metoprolol with one or more antiplatelet agents.
In an embodiment, when the once-a-day therapeutically synergistic
pharmaceutical dosage form of the present invention comprises metoprolol in
extended release form and antiplatelet agents, the amount of metoprolol and
antiplatelet agents in the dosage form ranges between about 25mg to about
200mg and between about 5mg to about 770mg respectively.
In another embodiment, the present invention provides a once-a-day
therapeutically synergistic pharmaceutical dosage form for treatment of
cardiovascular disorders, wherein a unit dosage form comprises an extended
release metoprolol and anti-platelet agent in following combinations:
Doses of “Anti-platelet agent” in combination with metoprolol
Metoprolol
Doses
Clopidogrel Aspirin Anagrelide Dipyridamole Cilostazol Ticagrelor Prasugrel Ticlopidine
25mg 75mg 25mg 0.5mg 25mg 5mg 90mg 5mg 250mg
50mg 300mg 75mg 1 mg 50mg 20mg 10mg
100mg 80mg 75mg 40mg
200mg 81mg
300mg
In a further embodiment, the present invention provides a pharmaceutical dosage
form for treatment of cardiovascular disorders suitable for once daily
administration comprising a fixed dose combination of metoprolol or salt thereof
in extended release form and one or more antiplatelet agents or salt thereof
along with one or more rate controlling excipients, wherein the composition
exhibits a dissolution profile such that less than 6% of metoprolol is released
within 1 hour; 30%-50% of metoprolol is released within 6 hours and at least 90%
of metoprolol is released after 20 hours when the release rate is measured in
Apparatus 2 (US P, Dissolution, paddle, 50 rpm) using 500 ml of pH 6.8
phosphate buffer at 37°C ± 0.5°C as dissolution medium.
As mentioned in several embodiments of the present invention, the rate
controlling excipient is polymeric rate controlling excipient, non-polymeric rate
controlling excipient, or combination thereof.
Suitable polymeric rate controlling excipients are selected from, but not limited to,
one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and
derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof;
maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid
polymers and acrylic acid derivatives; or any combinations thereof.
Cellulose derivatives include, but are not limited to, ethyl cellulose,
methylcellulose, hydroxypropylmethylcellulose (HP MC), hydroxypropyl cellulose
(HP C), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl
ethylcellulose, carboxymethylethylcellulose, carboxyethylcellulose,
carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl
cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CM C),
methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl
sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.
Polyhydric alcohols include, but are not limited to, polyethylene glycol (P EG) or
polypropylene glycol; or any combinations thereof.
Saccharides, gums and their derivatives include, but are not limited to, dextrin,
polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate,
polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch,
hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust
bean gum, xanthan gum, karaya gum, tragacanth, carrageenan, acacia gum,
arabic gum or gellan gum or the like; or any combinations thereof.
Vinyl derivatives, polymers, copolymers or mixtures thereof include, but are not
limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate ( 8
parts w/w) and polyvinylpyrrolidone (2 parts w/w) (K ollidon SR), copolymers of
vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (P VP) ; or
combinations thereof.
Polyalkylene oxides or copolymers thereof include, but are not limited to,
polyethylene oxide, polypropylene oxide, poly (o xyethylene) -poly (oxypropylene)
block copolymers (p oloxamers) or combinations thereof.
Maleic acid copolymers include, but are not limited to, vinylacetate-maleic acid
anhydride copolymer, styrene- maleic acid anhydride copolymer, styrene- maleic
acid monoester copolymer, vinylmethylether- maleic acid anhydride copolymer,
ethylene-maleic acid anhydride copolymer, vinylbutyiether- maleic acid anhydride
copolymer, acrylonitrile- methyl acrylate- maleic acid anhydride copolymer, butyl
acrylate-styrene-maleic acid anhydride copolymer or the like or any combinations
thereof.
Acrylic acid polymers include any suitable polyacrylic acid polymers or
carboxyvinyl polymers such as those available under the brand name carbopol.
Pharmaceutically acceptable acrylic polymer may be include one or more, but not
limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate
copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(a crylic acid), poly(m ethacrylic acid) , methacrylic
acid alkylamide copolymer, poly(m ethyl methacrylate), poly(m ethacrylic acid)
(a nhydride), methyl methacrylate, polymethacrylate, poly( m ethyl methacrylate),
poly( m ethyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(m ethacrylic acid anhydride), and glycidyl methacrylate.
Suitable non-polymeric rate controlling excipient includes, but not limited to fat,
fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester
or any combinations thereof.
Waxes are esters of fatty acids with long chain monohydric alcohols. Natural
waxes are often mixtures of such esters, and may also contain hydrocarbons.
Waxes employed in the present invention include, but are not limited to, natural
waxes, such as animal waxes, vegetable waxes, and petroleum waxes, paraffin
waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic
waxes. Specific examples include, but are not limited to spermaceti wax,
carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax,
Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor
wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like,
or mixtures thereof.
Waxes are also monoglyceryl esters, diglyceryl esters, or glyceryl esters
(g lycerides) and derivatives and mixtures thereof formed from a fatty acid having
from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the
hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides employed
in the present invention include, but are not limited to, glyceryl monostearate,
glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate,
glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl
trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate,
glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl
tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyhstate,
glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl
behenate (co mpritol) , polyglyceryl diisostearate, lauroyl macrogolglycerides
(G elucire), oleoyl macrogolglycerides, stearoyl macrogolglycerides, mixtures of
monoglycerides and diglycerides of oleic acid (P eceol), or combinations thereof.
Fatty acids include, but are not limited to, hydrogenated palm kernel oil,
hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil,
hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower
oil, hydrogenated castor oil (L ubritab), hydrogenated cottonseed oil, and mixtures
thereof. Other fatty acids include, but are not limited to, decenoic acid,
docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, or the like,
or mixtures thereof.
Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, or
stearyl alcohol or mixtures thereof.
The water-swellable core can comprise hydroxypropyl methylcellulose,
microcrystalline cellulose, starch or mixtures thereof.
The water-insoluble inert core can comprise silicon dioxide, small particles of
glass, plastic resin particles or mixtures thereof.
The pharmaceutical composition of the present invention further comprises other
pharmaceutically acceptable excipient selected from the group consisting of
diluent, binder, glidant, solubilizer, stabilizer, lubricants, disintegrants, cushioning
agents, suspending agent, thickening agent, sweetners, flavoring agent, or
plasticizer.
Examples of suitable diluents include but are not limited to one or more of
lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol,
sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose,
starch, calcium phosphate, or metal carbonate.
Examples of suitable binders include, but are not limited to, starch, gums,
pregelatinized starch, polyvinyl prrolidone ( P VP), copovidone, cellulose
derivatives, such as hydroxypropylmethyl cellulose (HP MC), hydroxypropyl
cellulose (HP C) and carboxymethyl cellulose (CM C) and their salts.
Suitable lubricants include but are not limited to one or more talc, magnesium
stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils,
stearic acid, sodium stearyl fumarate, talc and sodium benzoate.
Compositions of the present invention may include a glidant such as, but not
limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
Suitable disintegrant may include but are not limited to one or more of starch,
croscarmellose sodium, crospovidone, and sodium starch glycolate.
The solubilizer may include but are not limited to one or more surfactant, pH
modifier, complexing agent, or hydrotropic agent.
Suitable surfactants are those known to ordinary skilled in the art and may
include, but not limited to one or more of amphoteric, non-ionic, cationic or
anionic surfactants. Suitable surfactants comprises one or more of sodium lauryl
sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester
of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DO SS), lecithin,
stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,
polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the
like.
Suitable pH modifiers include but are not limited to buffers, amino acids or amino
acid sugars.
The complexing agents include cyclodextrin class of molecules, such as
cyclodextrins containing from six to twelve glucose units, especially, alpha-
cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as
hydroxypropyl beta cyclodextrins, or mixtures thereof. The complexing agents
may also include cyclic amides, hydroxyl benzoic acid derivatives as well as
gentistic acid.
Suitable plasticizers include, but are not limited to, one or more of diethyl
phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin,
propylene glycol, and polyethylene glycol.
The solvents comprise one or more of dichloromethane, acetone, ethanol,
methanol, isopropyl alcohol, water or mixture thereof.
Suitable cushioning agents include but are not limited to one or more of PEG,
and colloidal silicon dioxide.
Suitable thickening agents or viscosity modifiers may include, but note limited to
one or more of methylcellulose, carboxymethylcellulose, microcrystalline
cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, alginate, carageenan, xanthan gum, acacia,
tragacanth, locust bean gum, guar gum, carboxypolymethylene, polyvinyl
pyrrolidone, polyvinyl alcohol, poloxamer, magnesium aluminum silicate
(v eegum), bentonite, hectorite, povidone, maltitol, chitosan or combination
thereof.
Preservatives may include one or more of sodium benzoate, sorbates, such as
potassium sorbate, salts of edetate (a lso known as salts of
ethylenediaminetetraacetic acid or EDTA, such as disodium edetate),
benzaldionium chloride, parabens.
The formulations of the invention optionally include one or more stabilizing
agents to increase the stability and/or compatibility of the suspension when
formulated into a dosage form. Suitable stabilizing agents are suspending
agents, flocculating agents, thickening agents, gelling agents, buffering agents,
antioxidants, preservatives, antimicrobial agents, and mixtures thereof. Ideally,
the agent acts to minimize irreversible aggregation of suspended particles, and to
maintain proper flow characteristics to ease manufacturing processes, e.g., to
ensure that the formulation can be readily pumped and filled into desired
container.
Suspending agents may include, but are not limited to, one or more from
cellulose derivatives, clays, natural gums, synthetic gums, or other agents known
in the art. Specific suspending agents, by way of example, include
microcrystalline cellulose, sodium carboxymethylcellulose, powdered cellulose,
ethymethylcellulose, hydroyxypropyl methylcellulose, methylcellulose,
ethylcellulose, ethylhydroxy ethylcellulose, hydroxypropyl cellulose, attapulgite,
bentonite, hectorite, montmorillonite, silica gel, fumed silicon dioxide, colloidal
silicon dioxide, acacia, agar, carrageenan, guar gum, locust bean gum, pectin,
sodium alginate, propylene glycol alginate, tamarind gum, xanthan gum,
carbomer, povidone, sodium starch glycolate, starches, tragacanth, magnesium
aluminum silicate, aluminum silicate, magnesium silicate, gelatin, glycyrrhizin and
the like. These suspending agents can further impart different flow properties to
the suspension. The flow properties of the suspension can be Newtonian, plastic,
pseudoplastic, thixotropic or combinations thereof. Mixtures of suspending
agents may also be used to optimize flow properties and viscosity.
Suitable buffering agents may include, but are not limited to, one or more of a
bicarbonate salt of a Group IA metal, an alkali earth metal buffering agent, amino
acids, an acid salt of an amino acid, an alkali salt of an amino acid, and
combinations of any of the foregoing.
Moreover, the composition of the invention optionally include usual auxiliaries
known in the art such as saliva stimulating agents like citric acid, lactic acid,
malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids;
cooling sensation agents like maltitol, monomenthyl succinate, ultracool;
stabilizers like gums, agar; taste masking agents like acrylic polymers,
copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide,
natural food colors, dyes suitable for food, drug and cosmetic applications;
preservatives like alpha-tocopherol, citric acid, butylated hydroxytoluene,
butylated hydroxyanisole, ascorbic acid, fumaric acid, malic acid, sodium
ascorbate or ascorbic acid palmitate or effervescing agents like citric acid, tartaric
acid, sodium bicarbonate, sodium carbonate and the like.
The dosage form of the present invention may be in form of a tablet, a capsule,
granules, a tablet in tablet, an orally disintegrating tablet, pellets, tablet/s in
capsule, granules/pellets in capsule, a bilayer tablet, a trilayer tablet, an in-lay
tablet or suspension.
The tablet-in-tablet dosage form of the invention may be prepared by
compressing metoprolol with one or more rate controlling excipient, to form a
core tablet; and compressing one or more anti-platelet agent optionally along
with one or more pharmaceutically acceptable excipient onto the said core tablet
to form a compressed outer tablet.
The tablet-in-tablet dosage form of the invention may be prepared by
compressing metoprolol with one or more rate controlling excipient to form a core
tablet; and compressing one or more anti-platelet agents optionally along with
one or more pharmaceutically acceptable excipients onto said core tablet to form
a compressed outer tablet.
In an embodiment, the tablet-in-tablet dosage form is be prepared by blending
metoprolol with rate controlling excipient and other pharmaceutically acceptable
excipients. The prepared blend was compressed to form a core tablet.
Separately, anti-platelet agent is blended with one or more pharmaceutically
acceptable excipients. Some portion of the above blend is placed in die and the
core tablet was placed in center of the blend, the remaining blend is filled in die
and compressed such that the metoprolol tablet forms inner tablet and anti-
platelet agent forms outer tablet.
The once-a-day composition of the dosage form may include a tablet comprising
an extended release metoprolol with one or more rate controlling excipient,
wherein the tablet is inlayed in another layer comprising anti-platelet agent and
optionally other pharmaceutically acceptable excipients.
In another embodiment, the once-a-day dosage form is prepared by blending
metoprolol with rate controlling excipient and one or more other pharmaceutically
acceptable excipients. The prepared blend is compressed to form tablets. The
formed tablets then coated with dispersion comprising an anti-platelet agent,
dissolved or dispersed in suitable solvent system along with one or more
pharmaceutically acceptable excipient. The outer coating may completely or
partially surround the metoprolol tablet.
In another embodiment, the once-a-day dosage form may be prepared by
blending two portions with one or more pharmaceutically acceptable excipients
followed by compression. First portion may be prepared by coating the inert core
with a solution or suspension of metoprolol in a solvent. The metoprolol drug
layer is further coated with one or more release-controlling layers. Second
portion may be prepared by coating one or more anti-platelet agent on an inert
core, optionally along with one or more rate controlling layers.
In another embodiment, the once-a-day dosage form may be prepared by
blending two portions with one or more pharmaceutically acceptable excipients
followed by compression. The first portion was prepared by coating the inert core
with a dispersion comprising metoprolol, one or more rate controlling excipients
in a solvent. The coated inner core can further be coated with one or more rate
controlling layers or seal coat. The second portion was prepared by coating the
inert core with a dispersion comprising an anti-platelet agent in a solvent.
In an embodiment, the once-a-day dosage form may include a tablet comprising
an extended release metoprolol with one or more rate controlling excipient,
wherein the tablet is inlayed in another layer comprising an anti-platelet agent
and optionally other pharmaceutically acceptable excipients.
In a further embodiment, the inlayed dosage form can be prepared by blending
metoprolol with rate controlling excipient and other pharmaceutically acceptable
excipients. The prepared blend was compressed to form a core tablet. One or
more anti-platelet agents are separately blended with one or more
pharmaceutically acceptable excipients. Some portion of the above blend was
placed in die and the core tablet was placed in a way such that the upper surface
of metoprolol tablet is completely exposed after compression.
In a further embodiment, the once-a-day dosage form may be prepared by
compressing a first layer comprising an extended release metoprolol along with
one or more rate controlling excipients and a second layer comprising one or
more anti-platelet agents, one or more pharmaceutically acceptable excipients
and, optionally with rate controlling excipient into a bi-layer tablet.
In a further embodiment, the bi-layer dosage form is prepared by blending
metoprolol with rate controlling excipient and other pharmaceutically acceptable
excipients. The prepared blend was compressed to form a first layer. Onto this
first layer a blend comprising anti-platelet agent with one or more
pharmaceutically acceptable excipients is compressed to form a bi-layer tablet.
The present invention further provides a method of treating one or more
disorders selected form hypertension, congestive heart failure, angina,
myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac
myopathy, renal insufficiency, peripheral vascular disease, left ventricular
hypertrophy, cognitive dysfunction, and chronic heart failure, wherein the method
comprises administering a pharmaceutical dosage form of the present invention
to a patient in need of such treatment.
In another aspect, the present invention provides a method of treating
hypertension, wherein the method comprises administering a pharmaceutical
dosage form of the present invention to a patient in need of such treatment.
In an embodiment, a method of treating congestive heart failure comprises
administering a pharmaceutical dosage form of the present invention to a patient
in need of such treatment.
In another embodiment, a method of myocardial infarction comprises
administering a pharmaceutical dosage form of the present invention to a patient
in need of such treatment.
The invention is further illustrated by the following examples which are provided
merely to be exemplary of the invention and do not limit the scope of the
invention. Certain modifications and equivalents will be apparent to those skilled
in the art and are intended to be included within the scope of the invention.
Example 1: Metoprolol Succinate ER/ Clopidogrel Bisulfate Tablet 50/75 mg
Table 1: Metoprolol ER and Clopidogrel Tablet
Stage Sub-stage Ingredients %
Micro crystalline cellulose spheres 0.1-20
Seal coat I Ethyl cellulose 0.01-20
Triethyl citrate 0.001-1
Drug Layering Metoprolol Succinate 2-70
(M etoprolol
Opadry Clear 0.1-10
succinate)
Extended Ethyl cellulose 0.1-30
Release coating
Metoprolol Opadry Clear 0.1-10
Blend
Extended Eudragit L30-D55 0.1-10
Release coating Triethyl citrate 0.001-5
-II Talc 0.1-10
Seal coat II Opadry Clear 0.1-10
PEG coating Polyethylene glycol 0.1-10
Silicified microcrystalline cellulose 5-70
Blending Croscarmellose sodium 1-25
Polyethylene glycol 0.1-25
Clopidogrel Addition of Drug Clopidogrel Bisulfate 5-30
Blend (Cl opidogrel Polyethylene glycol 0.5-10
Bisulfate) Microcrystalline cellulose 5-40
Mannitol 0.1-25
Hydroxypropyl Cellulose 0.1-20
Glyceryl Behenate 0.01-5
Hydrogenated castor oil 0.01-5
Lubrication
& Lubrication Sodium Stearyl Fumarate 0.001-5
Compression
Film coating Film coating Opadry 0.1-10
Procedure:
Preparation of Metoprolol Blend: Microcrystalline cellulose spheres were given
seal coat I of ethyl cellulose. These seal coated I pellets were subjected to
metoprolol succinate layering with a binder in aqueous solvent system. Drug
layered pellets were provided with Extended Release coating-I using Ethyl
cellulose and opadry. An Extended Release coating-II of Eudragit was given
using Plasticizer (t riethyl citrate) & talc. Seal coat-II was given to Extended
Release coated-II pellets followed by PEG coating in suitable solvent system.
Final metoprolol blend was prepared by blending PEG coated pellets with
Silicified microcrystalline cellulose, Croscarmellose sodium and Polyethylene
glycol.
Preparation of Clopidogrel Blend: Compacts of Clopidogrel bisulfate, PEG,
Microcrystalline Cellulose, Mannitol and Hydroxypropyl cellulose were prepared
in roller compactor followed by granules preparation from the same. Separately
granules of Micro crystalline cellulose, Mannitol & Hydroxypropyl cellulose were
prepared by wet granulation method. Both the blends were lubricated with
Glyceryl Behenate and Hydrogenated Castor Oil.
Lubrication & Compression: Metoprolol blend and Clopidogrel blend were
lubricated with Sodium Stearyl Fumarate or any other suitable lubricant.
Lubricated blend was compressed into a tablet.
Coating: An opadry coat was given to core tablets.
Table 2: Dissolution profile
Tablets obtained from example 1 were subjected to dissolution studies. The
results of dissolution studies performed are provided in Table 2.
Dissolution of Metoprolol succinate Dissolution of Clopidogrel bisulfate
Method: 500ml of pH 6.8 phosphate Method: 1000ml of pH 2.0 hydrochloric
buffer, USP II apparatus at 50 rpm acid, USP II apparatus at 50 rpm
Time points ( h ) % Drug dissolved Time points (m in) % Drug dissolved
1 4 10 72
2 8 15 83
4 20 20 90
6 42 30 97
8 53 45 98
69 60 99
12 76 - -
16 89 - -
95 - -
24 96 - -
Example 2: Metoprolol Succinate ER/ Clopidogrel Bisulfate/ Aspirin Capsule
50/81/ 25 mg
Table 3: Metoprolol ER, Aspirin and Clopidogrel Capsule
Stage Sub-Stage Ingredients %
Micro crystalline cellulose spheres 0.1-20
Seal coat I Ethyl cellulose 0.01-20
Triethyl citrate 0.001-1
Drug Layering Metoprolol succinate 2-70
( M etoprolol
Opadry Clear 0.1-10
succinate)
Metoprolol
Ethyl cellulose 0.1-30
Extended Release
pellets
coating –I
Opadry Clear 0.1-10
Eudragit L30-D55 0.1-10
Extended Release
Triethyl citrate 0.001-5
coating –II
Talc 0.1-10
Seal coat II Opadry Clear 0.1-10
PEG coating Polyethylene glycol 0.1-10
Micro crystalline cellulose spheres 0.1-20
Drug Layering
Opadry clear 0.01-10
(A spirin)
Aspirin Aspirin 0.1-20
pellets Seal coat-I Opadry 0.001-5
Seal coat-II Mannitol 0.001-5
PVA coating Polyvinyl alcohol based opadry 1-25
Clopidogrel Bisulfate 5-30
Polyethylene glycol 0.5-10
Microcrystalline cellulose 5-40
Clopidogrel Addition of
blend Clopidogrel Bisulfate
Mannitol 0.1-25
Hydroxypropyl Cellulose 0.1-20
Glyceryl Behenate 0.01-5
Hydrogenated castor oil 0.01-5
Lubrication &
Lubrication Sodium Stearyl Fumarate 0.001-5
capsulation
Procedure:
Preparation of Metoprolol pellets: Microcrystalline cellulose spheres were
given seal coat of ethyl cellulose. These seal coated pellets were subjected to
metoprolol succinate layering with a binder in aqueous solvent system. Drug
layered pellets were provided with Extended Release coating-I using Ethyl
cellulose and opadry. An Extended Release coating-II of Eudragit was given
using Plasticizer (t riethyl citrate) & talc. The extended release pellets were then
seal coated Seal coat-II was given to Extended Release coated-II pellets
followed by PEG coating in suitable solvent system.
Preparation of Aspirin pellets: Microcrystalline cellulose spheres ( o r any other
suitable spheres) were given with drug layering of aspirin using opadry as binder.
Drug layered pellets were coated with seal coating-I and seal coating-II using
opadry and Mannitol respectively. Seal coated-II pellets were further coated with
PVA based opadry.
Preparation of Clopidogrel Blend: Compacts of Clopidogrel bisulfate, PEG,
Microcrystalline Cellulose, Mannitol and Hydroxypropyl Cellulose were prepared
in roller compactor followed by granules preparation from the same. Separately
granules of Micro crystalline cellulose, Mannitol & Hydroxypropyl Cellulose were
prepared by wet granulation method. Both the blend were lubricated with
Glyceryl Behenate and Hydrogenated Castor Oil.
Lubrication: Metoprolol and aspirin pellets were lubricated with Sodium Stearyl
Fumarate.
Capsulation: Lubricated blend of Clopidogrel and lubricated pellets were filled
into capsule shell of suitable size.
Table 4: Dissolution profile
Tablets obtained from example 2 were subjected to dissolution studies. The
results of dissolution studies performed are provided in Table 4.
Dissolution of Dissolution of
Dissolution of Aspirin
Metoprolol succinate Clopidogrel Bisulfate
Method: 500 ml of pH Method: 900ml of pH Method: 1000ml of pH
6.8 phosphate buffer, 0.01 N hydrochloric acid, 2.0 hydrochloric acid,
USP II apparatus at 50 USP I apparatus at 100 USP II apparatus at 50
rpm rpm rpm
Time
Time % Drug Time % Drug % Drug
points
points ( h ) dissolved points (h ) dissolved dissolved
(m in)
1 3 10 43 10 78
2 7 15 63 15 89
4 21 20 83 20 96
6 40 30 99 30 97
8 51 45 101 45 99
67 60 101 60 99
12 75 - - - -
16 88 - - - -
94 - - - -
24 95 - - - -
Example 3: Metoprolol succinate ER/ Clopidogrel Bisulfate/ Aspirin Capsule
100/75/50 mg
Table 5: Metoprolol ER, Aspirin and Clopidogrel Capsule
Stage Sub-Stage Ingredients %
Micro crystalline cellulose spheres 0.1-20
Seal coat I Ethyl cellulose 0.01-20
Triethyl citrate 0.001-1
Drug Layering Metoprolol succinate 2-70
( M etoprolol
Opadry Clear 0.1-10
succinate)
Metoprolol
Ethyl cellulose 0.1-30
Extended Release
pellets
coating –I
Opadry Clear 0.1-10
Eudragit L30-D55 0.1-10
Extended Release
Triethyl citrate 0.001-5
coating –II
Talc 0.1-10
Seal coat II Opadry Clear 0.1-10
PEG coating Polyethylene glycol 0.1-10
Micro crystalline cellulose spheres 0.1-20
Drug Layering
Opadry clear 0.01-10
( A spirin)
Aspirin 0.1-20
Aspirin pellets
Seal coat-I Opadry 0.001-5
Seal coat-II Mannitol 0.001-5
PVA coating Polyvinyl alcohol based opadry 1-25
Clopidogrel Bisulfate 5-30
Polyethylene glycol 0.5-10
Microcrystalline cellulose 5-40
Clopidogrel Addition of
blend Clopidogrel Bisulfate
Mannitol 0.1-25
Hydroxypropyl Cellulose 0.1-20
Glyceryl Behenate 0.01-5
Hydrogenated castor oil 0.01-5
Lubrication &
Lubrication Sodium Stearyl Fumarate 0.001-5
capsulation
Procedure:
Preparation of Metoprolol pellets: Microcrystalline cellulose spheres were
given seal coat I of ethyl cellulose. These seal coated I pellets were subjected to
metoprolol succinate layering with a binder in aqueous solvent system. Drug
layered pellets were provided with Extended Release coating-I using Ethyl
cellulose and opadry. An Extended Release coating-II of Eudragit was given
using Plasticizer (t riethyl citrate) & talc. Seal coat-II was given to Extended
Release coated-II pellets followed by PEG coating in suitable solvent system.
Preparation of Aspirin pellets: Microcrystalline cellulose spheres (o r any other
suitable spheres) were given with drug layering of aspirin using opadry as binder.
Drug layered pellets were coated with seal coating-I and seal coating-II using
opadry and Mannitol respectively. Seal coated-II pellets were further coated with
PVA based opadry.
Preparation of Clopidogrel Blend: Compacts of Clopidogrel bisulfate, PEG,
Microcrystalline Cellulose, Mannitol and Hydroxypropyl Cellulose were prepared
in roller compactor followed by granules preparation from the same. Separately
granules of Micro crystalline cellulose, Mannitol & Hydroxypropyl Cellulose were
prepared by wet granulation method. Both the blend were lubricated with
Glyceryl Behenate and Hydrogenated Castor Oil.
Lubrication: Metoprolol and aspirin pellets were lubricated with Sodium Stearyl
Fumarate.
Capsulation: Lubricated blend of Clopidogrel and lubricated pellets were filled
into capsule shell of suitable size.
Table 6: Dissolution profile
Tablets obtained from example 3 were subjected to dissolution studies. The
results of dissolution studies performed are provided in Table 6.
Dissolution of Dissolution of
Dissolution of Aspirin
Metoprolol succinate Clopidogrel Bisulfate
Method: 500 ml of pH Method: 900ml of pH Method: 1000ml of pH
6.8 phosphate buffer, 0.01 N hydrochloric acid, 2.0 hydrochloric acid,
USP II apparatus at 50 USP I apparatus at 100 USP II apparatus at 50
rpm rpm rpm
Time
Time % Drug Time % Drug % Drug
points
points ( h ) dissolved points ( h ) dissolved dissolved
( m in)
1 4 10 41 10 76
2 9 15 60 15 86
4 22 20 79 20 92
6 42 30 95 30 98
8 53 45 98 45 98
70 60 100 60 98
12 76 - - - -
16 90 - - - -
98 - - - -
24 98 - - - -
Example 4: Metoprolol succinate ER / Ticagrelor Tablet 50/90 mg
Table 7: Metoprolol succinate ER and Ticagrelor tablet
Stage Stage Ingredients %
Micro crystalline cellulose spheres 0.1-20
Metoprolol Seal coat I Ethyl cellulose 0.01-20
Pellets Triethyl citrate 0.001-1
Drug Layering Metoprolol succinate 2-40
(M etoprolol
Opadry Clear 0.1-10
succinate)
Extended Release Ethyl cellulose 0.1-30
coating -I Opadry Clear 0.1-10
Eudragit L30-D55 0.1-10
Extended Release
Triethyl citrate 0.001-5
coating -II
Talc 0.1-10
Seal coat II Opadry Clear 0.1-10
PEG coating Polyethylene glycol 0.1-10
Polyethylene glycol 0.1-10
Blending Prosolv SMCC 90 5-50
Croscarmellose sodium 0.1-10
Ticagrelor 5-70
Mannitol 10-80
Ticagrelor Addition of Drug
Dibasic calcium phosphate 0.5-15
blend ( T icagrelor)
Hydroxypropyl cellulose 0.1-10
Sodium starch glycolate 0.1-10
Blending & Blending and
Sodium Stearyl Fumarate 0.01-5
Lubrication Lubrication
Film coating Film coating Opadry white 0.1-10
Procedure:
Microcrystalline cellulose spheres was given seal coat I of ethyl cellulose. These
seal coated I pellets were subjected to metoprolol succinate layering with a
binder in aqueous solvent system. Drug layered pellets were provided with
Extended Release coating-I using Ethyl cellulose and opadry. An Extended
Release coating-II of eudragit was given using plasticizer, triethyl citrate & talc.
Seal coat-II was given to Extended Release coated-II pellets followed by PEG
coating in suitable solvent system. A blend from PEG coated pellets was
prepared by blending it with polyethylene glycol, prosolv SMCC 90 and
croscarmellose sodium.
Granules of Ticagrelor were prepared separately by wet granulation. Ticagrelor
was mixed with mannitol, dibasic calcium phosphate and sodium starch
glycolate, which were granulated using solution of hydroxypropyl cellulose in
water. Prepared granules were dried and mill to suitable size and mixed with
disintegrant. Prepared ticagrelor blend was mixed with metoprolol blend and
lubricated with sodium stearyl fumarate. Prepared blend was compressed into
tablet. An opadry coat was given to core tablets.
Example 5: Clinical study on human being
The study method involved a multicenter, randomized, placebo-controlled,
unbalanced factorial study for lowering the blood pressure and assessing the risk
of stroke. Patients, with confirmed diagnosis of stage II hypertension were
eligible to participate in the study. Patients were randomized to one of many
treatment groups: Group I were administered extended-release metoprolol
succinate (E q 25mg tartrate, Eq 50mg tartrate, Eq100mg tartrate) , Group II were
administered clopidogrel (7 5mg), Group III were administered extended release
of metoprolol succinate/Immediate release clopidogrel (d osages of present
invention). After one month of therapy non-responder patients were managed
with dose-titration or rescue medication.
Treatment groups were well balanced at base line and achieved absolute change
at one week from the baseline in blood pressure. Inventors of the present
application surprisingly found at least 10% improvement in blood pressure
(sy stolic blood pressure and diastolic blood pressure) after 3 months treatment
and at least 5% reduction in the risk of stoke after 6months of treatment.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Where the terms “comprise”, “comprises”, “comprised” or “comprising” are used
in this specification, they are to be interpreted as specifying the presence of the
stated features, integers, steps or components referred to, but not to preclude the
presence or addition of one or more other feature, integer, step, component or
group thereof.
Claims (12)
1. A pharmaceutical dosage form for treatment of cardiovascular disorders and suitable for once daily administration comprising a fixed dose combination of: (a ) metoprolol or a pharmaceutically acceptable salt thereof in extended release form, ( b ) Clopidogrel or a pharmaceutically acceptable salt thereof, and (c ) one or more rate controlling excipients; wherein the dosage form exhibits a dissolution profile such that less than 6% of metoprolol or a pharmaceutically acceptable salt thereof is released within 1 hour, when the release rate is measured in USP Type 2 Dissolution apparatus in paddle type at 50 rpm using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.
2. The pharmaceutical dosage form of claim 1, wherein the dosage form comprises about 25mg to about 200mg of metoprolol or a pharmaceutically acceptable salt thereof and about 5mg to about 770mg of Clopidogrel or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical dosage form of claim 1, wherein the dosage form exhibits immediate release of Clopidogrel or a pharmaceutically acceptable salt thereof.
4. The pharmaceutical dosage form of any one of claims 1 to 3, wherein the dosage form comprises one or more water swellable or water insoluble inert cores coated with one or more rate controlling excipients.
5. The pharmaceutical dosage form of claim 4, wherein the water swellable core comprises microcrystalline cellulose, hydroxypropyl methylcellulose, starch, or a mixture thereof.
6. The pharmaceutical dosage form of claim 4, wherein the water insoluble inert core comprises silicon dioxide, glass particles, plastic resin particles, or a mixture thereof.
7. The pharmaceutical dosage form of one of claims 1 to 6, wherein the rate controlling excipient comprises polymeric rate controlling excipient, non- polymeric rate controlling excipient, or a combination thereof.
8. The pharmaceutical dosage form of claim 7, wherein the polymeric and non-polymeric rate controlling excipient comprises one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; fat; wax; fatty acid; fatty acid ester; long chain monohydric alcohol or their ester; or a mixture thereof.
9. The pharmaceutical dosage form of any one of claims 1 to 8, wherein the dosage form exhibits a dissolution profile such that less than about 6% of metoprolol or a pharmaceutically acceptable salt thereof is released within 1 hour; between about 30% and about 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours when the release rate is measured in USP Type 2 Dissolution Apparatus in a paddle type at 50 rpm using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.
10. The pharmaceutical dosage form of any one of claims 1 to 9, wherein the dosage form is in the form of a tablet, a capsule, granules, pellets, a tablet in tablet, tablet/s in capsule, granules or pellets in capsule, a bi-layer tablet, a trilayer tablet, and an in-lay tablet.
11. Use of a pharmaceutical dosage form of any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a disorder selected from one or more of hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction and chronic heart failure.
12. A pharmaceutical dosage form of any one of claims 1 to 10, substantially as hereinbefore described with reference to any of the Examples.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3481MU2011 | 2011-12-09 | ||
IN3481/MUM/2011 | 2011-12-09 | ||
PCT/IB2012/056084 WO2013084089A1 (en) | 2011-12-09 | 2012-11-01 | Methods for treating cardiovascular disorder |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625998A NZ625998A (en) | 2015-10-30 |
NZ625998B2 true NZ625998B2 (en) | 2016-02-02 |
Family
ID=
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