WO2013116738A1 - Drug formulations - Google Patents

Abstract

YM758 formulations and unit dose forms suitable for oral and intravenous administration are useful for treating patients with stable angina, atrial fibrillation, heart failure and other cardiovascular diseases.

Description

DRUG FORMULATIONS

[0001] This application claims the benefit of U.S. Patent Application No. 61/594,903 filed February 3, 2012, which is hereby incorporated by reference.

[0002] Provided are drug formulations of a cardiovascular drug suitable for oral and parenteral (including intravenous, subcutaneous, intraperitoneal, and intramuscular) administration, unit dose forms of those formulations, and methods for using them alone and in combination with other medications for the treatment of cardiovascular disease. The invention thus relates to the fields of medicine and pharmacology.

[0003] U.S. Patent No. 6,573,279, incorporated herein by reference, describes isoquinoline compounds with 1 channel blocker activity and their use in treating a variety of cardiovascular diseases. U.S. Patent Application Publication Nos. 20060084807 and

20070129357, each of which is incorporated herein by reference, describe methods for making those isoquinoline compounds as well as crystals of certain fluorobenzamide derivatives of them. U.S. Patent Publication No. 20090247572, incorporated herein by reference, relates to the use of one of these isoquinoline fluorobenzamide derivatives, (-)-N- {2-[(i?)-3-(6,7-dimethoxy-l ,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4- fluorobenzamide monophosphate (referred to in that patent publication as "compound A" and "chemical formulation I" and referred to herein as "YM758"), for treating atrial fibrillation.

[0004] To date, however, these isoquinoline compounds in general and YM758 in particular have not been developed as cardiovascular drugs. Thus, there remains a need for methods of using these compounds, alone and in combination with other cardiovascular drugs, to treat cardiovascular disease, as well as a need for pharmaceutical formulations and unit dose forms useful in such methods. This invention meets those needs.

[0005] Provided herein are fast-acting (immediate release) and modified (sustained) release oral formulations as well as intravenous formulations of YM758. The present invention also provides unit dose forms of these formulations. The present invention also provides methods for using these formulations and unit dose forms alone and in combination with other drugs for the treatment of cardiovascular disease, including but not limited to stable angina, atrial fibrillation, and heart failure. In these methods, the pharmaceutical formulations and unit dose forms of the invention may be dosed alone or in combination with other drugs, including but not limited to drugs such as beta-blockers, anti-arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis. The invention also provides formulations and unit dose forms of YM758 and another drug selected from the group of drugs including beta-blockers, anti-arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis. The single agent and combination pharmaceutical formulations and unit dose forms of the invention include capsule, tablet, and solution formulations and unit dose forms that provide either immediate or sustained release. The pharmaceutical formulations in solution forms are, in various embodiments, suitable for intravenous, subcutaneous, intraperitoneal, and intramuscular administration.

[0006] Thus, in one aspect, the present invention provides an oral formulation comprising or consisting essentially of YM758 and optionally an excipient. As used herein, the excipient is suitable for administration to human patients with various cardiovascular diseases and includes, without limitation, one or more of the following: an additive, an anti- foaming agent, a binder, a chemical stabilizer, a coloring agent, a diluent, a disintegrating agent, an emulsifying agent, a filler, a flavoring agent, a glidant, a lubricant, a pH modifier, a plasticizer, a solubilizer, a swelling enhancer, a spheronization aid, a solubility enhancer, and a suspending agent. In some embodiments, the formulation is provided in a unit dose form, which may be, for example, a tablet or capsule. In various embodiments, the unit dose forms contain from about 5 mg to about 80 mg of YM758. In some embodiments, the unit dose forms contain from about 5 mg to about 50 mg of YM758. In other embodiments, the unit dose form contains from about 10 mg to about 40 mg of YM758. In one embodiment, the unit dose form contains about 25 mg of YM758.

[0007] In another aspect, the present invention provides formulations comprising or consisting essentially of YM758 and optionally an excipient that are suitable for intravenous, subcutaneous, intraperitoneal, and intramuscular administration. As used herein, the excipient is suitable for administration to human cardiovascular disease patients and includes, without limitation, one or more of the following: an additive, an anti-foaming agent, a chemical stabilizer, a diluent, an emulsifying agent, a pH modifier, a buffering agent, an osmolality modifier, a salt, a solubilizer, a solubility enhancer, and a suspending agent. In some embodiments, the formulation is a solution formulation. In one embodiment, the solution formulation is provided in a unit dose form, which may be, for example, in a vial, an ampoule or an intravenous bag. In various embodiments, the unit dose forms contain from about 5 mg to about 80 mg of YM758. In some embodiments, the unit dose forms contain from about 5 mg to about 50 mg of YM758. In another embodiment, the unit dose form contains from about 10 mg to about 40 mg of YM758. In one embodiment, the unit dose form contains about 25 mg of YM758. [0008] In various embodiments, the oral formulation is an immediate release formulation, including, and unit dose forms of this formulation include, without limitation, a gelatin capsule comprising a YM758 formulation.

[0009] In various embodiments, the oral formulation is a modified release

formulation. In one embodiment, the modified release formulation is provided in a unit dose form that is a tablet or capsule. In one embodiment, the modified release formulation comprises micro particles of YM758. In one embodiment, the modified release formulation comprises a controlled release matrix. In one embodiment, the modified release formulation further comprises a core comprising YM758. In one embodiment, the modified release formulation further comprises a coat encasing some or all of the YM758 in the formulation. In one embodiment, the coat is a controlled release coat. In one embodiment, the coat is a moisture barrier coat. In one embodiment, the modified release formulation further comprises one or more of the following: an additive that facilitates water penetrating into the formulation (unit dosage form), a binder, a lubricant, a glidant, a plasticizer, a diluent, a solubilizer, and/or a swelling enhancer. In one embodiment, the modified release formulation shows a pulsatile YM758 release profile.

[0010] In various embodiments, the formulations of the invention comprise nanoparticles.

[0011] In one aspect, the present invention provides methods of treating

cardiovascular disease by administering a pharmaceutical formulation or unit dose form of the invention to a patient in need of treatment. In these methods, the formulation or unit dose form of the invention is either administered alone or in combination with one or more other drugs to treat stable angina, atrial fibrillation, heart failure, or other cardiovascular disease. Other drugs that can be administered in these methods include, without limitation, beta- blockers, anti-arrhythmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis.

[0012] In one aspect, the present invention provides pharmaceutical formulations and unit dose forms comprising YM758 and at least one other drug. The other drug can be, without limitation, selected from the group of drugs consisting of beta-blockers, anti- arrhythmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis. In one embodiment, the combination formulation and corresponding unit dose form provide for sustained release of both YM758 and the other drug. In one embodiment, the other drug is a beta-blocker. In one embodiment, the beta- blocker is metoprolol. In another embodiment, the beta blocker is carvedilol. In another embodiment, the beta blocker is bisoprolol.

[0013] In one embodiment, the pharmaceutical formulation of the invention is provided in a unit dose form as a solution in a vial and is suitable for direct administration into the patient by injection intravenously, subcutaneously, intraperitoneally and/or intramuscularly. In one embodiment, the pharmaceutical formulation is provided in a unit dose form as a solution in a vial suitable for administration into an intravenous bag.

[0014] Any pharmaceutical formulation or unit dose form of the invention can be used in the methods of treatment described herein; however, the pharmaceutical formulations and unit dose forms suitable for administration intravenously, subcutaneously,

intraperitoneally and/or intramuscularly will more typically find use in the hospital (acute care setting).

[0015] These and other aspects and embodiments of the invention are described in more detail below.

BRIEF DESCRIPTION OF FIGURES

[0016] Figure 1, as described in more detail in Example 1, demonstrates the superior effect of YM758 (Figure 1A) in comparison with metoprolol (Figure IB) on survival rates of rats after myocardial infarction (MI) using Kaplan Meier curve analysis. YM758, metoprolol or vehicle was administered for 6 weeks, beginning 2 weeks after surgery of MI. YM758 monophosphate was used as the test compound. The model of MI involved in the procedure is described in Tables 2 and 3, in Example 1.

[0017] Figure 2, as described in more detail in Example 1, shows the effect of short- term treatment with YM758 and metoprolol on hemodynamic parameters in rats with MI. From left to right, sham, control, YM758 and metoprolol are shown by the bars in each chart. YM758 monophosphate salt was used as the test compound. Each value represents the mean + SEM. #P<0.05; significant difference between sham and control (Student's t test). *P<0.05; significant difference between test compounds and control (Dunnett's test).

[0018] Figure 3, as described in more detail in Example 2, shows resting heart rate

(HR) (in bpm) in comparison with baseline for increasing doses of YM758 in mg given either daily or twice a day. From left to right, 2 week trough, 2 week peak, 4 week trough, 4 week peak and one week follow-up (f/u) without drug are shown by bars at YM758 doses of 5, 10, 20 and 40 mg once daily (OD) or 20 mg twice daily (BID) and placebo. The patient population was pre-screened, and the placebo wash-in period was one week, with 4 weeks on drug/placebo, and follow-up period of one week. [0019] Figure 4, as described in more detail in Example 2, shows maximum heart rate during Exercise Tolerance Testing (ETT), as change from baseline, for increasing doses of YM758 given in mg once daily or twice a day. From left to right, 2 week trough, 2 week peak, 4 week trough, and 4 week peak are shown by bars at YM758 doses of 5, 10, 20 and 40 mg once daily (OD) or 20 mg twice daily (BID) and placebo. Testing was done during screening for baseline measurement and then at 2 week trough and 2 week peak as well as 4 week trough and 4 week peak.

[0020] Figure 5, as described in more detail in Example 3, shows the design for dose escalation of atenolol and YM758 in anesthetized dogs. Heart rate and blood pressure measurements were tested every 30 minutes after administration of a dose. Vehicle infusion, atenolol (0.001, 0.01, 0.03 and 0.1 mg/kg/min iv) plus vehicle, or vehicle infusion with YM758 (0.01, 0.03, 0.1 and 0.3 mg/kg iv) were administered at 30 minutes intervals with increasing doses.

[0021] Figure 6, as described in more detail in Example 3, shows the effect of increasing doses of atenolol and YM758 on heart rate (6A), rate pressure product (6B), and mean blood pressure (6C) in anesthetized dogs. Symbols express the mean + SEM of 5 experiments. *P<0.05, **P<0.01, ***P<0.001 compared with the basal value of atenolol and ##P<0.01, ###P<0.001 compared with the basal value of YM758 (Dunnett's test using within subject error). YM758 lowered heart rate in a dose dependent manner without lowering blood pressure.

[0022] Figure 7, as described in more detail in Example 3, shows the time-course change of heart rate (7 A), rate pressure product (7B), and mean blood pressure (7C) in anesthesized dogs treated with a continuous infusion of atenolol followed by YM758 (0.1 mg/kg or 0.3 mg/kg) or vehicle injection at 30 minutes into atenolol infusion. Square represents atenolol alone, upward triangle represents atenolol plus YM758 at 0.1 mg/kg, and downward triangle represents atenolol plus YM758 at 0.3 mg/kg. Symbols express the mean + SEM of 5 experiments.

[0023] Figure 8, as described in more detail in Example 3, shows the effects of

YM758 on heart rate (8 A), rate pressure product (8B), and mean blood pressure (8C) in the presence of atenolol in anesthetized dogs after 30 minutes of YM758 and 60 minutes of atenolol. Columns express the mean + SEM of 5 experiments. **P<0.01, ***P<0.001 compared with the vehicle/atenolol infusion group (Dunnett's test using within subject error).

[0024] Figure 9, as described in more detail in Example 4, shows the amount of

YM758 in the plasma over time in a dose escalation study in humans. [0025] Figure 10, as described in more detail in Example 5C, demonstrates percent dissolution of a sustained release formulation of YM758 SR tablets, 40 mg, over 10 hours, using a USP Apparatus 2 (paddle) at 50 RPM. The amount of YM758 tablet dissolved was determined by UV Spectroscopy.

DETAILED DESCRIPTION

[0026] This detailed description is divided into sections solely for the convenience of the reader, and it will be apparent to the skilled artisan when disclosure found in a section is useful in another section. Section I provides useful definitions of terms and phrases used herein. Section II describes treatment methods of the invention and the results of animal model and human clinical testing. Section III describes oral formulations of the invention. Section IV describes solution formulations of the invention suitable for intravenous, subcutaneous, intraperitoneal, and intramuscular administration. Section V describes unit dose forms of the invention.

I. Definitions

[0027] All numerical designations, e.g., pH, temperature, time, concentration, and weight, including ranges, are approximations that typically may be varied ( + ) or ( - ) by increments of 0.1, 1.0, or 10.0, as appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term "about". It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0028] As used in the specification and claims, the singular form "a", "an", and "the" includes plural references unless the context clearly dictates otherwise.

[0029] As used herein, the term "comprising" means any recited elements are necessarily included and other elements may optionally be included. "Consisting essentially of means any recited elements are necessarily included, elements that would materially affect the basic and novel characteristics of the listed elements are excluded, and other elements may optionally be included. "Consisting of means that all elements other than those listed are excluded. Embodiments defined by each of these terms are within the scope of this invention.

[0030] "Administering" or "administration of a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect

administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.

[0031] "Control releasing coat" or "controlled release coat" refers to a functional coat which can, for example, include at least one pH independent polymer, pH dependent (such as for example enteric or reverse enteric types) polymer, soluble polymer, insoluble polymer, lipids, lipidic materials or combinations thereof, which, when applied onto a formulation can slow (for example, when applied to an immediate release formulation or a normal release matrix formulation), further slow (for example when applied to a controlled release matrix formulation) or modify the rate of release of YM758 when applied to an uncoated

formulation.

[0032] "Controlled release matrix" refers to a formulation in which the YM758 is dispersed within a matrix, which matrix can be either insoluble, soluble, or partly so.

Controlled release matrix formulations of the insoluble type are also referred to as insoluble polymer matrices, swellable matrices, or lipid matrices depending on the components that make up the matrix. Controlled release matrix formulations of the soluble type are also referred to as hydrophilic colloid matrices, erodible matrices, or reservoir systems. Controlled release matrix formulations of the present invention refer to formulations comprising an insoluble matrix, a soluble matrix or a combination of insoluble and soluble matrices in which the rate of release is slower than that of an uncoated non-matrix conventional or immediate release formulations or uncoated "normal release matrix" formulations. Controlled release matrix formulations can be coated with a control releasing coat to further slow the release of YM758 from the controlled release matrix formulation. Such coated controlled release matrix formulations can exhibit modified-release, controlled-release, sustained- release, extended-release, prolonged-release, delayed-release or combinations thereof, of YM758.

[0033] "Core" refers to a structure that is surrounded by a wall, membrane, or coating. The wall, membrane, or coating can be a functional or nonfunctional coating.

[0034] "Enhanced absorption formulation" of YM758 refers to a formulation that demonstrates enhanced absorption of YM758, such that, when exposed to like conditions, will show higher release and/or more absorption of YM758 as compared to an immediate release formulation with the same or higher amount of YM758. It is contemplated that the same therapeutic effect can be achieved with less YM758 in the enhanced absorption formulation as compared to an immediate release form. [0035] "Extended or sustained release formulation" of YM758 refers to a modified- release formulation that demonstrates extended or sustained release of YM758, such that, e.g., and without limitation, the formulation releases YM758 slowly, so that plasma concentrations of YM758 are maintained at a therapeutic level for an extended period of time.

[0036] "Patient" or "subject" refers to mammals, including humans and animals, such as simians, cattle, horses, dogs, cats, and rodents suffering from stable angina, atrial fibrillation, heart failure and other cardiovascular diseases or another disease.

[0037] "Immediate release formulation" refers to a formulation from which the drug is released without any substantial delay and substantially at once.

[0038] "Microparticle" refers to a drug formulation in discrete particulate form, and is interchangeable with such terms as "microspheres", "spherical particles", "microcapsules", "particles", "multiparticulates", "granules", "spheroids", "beads", and "pellets."

[0039] "Modified release formulation" refers to formulation with drug release characteristics of time course and/or location that accomplish therapeutic or convenience objectives not offered by conventional, immediate release or uncoated normal matrix formulations with immediate release characteristics. The rate of release of the active drug from a modified release formulation is controlled by features of the formulation and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone. In contrast to conventional, immediate release, or uncoated normal matrix formulations, which typically produce large differences between maximum and minimum plasma drug concentrations (C_max and C_mi_n) due to rapid absorption of the drug into the body (i.e., in vivo, relative to the drug's therapeutic index; i.e., the ratio of the maximum drug concentration needed to produce and maintain a desirable pharmacological response), the rate of release of the active drug from a modified release formulation is controlled by features of the formulation and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone and so typically produce relatively smaller differences. In conventional, immediate release or uncoated normal matrix formulations, the drug content is released into the gastrointestinal tract within a short period of time, and plasma drug levels peak shortly after dosing. The design of conventional, immediate release or uncoated normal matrix formulations is generally based on getting the fastest possible rate of drug release. Modified release formulations include those that release the drug (or some portion of the drug in the dosage form) more slowly than an immediate release formulation. [0040] "Moisture barrier" refers to a barrier that impedes or retards the absorption of moisture by the formulation. In various embodiments, the moisture barrier is comprised of an enteric and/or acrylic polymer, such as an acrylic polymer, and optionally may include a plasticizer and/or a permeation enhancer.

[0041] "Permeation enhancer" refers to a hydrophilic substance, which, when applied as part of a coat on a formulation, allows water to enter the formulation without physical disruption of the coat.

[0042] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art that include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use, 2002, incorporated herein by reference.

[0043] "Plasticizer" refers to a compound capable of plasticizing or softening a polymer or a binder. Plasticizers can broaden the average molecular weight of a polymer in which they are included thereby lowering its glass transition temperature or softening point. Plasticizers also can reduce the viscosity of a polymer. The use of plasticizers is optional, but they can be included in a formulation to modify the properties and characteristics of the polymers used in the coat(s) or core of the formulation for convenient processing during manufacture of the coat(s) and/or the core of the formulation. Once the coat(s) and/or core has been manufactured, certain plasticizers can function to increase the hydrophilicity of the coat(s) and/or the core of the formulation in the environment of use. During manufacture of the coat(s) and/or core, the plasticizer can lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder.

[0044] "Reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) refers to decreasing the severity or frequency of the symptom(s), or elimination of the symptom(s).

[0045] "Solid formulation" refers to a formulation that is neither liquid nor gaseous.

Solid formulations include tablets, powders, microparticles, capsules, matrix forms, suppositories, sachets, troches, patches and lozenges as well as liquid suspensions and elixirs. Solid formulations in the form of capsules contain a solid composition within a capsule that can be made of gelatin or other conventional encapsulating material. [0046] "Swelling enhancer" refers to an excipient that swells rapidly resulting in an increase in the size of the tablet. At lower concentrations, these excipients can be used as super disintegrants; however at concentrations above about 5% w/w, these excipients function as swelling enhancers and increase the size of the matrix formulation.

[0047] "Therapeutically effective amount" of a drug refers to an amount of the drug that, when administered to a patient with cardiovascular disease, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cardiovascular disease in the patient. In the case of YM758, the

therapeutically effective amount will lower heart rate when administered to the patient. A therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Typically, cardiovascular drugs are

administered in a repeating series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0048] "Treating" or "treatment of a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cardiovascular disease; diminishment of extent of cardiovascular disease; delay or slowing of cardiovascular disease progression; amelioration, palliation, or stabilization of the disease state; or other beneficial results.

II. Treatment Methods

[0049] An association between elevated resting heart rate (HR) and both

cardiovascular and all-cause mortality has been known for many years, based on the results of large-scale epidemiological studies. The survival benefit of some cardiovascular drugs (such as beta blockers) seems to be related in part to their heart rate-lowering effects.

However, beta blockers in patients with heart failure have undesirable effects as well such as negative inotropism so that dose titration must be done carefully. Many heart failure patients do not tolerate beta blockers at all. There are several mechanisms by which a low or reduced heart rate could be of benefit. First, myocardial ischemia occurs when coronary perfusion is insufficient to satisfy myocardial oxygen demand and heart rate is an important determinant of myocardial oxygen demand. Secondly, a reduction in heart rate may improve myocardial perfusion by increasing the duration of diastole relative to cardiac cycle length. Finally, in patients with impaired left ventricular function, a slow heart rate can prolong diastolic filling time, and thus may improve ventricular filling and stroke volume. Taken together, drugs that specifically reduce heart rate improve myocardial pumping performance and efficiency, which in turn leads to a reduction of sympathetic drive to the heart and should be of benefit in a range of cardiovascular conditions. The pharmaceutical formulations and unit dose forms of the invention are, in one embodiment, administered to a patient to reduce, lower, or slow the heart rate.

[0050] Heart rate is one of the major determinants of myocardial oxygen

consumption. HR-lowering drugs have therapeutic potential for the treatment of several types of heart diseases including but not limited to stable angina, atrial fibrillation and heart failure. I_f channels are primarily activated by membrane hyperpolarization, and an increase of intracellular cAMP enhances the activity by shifting the current activation curve toward the positive voltage range. While hyperpolarization-dependent activation acts to generate diastolic depolarization and spontaneous activity, cAMP-dependent activation contributes to mediate neurotransmitter-induced activity. Intracellular cAMP production is increased by autonomic β-adrenergic stimuli through adenylate-cyclase activation. The increased cAMP activates I_f channels through direct binding to the cyclic nucleotide binding domain (CNBD) at the C terminus of I_f channels which is a key element in the basal channel inhibition. Cyclic AMP bound to CNBD causes the open probability curve to shift to positive in a dose- dependent manner. Beta blockers suppress the increase in cAMP and positive shift in the open probability curve, resulting in the inhibition of activation of I_f channels.

[0051] The I_f channel inhibitors were previously reported simply to reduce the overall

I_f conductance as their mode of inhibitory action of I_f channel. However, it is now believed that the I_f blocking action of these inhibitors rather depends on the direction of ion flow across the channel pore. In other words, the blocking action can be expressed as "current- dependent". The "current-dependence" of the block can be interpreted biophysically with the assumption that the I_f channel inhibitors are "kicked into" the pore from the intracellular side of the channel and reach the blocking site when ions flow in the outward direction during a depolarization, and are "kicked out" when ions flow in the inward direction during a hyperpolarization.

[0052] I_f channels are referred to as hyperpolarization-activated cyclic nucleotide- gated cation (HCN) channels. According to the theoretical structure of the native human I_f channel HCN4, which is considered a major cardiac HCN isoform, they have a "pore cavity" just below the intracellular side of the selectivity filter to which K⁺ and Na⁺ ions may bind in their pathway across the channels. Thus, an I_f channel inhibitor might bind to the channel within the pore cavity and interfere with the binding of permeating ions to the pore sites. [0053] As described above, beta blockers reduce the open probability of I_f channels, and YM758 is believed to interfere with the permeation of ions into the I_f channels. Because the I_f conductance decreasing effect seems to be independent of the current activation curve shift, YM758 exerts its inhibitory effect even in the presence of beta blockers which maximally shifts the current activation curve to a negative voltage. The present invention arose in part from the discovery that these two inhibitory mechanisms for the I_f channel can coexist as demonstrated below.

[0054] YM758 is a selective I_f channel inhibitor suitable for use in treatment of cardiovascular disease. YM758 decreases HR in conscious rats, anesthetized pigs and conscious beagle dogs with isoproterenol-induced tachycardia. In addition, YM758 reduces myocardial oxygen consumption in anesthetized pigs with dobutamine infusion. Furthermore, YM758 ameliorates the ST-segment depression in pigs with coronary stenosis when cardiac work was increased by exogenous infusion of dobutamine. Thus, YM758 exerts HR- lowering effects in animal models. Single and multiple ascending dose studies in humans as well as a Phase 2 study in patients with stable angina demonstrate the animal results are relevant to the drug's efficacy in humans.

[0055] Congestive heart failure (CHF), also known as heart failure, is a

pathophysiologic state in which primary cardiac abnormality leads to a reduction in cardiac output such that peripheral oxygen delivery is not adequate. There are diverse underlying causes of CHF, such as myocarditis, valvular disease, hypertension, and ischemic heart disease. This is why it can be considered a terminal clinical condition of these cardiovascular diseases. Patients that have CHF have an autonomic imbalance that manifests itself in increased sympathetic activity, reduced vagal activity, or both, so it is often present with tachycardia. Whereas heart rate elevation causes an increase in cardiac contractility in a normal heart, if it is above a certain threshold, the contractility is decreased due to

disturbance in the force-frequency relationships in dysfunctional myocardium. Thus, in patients with CHF, tachycardia could be considered a compensatory reaction to maintain homeostasis by preserving cardiac output. But, on the contrary, tachycardia that is not accompanied by positive inotropic effect may cause hemodynamic deterioration by increasing cardiac workload. Therefore, inhibition of tachycardia should not only reduce myocardial oxygen consumption but also increase local blood flow in myocardium, so that it might improve the balance of oxygen supply and demand in myocardial dysfunction.

[0056] Patients with CHF often develop ventricular arrhythmias, which may cause sudden death. Persistent tachycardia in patients with CHF reduces the effective refractory 2__|_

period (ERP) and increases the intracellular Ca concentration, which is considered an initiating factor for ventricular arrhythmias. These findings suggest that inhibition of

2__|_

tachycardia may prevent ERP reduction and intracellular Ca increase, and so suppress ventricular arrhythmias.

[0057] Several meta analyses have shown that β-receptor blockers reduced morbidity and mortality in patients with CHF. Effectiveness of β-blockers on CHF at least partly attribute to heart rate reduction. However, in patients with CHF, β-blockers may have undesirable effects, such as negative inotropism, so an optimal dose must be found by careful titration over 4-6 weeks. Moreover, it is known that there are patients with CHF who do not tolerate β-receptor blockers. The pharmaceutical formulations and unit dose forms of the invention are useful in treating patients with CHF.

[0058] The I_f channel has the unique property of being activated by hyperpolarization and intracellular cAMP increase. I_f channels are present in the sinoatrial node (SAN) and Purkinje fibers, which regulate cardiac pacemaking. Activation of the I_f channel enhances the diastolic depolarization rate of the action potentials (APs) of the pacemaker cells, thereby increasing heart rate. Zatebradine and ivabradine, known as I_f channel inhibitors, reportedly reduce heart rate without causing negative inotropism. Ivabradine has been studied in patients with chronic heart failure (long term heart failure) and on background medications that may include β-blockers. The present invention arose in part from the discovery that YM758 has anti-heart failure effects as demonstrated in a rat model using rats with myocardial infarction- induced heart failure as shown in Example 1, Figures 1 and 2, and Tables 2 and 3.

[0059] YM758 also has benefit in treating patients suffering from stable angina, also called angina pectoris, as shown in Example 2 and Figures 3 and 4. Angina pectoris is a discomfort in the chest or adjacent areas caused by myocardial ischemia. Stable angina pectoris (stable angina) is brought on by exertion and associated with a disturbance of myocardial function, but without myocardial necrosis. The definition of stable or unstable angina is largely based on the clinical presentation. Stable angina is characterized by a deep, poorly localized chest or arm discomfort (rarely described as pain) that is reproducibly associated with physical exertion or emotional stress and relieved within 5-15 minutes by rest and/or sublingual nitroglycerin. In patients with stable angina, the chest discomfort occurs on exertion or under mental or emotional stress, when there is an increase in myocardial oxygen demand that cannot be met due to insufficient coronary blood flow.

[0060] In patients with stable angina, symptomatic relief can be achieved by decreasing myocardial oxygen demand (MV0₂) and increasing coronary blood flow. This can be achieved via heart rate reduction or coronary vasodilation. Beta-blockers provide

2__|_

symptomatic relief in part by decreasing oxygen demand, while Ca -channel blockers and nitrates increase coronary blood flow. Disadvantages of these therapeutics include the

2__|_

negative inotropy of β-blockers and Ca -channel blockers, venous pooling and headache for

2__|_ the nitrates, and headache, flushing, constipation and peripheral edema for the Ca -channel blockers. It is known that I_f channel inhibitors lower heart rate without any negative inotropic effect, thus preserving ventricular contractility. Thus, the pharmaceutical formulations and unit dose forms of the invention are useful in treating patients with stable angina.

[0061] YM758 has a favorable I_f/I channel inhibition ratio and so minimizes negative effects on visual perception (which is a problem for certain other compounds, the visual symptoms being a result of effects on the neuronic I_h channel). YM758 has a 10-fold more favorable I_f/I_h channel inhibition ratio compared with other known drugs such as ivabradine. YM758 has a potent effect on both heart rate and heart beat rhythm control. YM758 was administered in a dose escalating study and a food effect study to healthy subjects. A multiple dosing study in healthy subjects was also done. In these studies, YM758 reduced the heart rate in a dose-dependent manner. Studies in patients with stable angina showed safety, tolerability, and efficacy, as described in Example 2 and shown in Figures 3 and 4.

[0062] The results of this study, described in Example 2 and summarized in Figures 3 and 4, show that YM758 gives a dose-dependent reduction in heart rate both at baseline and with exertion. Dosing at 20 mg BID vs 40 mg once daily (OD) does not significantly change the trough characteristics but does reduce the peak characteristics in this study. This data supports the benefits of a lower peak dose through continuous sustained release dosing where 5 to 50 mg total dose is released over a 12-24 hour period. Thus, the sustained release formulations of the invention can be co-administered with other heart medications, for example, with sustained or immediate release β-blockers. Although the data above was obtained from patients with stable angina, the dosing benefits of sustained release

administration would be realized in treatment of patients with other cardiovascular disease, such as heart failure and atrial fibrillation.

[0063] Many heart conditions, including stable angina, atrial fibrillation and heart failure, are treated with β-blockers. β-blockers work by competitively blocking β-adrenergic receptors and competing with neurotransmitters such as catecholamines to inhibit

sympathetic stimulation of the heart. This results in a reduction of resting heart rate. In addition, β-blockers reduce systolic and diastolic blood pressure by blocking renin secretion and reducing vascular tone. They also have negative inotropic effects (decreasing myocardial contractility) and reduce cardiac workload. However, in certain patients with limited cardiac reserve, the negative inotropic effects may result in profound decreases in left ventricular function.

[0064] YM758, an inhibitor of the I_f channel, can, in accordance with the methods of the invention, be administered to heart disease patients alone or in combination with β- blockers for treatment of heart disease by lowering heart rate without negative inotropic effects or a decrease in blood pressure.

[0065] In addition to working independently as heart rate lowering agents, YM758 and β-blockers work additively to lower heart rate. This effect was demonstrated in a dog model as described in Example 3 and shown in Figure 7, where heart rate and blood pressure were measured every 10 minutes for the first 30 minutes, and atenolol was administered as a continuous infusion of 0.03 mg/kg/min. After 30 minutes, YM758 at one of two different doses or vehicle was added. Heart rate and blood pressure were continuously monitored every 10 minutes for an additional 30 minutes.

[0066] This model demonstrated that it was possible to use atenolol (or other beta- blocker) and have heart rate lowering effect in addition to that seen with YM758. This is important as YM758 and beta blockers are well suited to be used together in the clinical setting in accordance with the invention. The 60 minute time point of this test is described in Example 3 and shown in Figures 7 and 8. As can be seen, although there is clear additional benefit for heart rate lowering with YM758, there is no additional blood pressure lowering when YM758 is combined with atenolol.

[0067] In the above described animal model studies, atenolol dose-dependently decreased the HR and MBP, and consequently reduced RPP, and these effects seemed to be saturated at 0.03 mg/kg/min iv continuous infusion. YM758 also decreased the HR in a dose dependent manner without affecting the MBP, and as a result, the RPP was reduced. When atenolol 0.03 mg/kg/min iv was given by continuous infusion, additional intravenous administration of YM758 (0.1 and 0.3 mg/kg iv) reduced the HR further without any marked changed in the MBP, resulting in a further RPP reduction, compared with atenolol administered at a rate of 0.03 mg/kg/min iv alone.

[0068] This additive effect of YM758 and atenolol may be explained by the differences between YM758 and β-b lockers in their mechanism of action on the I_f channel.

[0069] These results support the beneficial effects of the methods of the invention for treating cardiovascular diseases such as stable angina (SA), CHF, and atrial fibrillation. Use of YM758 with β-b lockers in accordance with the methods of the invention leads to an additive antianginal effect in SA patients, additive heart failure survival benefit and less time to next hospitalization with CHF, and additive and quicker rate/rhythm control in atrial fibrillation leading to fewer hospitalizations and reduced mortality.

[0070] In patients who cannot be administered the recommended clinical dose of a β- blocker for heart disease because of its adverse effects, the present invention offers an important alternate therapy in which YM758 is administered in combination with a lower than the recommended clinical dose of the β-b locker. The combined therapy with YM758 in accordance with the invention provides a sufficient heart rate lowering effect for therapeutic benefit and reduces adverse effects via the decrease in the dose of the β-blocker.

[0071] In many patients, combined administration of YM758 and a beta-blocker will be beneficial without undesired side effects when each drug is administered at its standard dose. However, there may be benefits in these patients and especially in patients that cannot be administered the recommended clinical dose of either drug to administer one or both drugs at a dose lower than the usual dose. Thus, in various embodiments of the methods of the invention, one or both drugs will be administered at a dose lower than the usual dose, as described in Example 3 and illustrated in Table 1 below.

TABLE 1 Dosing Information

Table 1 shows illustrative doses of YM758 and a variety of beta blockers for typical daily dosing or lower than usual daily dosing in accordance with the combination therapies of the invention. Atenolol, bioprolol, metaprolol, carvedilol, and carvedilol ER are shown at recommended daily dosing in the top row and illustrative lower doses (along with lower suggested doses of YM758) in bottom row. In addition, YM758 may be given at its suggested usual daily dose and beta-blockers be given at a lower dose. Beta-blockers are titrated up over a period of time, and the doses in Table 1 are illustrative of the final (highest) therapeutic dose.

[0072] Certain aspects of the present invention arose from the discovery that YM758 can be safely and efficaciously administered in a sustained release formulation. The benefits of this sustained release formulation are described in Example 4 and shown in Figure 9 and Table 4, which summarize data from a dose-escalation study. Figure 9 shows the mean YM758 concentration (in plasma) versus time profiles in the dose escalation study, which was a single dose-escalation design in which 54 healthy male subjects received YM758 at doses ranging from 0.5 mg to 90 mg (9 groups, N=6/YM758 dosage, 8 subjects received placebo).

[0073] This and other studies showed that YM758 is rapidly absorbed (T_max of about

1 hour) with a variable half-life (15.1 hr to 18.2 hr for females; and 12.4 hr to 18.9 hr for males) and expected peak plasma concentrations about 2.4 fold to about 3.7 fold higher than trough levels. These properties make it difficult to maintain efficacious levels of the drug over a 24 hour period with once daily dosing without nearing or exceeding peak plasma concentrations associated with potentially undesirable side effects (visual side effects at moderate to high dose and bradycardia at high dose). The present invention provides a variety of methods, pharmaceutical formulations, and unit dose forms that overcome this difficulty.

[0074] Thus, in one aspect, the invention provides a means for overcoming these difficulties by administering a daily dose of YM758 in the range of 5 mg to 80 mg. Typically, the daily dose will be in the range of 5 mg to 50 mg. Often, the daily dose will be 20 mg or 25 mg. In some embodiments, potentially undesirable side effects are avoided by

administering a single daily dose of an immediate release form of 10 mg to 50 mg, e.g. a dose of 20 mg or 25 mg. In some embodiments, undesirable side effects are avoided by

administering a dose of an immediate release form twice a day, e.g. each dose in the range of 5 mg to 20 mg. In some embodiments, undesirable side effects are avoided by administering a single dose of a sustained release formulation, e.g., at a dose in the range of 5 mg to 50 mg, e.g., a dose of 20 mg or 40 mg. Any of these doses can be administered in accordance with the methods of the invention.

[0075] In one embodiment, the present invention provides a method of treating patients with stable angina, atrial fibrillation, heart failure and other cardiovascular diseases comprising administering a therapeutically effective amount of a formulation of the present invention to a patient in need of such treatment. In one embodiment, YM758 is administered as the sole agent to treat stable angina, atrial fibrillation, heart failure and other

cardiovascular diseases.

[0076] In one embodiment of the methods of the invention, YM758 is administered in combination with another drug to treat stable angina, atrial fibrillation, heart failure and other cardiovascular diseases. Suitable drugs for use in these methods include beta-blockers, anti- arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis.

[0077] Beta-blockers (also referred to herein as β-blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly used for the management of cardiac arrhythmias, cardioprotection after myocardial infarction (heart attack), heart failure and hypertension. Beta-blockers that can be used in combination with YM758 in accordance with the methods of the invention include both non-selective agents (such as alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, timolol and eucommia bark) as well as beta 1- selective agents (such as acebtolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol and nebivolol). In various embodiments, sustained release forms of these beta- blockers are used in the methods of the invention. In various embodiments, the beta blockers administered are selected from the group consisting of metoprolol, bisoprolol and carvedilol.

[0078] Anti-arrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Anti-arrhythmic products that can be used in combination with YM758 in accordance with the methods of the invention include Class I agents that interfere with the sodium (Na⁺) channel (such as quinidine, procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainide flecainide, propafenone and moirizine), Class II agents that are anti-sympathetic nervous system agents (most agents in this class are beta-blockers such as propanolol, esmolol, timolol, metoprolol, atenolol, and bisoprolol), Class III agents that affect potassium (K⁺) efflux (such as amiodarone, sotalol, ibutilide, dofetilide, dronedarone and E-4031), Class IV agents that slow-channel blockers affecting calcium channels and the AV node (such as verapamil and diltiazem), and Class V agents that work by other or unknown mechanisms (such as adenosine, digoxin and magnesium sulfate).

III. Oral Formulations of YM758

[0079] An illustrative oral formulation of YM758 provided by the invention is an immediate release formulation. Illustrative unit dose forms of this formulation include immediate release tablets with 5, 10, and 20 mg of YM758. Inactive ingredients (excipients) are lactose monohydrate, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, sodium stearyl fumarate and a film coating which includes hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 8000, talc and yellow ferric oxide.

[0080] More generally, the present invention provides an oral formulation of YM758 comprising or consisting essentially of YM758 and optionally an excipient. The excipient is suitable for administration to patients with stable angina, atrial fibrillation, heart failure and other cardiovascular diseases, which are typically human patients, although the formulations and dosage forms of the invention have veterinary application as well.

[0081] In one embodiment, the oral formulation is an immediate release formulation.

Suitable unit dose forms include a gelatin capsule or tablet formulation comprising YM758.

[0082] In one embodiment, the oral formulation is a modified release formulation. In one embodiment, the modified release formulation is provided in a unit dose form that is a tablet. In one embodiment, the modified release formulation comprises microparticles of YM758. In one embodiment, the modified release formulation comprises a controlled release matrix. In one embodiment, the modified release formulation is provided in a unit dose form that comprises a core that comprises YM758. In one embodiment, the modified release formulation is provided in a unit dose form that includes an immediate release component. In one embodiment, the modified release formulation is provided in a unit dose form that further comprises a coat. In one embodiment, the coat is a controlled releasing coat. In one embodiment, the coat is a moisture barrier coat. In one embodiment, the modified release formulation further comprises an additive selected from the group consisting of additives that facilitate water penetrating into the formulation, a binder, a lubricant, a glidant, a plasticizer, a diluent, a solubilizer, and/or a swelling enhancer. In one embodiment, the modified release formulation shows a pulsatile YM758 release profile.

[0083] An illustrative oral formulation of YM758 is a modified release formulation.

Illustrative unit dose forms of this formulation include modified release tablets with 5 to 80 mg of YM758. Inactive ingredients (excipients) are polyvinylpyrolidone, microcrystalline cellulose, carbosil, carbomer, citric acid, carboxymethyl cellulose (cellulose gum), co- processed starch, talc and magnesium stearate in the proportions described in Example 5C. Such a formulation will reduce the level of short-term spikes in plasma concentration (and changes in heart rate that may accompany these) and extend the period during which a dose of the drug has therapeutically beneficial effect. For example, a once-a-day sustained-release formulation at 40 mg, as described in Example 5C, Figure 10, and Table 6, may provide superior therapeutic effect than administration twice-a-day of an immediate release formulation containing 20 mg of YM758. A further advantage of such a sustained release formulation is the reduction in maximum plasma concentration (C_max), as certain C_max concentrations can trigger excessive bradycardia and visual side effects.

[0084] In one embodiment, the formulation comprises nanoparticles of YM758.

[0085] In one embodiment, the formulation is given separately and concomitantly with one or more other products to treat stable angina, atrial fibrillation, heart failure and other cardiovascular diseases. These products include beta-blockers, anti-arrhythmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis, among others.

[0086] In one embodiment, the YM758 formulation of the invention is given together with and in combination with (in the same dosage form) one or more other products to treat stable angina, atrial fibrillation, heart failure and other cardiovascular diseases. These products include beta-blockers, anti-arrhythmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine and digitalis, among others.

[0087] In one embodiment, the YM758 formulation is an immediate release formulation. In one embodiment, the immediate release formulation is an uncoated normal matrix formulation. In one embodiment, the immediate release formulation is provided in a unit dose form that is a gelatin capsule containing YM758. The YM758 contained in the gelatin capsule is, in various embodiments, a powder, a granular substance, or substantially spherical microp articles. Gelatin capsules are reported in Manegold et al., Ann Oncol. 1996; 7(6):637-9, incorporated herein by reference. An immediate release formulation generally provides a fast rate of drug release and/or a high C_max. Various methods of making other immediate release formulations, which can be applied to making those of the present invention in view of the disclosure herein, are well known to the skilled artisan and can be employed or adapted to make the formulations and dosage forms of the present invention. [0088] In one embodiment, the YM758 formulation is a modified release formulation.

In one embodiment, the modified release formulation is a monolithic formulation. In one embodiment, the modified release formulation is a multiparticulate formulation. Examples of modified release formulations are disclosed in U.S. Pat. Nos. 5,591,452 and 5,965,161, and such examples can be modified in accordance with the present disclosure to prepare modified release YM758 formulations of the invention. In one embodiment, the modified release formulation is provided in a unit dose form that is coated. In one embodiment, the coating is a functional coating. In one embodiment, the functional coating includes one or more of the following: a polymeric coating, a moisture barrier coating, an enteric polymeric coating, and mixtures of the same. In one embodiment, the coating is a nonfunctional coating in that it does not affect YM758 release. A non- functional coating may instead affect other properties of the formulation, including, without limitation, enhancing chemical, biological, or physical stability of the YM758 formulation or dosage form.

[0089] In one embodiment, the functional coating is a polymeric coating. In one embodiment, the polymeric coating is a control releasing coating. In one embodiment, the control releasing coating comprises an acrylic polymer. Suitable acrylic polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

[0090] In one embodiment, the acrylic polymer is a polymerizable quaternary ammonium compound. Nonlimiting examples of such polymerizable quaternary ammonium compounds include quaternized aminoalkyl esters and aminoalkyl amides of acrylic acid and methacrylic acid, for example β-methacryl-oxyethyl-trimethyl-ammonium methosulfate, β- acryloxy-propyl-trimethyl-ammonium chloride, and trimethylaminomethyl-methacrylamide methosulfate. The quaternary ammonium can also be part of a heterocycle, as in

methacryloxyethylmethyl-morpholiniom chloride or the corresponding piperidinium salt, or it can be joined to an acrylic acid group or a methacrylic acid group by way of a group containing hetero atoms, such as a polyglycol ether group. Other suitable polymerizable quaternary ammonium compounds include, without limitation, quaternized vinyl-substituted nitrogen heterocycles such as methyl-vinyl pyridinium salts, vinyl esters of quaternized amino carboxylic acids, styryltrialkyl ammonium salts, and the like. Still other polymerizable quaternary ammonium compounds include, without limitation, acryl- and methacryl- oxyethyltrimethyl-ammonium chloride, benzyldimethylammoniumethyl-methacrylate chloride, diethylmethylammoniumethyl-acrylate, N- trimethylammoniumpropylmethacrylamide chloride, and N-trimethylammonium-2,2- dimethylpropyl- 1 -methacrylate chloride.

[0091] In one embodiment, the polymeric control releasing coating comprises an acrylic polymer and a polymerizable quaternary ammonium compound.

[0092] In one embodiment, the control releasing coat further includes a polymer whose permeability is pH dependent, such as anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester. In some embodiments, the polymer is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0-pH 7.0. Such hydrophobic acrylic polymer can include a cationic polymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid. The hydrophobic acrylic polymer coatings utilized in the present invention can include a neutral copolymer based on poly (meth)acrylates or lacquer films that are insoluble in water and digestive fluids, but are water permeable and water swellable.

[0093] In one embodiment, the control releasing coat comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate. The dissolution profile of such a coat can by altered by changing the relative amounts of different acrylic resin lacquers included in the coating. Also, by changing the molar ratio of polymerizable permeability- enhancing agent (e.g., the quaternary ammonium compounds) to the neutral (meth)acrylic esters, the permeability properties (and thus the dissolution profile) of the resultant coating can be modified.

[0094] Other examples of polymers that can be used in the control releasing coat include cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl

methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, swellable hydrophilic polymers, poly(hydroxyalkyl methacrylate) (molecular weight 5 kilo Dalton (k) to 5000 k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, polyethylene oxides (molecular weight 100 k to 5000 k), diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof.

[0095] In another embodiment, the YM758 formulation of the invention is provided in a unit dose form that is coated with polymers to facilitate mucoadhesion within the gastrointestinal tract. Non limiting examples of polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic acid, gelatin and other natural or synthetic polymers.

[0096] In one embodiment, the modified release YM758 formulation of the invention is provided in a unit dose form that is a tablet. In one embodiment, the tablet comprises a core comprising YM758 and one or more excipients. When mixed with a conventional excipient, the YM758 core may be an immediate release formulation. In one embodiment, the core is surrounded by a control releasing coat which controls the release of the YM758. In various embodiments, a moisture barrier surrounds the control releasing coat. If present, the moisture barrier coat affects YM758 release and retards moisture from coming into contact with the YM758. Optionally, this tablet may further comprise one or more additional functional or non-functional coatings surrounding the core, moisture barrier and/or control releasing coat.

[0097] In one embodiment, the tablet is an extended-release tablet. In one

embodiment, the tablet comprises a core comprising YM758 and one or more excipients. In one embodiment, the core is surrounded by a control releasing coat, which controls the release of the YM758. The tablet may optionally comprise one or more additional functional or nonfunctional coats surrounding the core or control releasing coat. [0098] In one embodiment, the core of the extended-release tablet comprises YM758, a binder, and a lubricant and can contain other conventional inert excipients. Various binders, lubricants, glidants, and other conventional inert excipients useful in accordance with the present formulations are well known to the skilled artisan and can be readily selected in view of the present disclosure. Additional inert excipients well known to the skilled artisan are found in the relevant literature, for example in the Handbook of Pharmaceutical Excipients, 5^th Edition, Edited by Raymond C. Rowe et al., incorporated herein by reference. Thus, in some embodiments, the extended release core formulation is an uncoated immediate release formulation or a normal release matrix formulation.

[0099] These and other tablet cores utilized according to the present invention can be manufactured by wet and dry granulation, direct compression, extrusion, spheronization, melt granulation, and rotary granulation processes well known to the skilled artisan.

[00100] In various embodiments, the tablet cores are coated with an extended release, control releasing coating. In another embodiment, the tablet cores are coated with an aqueous control releasing coating that comprises an aqueous dispersion of a neutral ester copolymer without any functional groups. In another embodiment, the tablet further comprises a moisture barrier. The control releasing coat and the moisture barrier can be applied in two stages. The control releasing coating can be applied directly onto the surface of the tablet core and functions primarily to control the release of YM758. The moisture barrier can be applied directly onto the surface of the control releasing coat to impede or retard the absorption of moisture by the tablet.

[00101] In one embodiment, the tablet formulation of YM758 provided by the invention comprises an extended release control releasing coat. The extended release control releasing coat is a semi permeable coat comprising a water insoluble, water-permeable film- forming polymer, optionally a water-soluble polymer, and optionally a plasticizer. Non limiting examples of water-insoluble, water-permeable film-forming polymers useful for the extended release control releasing coat include cellulose ethers, cellulose esters, and polyvinyl alcohol. Other non-limiting examples of water-soluble polymers useful for the extended release control releasing coat include polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[00102] In certain embodiments, the extended release control releasing coat further comprises a plasticizer. Non limiting examples of plasticizers useful in the control releasing coats include without limitation, acetylated monoglycerides, acetyltributyl citrate, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, propylene glycol, triacetin, tripropioin, diacetin, dibutyl phthalate, acetyl monoglyceride, acetyltriethyl citrate, polyethylene glycols, castor oil, rape seed oil, olive oil, sesame oil, triethyl citrate, polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i- decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate, polyols (e.g. polyethylene glycol) of various molecular weights.

[00103] In certain embodiments, a moisture barrier is applied directly onto the control releasing coat. The moisture barrier may comprise an enteric polymer (e.g. acrylic polymer), a permeation enhancer and optionally a plasticizer. In certain embodiments, the enteric polymer is an acrylic polymer. For example, the acrylic polymer can be a methacrylic acid copolymer comprising 1 : 1 poly-methacrylic acid-methyl methacrylate.

[00104] In one embodiment, the permeation enhancer is selected from

hydroxypropylmethylcellulose, cellulose ethers and protein-derived materials of these polymers. In another embodiment, the permeation enhancer is polyvinylpyrrolidone, cross- linked polyvinyl-pyrrolidone, polyethylene oxide, water-soluble polydextrose, saccharides and polysaccharides, such as pullulan, dextran, sucrose, glucose, lactose, fructose, mannitol, mannose, galactose, sorbitol and the like. Other non-limiting examples of permeation enhancers include alkali metal salts such as aluminum oxidelithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, and the like. In some embodiments, the permeation enhancer is a pore forming solid. Examples of pore forming solids include, without limitation, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyglycols, poly(a-w)alkylenediols, and the like. Other permeation enhancers which can be useful in the formulations of the present invention include starch, modified starch, and starch derivatives, gums, including but not limited to xanthan gum, alginic acid, other alginates, benitonite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, cross-linked

polyvinylpyrrolidone, ion-exchange resins, such as potassium polymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan, gum karaya, and biosynthetic gum. Still other pore forming solids include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain, microporous materials such as bisphenol, a microporous poly(vinylchloride), micro-porous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and its copolymers, porous polysulfones, halogenated poly(vinylidene), polychloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol,

poly(alkylenesulfides), phenolics, polyesters, asymmetric porous polymers, cross-linked olefin polymers, hydrophilic microporous hiomopolymers, copolymers or interpolymers having a reduced bulk density, and other similar materials, poly(urethane), cross-linked chain-extended poly(urethane), poly(imides), poly(benzimidazoles), collodion, regenerated proteins, semi-solid cross-linked poly(vinylpyrrolidone), silicon dioxide, colloidal silica, microcrystalline cellulose, and any combination thereof.

[00105] These and other coats utilized according to the present invention can be applied by various methods well known to the skilled artisan from other applications, including, without limitation, spray coating. Spray coating is performed using a tablet coater, fluidized bed apparatus or other suitable coating apparatus, well known to the skilled artisan for other applications.

[00106] In one embodiment, the tablet formulation of YM758 provided by the invention is an enhanced absorption tablet. In one embodiment, the enhanced absorption tablet comprises a core comprising YM758 and one or more excipients. In one embodiment, the core is surrounded by an enhanced absorption coating, which controls the release of the YM758. In certain embodiments, the enhanced absorption coating consists of one coat. The advantages of the enhanced absorption tablet include the lower amount of drug, relative to certain other types of tablets or dosage forms, required in the composition, which can lead to a reduction of side effects and/or decreased manufacturing costs.

[00107] The core of the enhanced absorption tablet comprises YM758, a binder and a lubricant, and can contain other conventional excipients. Various binders, lubricants, glidants, and other conventional inert excipients useful in accordance with the present formulations are well known to the skilled artisan. The additional inert excipients are well known to the skilled artisan from other applications and can be found in the relevant literature, for example in the Handbook of Pharmaceutical Excipients supra.

[00108] The enhanced absorption tablet further comprise a coat. In one embodiment, the coat is a semi permeable coat comprising a water insoluble, water-permeable film- forming polymer, optionally a water-soluble polymer, and optionally a plasticizer. In certain embodiments, a moisture barrier is applied directly onto the control releasing coat. In some embodiments, the moisture barrier may comprise an enteric polymer (e.g. acrylic polymer), a permeation enhancer and optionally a plasticizer. Various water insoluble, water-permeable film-forming polymers, water-soluble polymers, plasticizer, enteric polymer, and permeation enhancers useful for the extended release tablets of the invention are also useful in the enhanced absorption tablets of the invention.

[00109] In one embodiment, the YM758 formulation provided by the invention is a controlled release matrix comprising YM758. The kinetics of drug release from the matrix core depend at least in part upon the diffusion and/or erosion properties of excipients within the formulation. Suitable excipient materials for use in such controlled release matrices include, by way of example, release-resistant or controlled release materials such as hydrophobic polymers, hydrophilic polymers, lipophilic materials and mixtures thereof.

[00110] Non-limiting examples of hydrophobic, or lipophilic components include glyceryl monostearate, mixtures of glyceryl monostearate and glyceryl monopalmitate, glycerylmonooleate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters, long chain carboxylic acid alcohols, and mixtures thereof. In some embodiments, the long chain carboxylic acids contain from 6 to 30 carbon atoms; in certain embodiments, at least 12 carbon atoms, and in other embodiments, from 12 to 22 carbon atoms. In some embodiments, this carbon chain is fully saturated and unbranched, while other embodiments utilize carboxylic acids that contain one or more double bonds. In another embodiment, the long chain carboxylic acids contain 3-carbon rings or hydroxyl groups. Non limiting examples of saturated straight chain acids include n-dodecanoic acid, n-tetradecanoic acid, n- hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefmic straight chain monocarboxylic acids. Non limiting examples of these include oleic acid, gadoleic acid and erucic acid. Also useful are polyolefmic straight chain monocaboxyic acids. Non limiting examples of these include linoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Non limiting examples of long chain carboxylic acid esters include glyceryl monostearates, glyceryl monopalmitates, mixtures of glyceryl monostearate and glyceryl monopalmitate, glyceryl monolinoleate, glyceryl monooleate, mixtures of glyceryl monopalmitate, glyceryl monostearate glyceryl monooleate and glyceryl monolinoleate, glyceryl monolinolenate, glyceryl monogadoleate, mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate, acetylated glycerides such as distilled acetylated

monoglycerides, mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide, mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide, d-a tocopherol polyethylene glycol 1000 succinate, mixtures of mono- and diglyceride esters such as Atmul, calcium stearoyl lactylate, ethoxylated mono- and di-glycerides, lactated mono- and di-glycerides, lactylate carboxylic acid ester of glycerol and propylene glycol, lactylic esters of long chain carboxylic acids, polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids, sodium stearoyl lactylate, sorbitan monostearate, sorbitan monooleate, other sorbitan esters of long chain carboxylic acids, succinylated monoglycerides, stearyl monoglyceryl citrate, stearyl heptanoate, cetyl esters of waxes, cetearyl octanoate, C10-C30 cholesterol/lavosterol esters, sucrose long chain carboxylic acid esters, and mixtures thereof.

[00111] Non-limiting examples of hydrophilic polymers that can be used in certain embodiments of the controlled release matrix formulation include

hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,

carboxymethylcellulose or other cellulose ethers, polyoxyethylene, alginic acid, acrylic acid derivatives such as polyacrylic acid, carbopol, polymethacrylate polymer such as, acrylic acid polymer, methacrylic acid polymer, hydroyethyl methacrylic acid polymer, hydroxymethyl methacrylic acid polymer, polyvinyl alcohols, and polyethylene oxide or polyethylene glycol.

[00112] In one embodiment, the controlled release matrix formulation provided by the invention further comprises one or more of a lubricant, a binder, and a plasticizer. In one embodiment, the controlled release matrix formulation further comprises one or more of a diluent, a solubilizer, a swelling enhancer, and an additive for allowing water to penetrate into the core of the formulation ("additive").

[00113] Non-limiting examples of diluents include dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol, sucralfate, calcium hydroxyl-apatite, calcium phosphates and fatty acid salts such as magnesium stearate. [00114] The solubilizer can act to increase the instantaneous solubility of YM758 and can be selected from hydrophilic surfactants, lipophilic surfactants, or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.

[00115] The hydrophilic non-ionic surfactants include, without limitation,

polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group from triglycerides, vegetable oils, hydrogenated vegetable oils, and d-a-tocopheryl polyethylene glycol 1000 succinate.

[00116] The ionic surfactants include, without limitation, alkylammonium salts, fusidic acid salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithins and hydrogenated lecithins, lysolecithins and hydrogenated lysolecithins, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, salts of

alkylsulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- and di-acetylated tartaric acid esters of mono- and di-glycerides, succinylated mono- and di-glycerides, citric acid esters of mono- and di-glycerides, and mixtures thereof.

[00117] The lipophilic surfactants include, without limitation, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acids esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and di-glycerides, hydrophobic transesterification products of a polyol with at least one member of the group from glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins/vitamin derivatives, PEG sorbitan fatty acid esters, PEG glycerol fatty acid esters, polyglycerized fatty acid, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, and mixtures thereof.

[00118] In another embodiment, the solubilizer is selected from PEG-20-glyceryl stearate, PEG-40 hydrogenated castor oil, PEG 6 corn oil, lauryl macrogol-32 glyceride stearoyl macrogol glyceride, polyglyceryl-10 mono dioleate, propylene glycol oleate, propylene glycol dioctanoate, propylene glycol caprylate/caprate, glyceryl monooleate, glycerol monolinoleate, glycerol monostearate, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, sucrose distearate, sucrose monopalmitate, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol 660 hydroxystearate, sodium lauryl sulfate, sodium dodecyl sulphate, dioctyl suphosuccinate, L-hydroxypropyl cellulose, hydroxylethylcellulose, hydroxylpropylcellulose, propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol, d-a-tocopheryl polyethylene glycol 1000 succinate, and mixtures thereof. In one other embodiment, the solubilizer can be selected from PEG-40 hydrogenated castor oil, lauryl macrogol-32 glyceride stearoyl macrogol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyoxyethylene-polyoxypropylene block copolymer, sodium lauryl sulphate, sodium dodecyl sulphate, polyethylene glycol, and mixtures thereof.

[00119] Examples of swelling enhancers include but are not limited to, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinised starch, co-processed starch, sodium carboxymethyl starch and mixtures thereof. In another embodiment of the matrix formulations, the swelling enhancer is cross-linked polyvinyl pyrrolidone.

[00120] Additives suitable for use in the formulations of the invention include, without limitation, hydrophilic polymers such as polyethylene glycol (PEG), and

polyvinylpyrrolidone, sugar such as D-sorbitol, xylitol, or the like, sugars such as sucrose, anhydrous maltose, D-fructose, dextran (e.g. dextran 40), glucose or the like, surfactants such as polyoxyethylene-hydrogenated castor oil, polyoxyethylene-polyoxypropylene glycol, polyoxyethylene-sorbitan high molecular fatty acid ester, or the like, salts such as sodium chloride, magnesium chloride, or the like, organic acids such as citric acid, tartaric acid, or the like, amino acids such as glycine, β-alanine, lysine hydrochloride, or the like, and amino sugars such as meglumine, glidants and lubricants and thickening agents such as carbosil, carbomer, talc and magnesium stearate.

[00121] Non-limiting examples of disintegrants for use in the matrix formulations include croscamellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and the like. In another embodiment, the disintegrant is selected from cross-linked polyvinylpyrrolidone, cross-linked sodium

carboxymethylcellulose, starch or starch derivatives such as sodium starch glycolate, co- processed starch or combinations with starch, swellable ion-exchange resins, such as

Amberlite IRP 88, formaldehyde-casein, and mixtures thereof.

[00122] In another embodiment, a swellable matrix formulation is provided in which the YM758 is dispersed in a polymeric matrix that is water- swellable rather than merely hydrophilic, that has an erosion rate that is slower than its swelling rate, and that releases the YM758 substantially by diffusion. Non limiting examples of polymers suitable for use in the swellable matrix include, cellulose polymers and their derivatives (such as for example, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, and

microcrystalline cellulose, polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly( vinyl pyrrolidone), starch and starch-based polymers, poly (2-ethyl-2- oxazoline), poly(ethyleneimine), polyurethane hydrogels, and crosslinked polyacrylic acids and their derivatives, and mixtures thereof.

[00123] Methods of manufacturing controlled release matrices, which are well known to the skilled artisan from other applications, include wet granulation, dry granulation (e.g. slugging, roller compaction), direct compression, melt granulation, melt extrusion, and rotary granulation. Controlled release particles utilized in controlled release matrixes, which can be compressed or placed in capsules, can be produced by combining YM758 and a hydrophobic fusible component and/or a diluent. Controlled release matrices can also be produced by mechanically working a mixture of YM758, a hydrophobic fusible component, and optionally a release component including a water soluble fusible material or a particulate material under mixing conditions that yield agglomerates, breaking down the agglomerates to produce controlled release seeds having desired release properties, and optionally adding more carrier or diluent and repeating the mixing steps until controlled release seeds having desired release properties are obtained. These particles also can be size separated (e.g. by sieving) and compressed into a matrix, or even encapsulated in capsules.

[00124] Also provided is a solid pharmaceutical composition in the form of a tablet obtained by wet granulation. In one embodiment, wet granulation comprises mixing YM758 with at least one solution binder and at least one wetting agent. In some embodiments, the solution binder is polyvinylpyrrolidone. In some embodiments, the wetting agent is water.

[00125] Also provided is a premix which can be used in a granulation process or for filling capsules. In one embodiment, the premix comprises YM758, microcrystalline cellulose, and cabosil. In one embodiment, the premix further comprises

polyvinylpyrrolidone .

[00126] Also provided is a solid pharmaceutical composition in the form of a capsule filled with a premix obtained by wet granulation, and optionally one or more excipients.

[00127] In some embodiments, the method of wet granulation comprises: combining a premix and a granulation solution to form wet granules. In some embodiments, the method of wet granulation comprises: (a) forming a premix; (b) transferring the premix to a granulator; (c) adding a granulation solution to the granulator; and (c) obtaining wet granules from the granulator. In some embodiments, the method further comprises drying and sieving the granules. In some embodiments, the method further comprises blending the granules with one or more additional excipients. In some embodiments, the method further comprises compressing the granules and optionally one or more excipients to form tablets. In some embodiments, the method further comprises filling capsules with the premix and optionally one or more excipients.

[00128] In one embodiment, the YM758 formulation provided by the invention is a multiparticulate system, which contains multiple microparticles containing YM758 and a pharmaceutically acceptable excipient. The microparticles can be contained within a capsule or can be compressed into a matrix or tablet that upon ingestion dissolves into multiple sub- units, wherein the sub-units or pellets possess the desired controlled release properties of the formulation. The multiparticulates or the multiple unit formulations can be surrounded by one or more coatings. Examples of such coatings include polymeric controlled release coatings, delayed release coatings, enteric coatings, immediate release coatings, taste -masking coatings, extended release coatings, and non-functional coatings. The excipient includes, without limitation spheronization aids, solubility enhancers, disintegrating agents, diluents, lubricants, binders, fillers, glidants, suspending agents, emulsifying agents, anti-foaming agents, flavoring agents, coloring agents, chemical stabilizers, and pH modifiers.

[00129] Solubility enhancers can be any surfactant suitable for use in pharmaceutical compositions, which can be anionic, cationic, zwitterionic or non-ionic. The microparticles of the present invention can be coated with a control releasing coat.

[00130] YM758 containing microparticles can be prepared by a number of different procedures, such as spray drying, fluidized bed based granulation/pelletization process, a spheronization process, and the like, which are well known to the skilled artisan.

[00131] YM758 layered microparticles can be made by coating an inert particle or core, such as a sugar sphere, with YM758 and a polymeric binder. In certain embodiments, the inert cores include water-insoluble materials such as cellulose spheres or silicon dioxide. In other embodiments, the inert cores include water-soluble materials such as starch, salt or sugar spheres.

[00132] In one embodiment, the YM758 formulation of the invention provides for pulsatile release of YM758. Pulsatile release refers to drug release at one or more time intervals, for example an initial quick release followed by a slow release of the drug or an initial quick release followed by, after some period of time, usually 1 to 4 hours, another quick release. For example, by combining uncoated, taste-masked or enteric coated microp articles with delayed or sustained release coated microparticles, a pulsatile drug release profile or chronotherapeutic profile can be achieved.

[00133] In one embodiment, the YM758 formulation comprises a nanoparticle.

Nanoparticles as used herein are submicron (e.g, and without limitation, < Ιμιη) colloidal particles. This includes monolithic nanoparticles or nanospheres in which the drug is adsorbed, dissolved, or dispersed throughout the matrix, and nanocapsules in which the drug is confined to an aqueous or oily core surrounded by a shell-like wall.

[00134] Nanoparticles can be made from biocompatible and biodegradable materials such as polymers, either natural (e.g., gelatin, albumin) or synthetic (e.g., polylactides, polyalkylcyanoacrylates), or solid lipids. In the body, the drug loaded in nanoparticles is usually released from the matrix by diffusion, swelling, erosion, or degradation. Nanoparticles of the invention also include those that provide for controlled and/or sustained drug release from the matrix. The methods for preparing nanoparticles suitable for drug formulation are well known to the skilled artisan from other applications. See, for example, Bala et al. PLGA nanoparticles in drug delivery: the state of the art. Crit. Rev. Ther. Drug Carrier Syst. 2004, 21 :387-422; Vauthier et al., Poly(alkylcyanoacrylates) as biodegradable materials for biomedical applications. Adv. Drug Deliv. Rev. 2003, 55:519-548; Couvreur et al,

Nanocapsule technology: a review. Crit. Rev. Ther. Drug Carrier Syst., 2002, 19:99-134, each of which is incorporated herein by reference.

IV. Solution Formulations of YM758

[00135] In one aspect, the present invention provides a pharmaceutical formulation comprising or consisting essentially of YM758 and optionally an excipient in solution that is referred to herein as a "solution formulation". As used herein, the excipient is suitable for administration to patients with stable angina, atrial fibrillation, heart failure and other cardiovascular diseases, which are typically human patients, although the formulations and dosage forms of the invention have veterinary application as well. Such a solution

formulation was used in the dog tests described in the examples below and demonstrated effective heart rate lowering activity.

[00136] In one embodiment, the solution formulation is provided in a vial and can be administered directly into the patient by injection intravenously, subcutaneously,

intraperitoneally and/or intramuscularly. In one embodiment, the solution formulation is provided in a vial and may be administered directly into an intravenous bag. [00137] In one embodiment, the solution formulation is administered separately and concomitantly with one or more other products to treat stable angina, atrial fibrillation, heart failure and other cardiovascular diseases. These products include beta-blockers, anti- arrhythmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine and digitalis, among others.

[00138] In one embodiment, the solution formulation is administered together with and in combination with (in the same dosage form) one or more other products to treat stable angina, atrial fibrillation, heart failure and other cardiovascular diseases. These products include beta-blockers, anti-arryhthmia products, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine and digitalis, among others.

[00139] In one embodiment, the present invention provides a pharmaceutical formulation comprising or consisting essentially of YM758 and optionally an excipient suitable for intravenous administration. As used herein, the excipient is suitable for administration to human cardiovascular patients and includes, without limitation, one or more of the following: an additive, an anti-foaming agent, a chemical stabilizer, a diluent, an emulsifying agent, a pH modifier, a buffering agent, an osmolarity modifier, a salt, a solubilizer, a solubility enhancer, and a suspending agent. In some embodiments, the formulation is a solution formulation, which may be, for example, in a vial, an ampoule or an intravenous bag.

[00140] The intravenous bag formulation may include components in standard intravenous isotonic and/or iso-osmotic products such as Lactated Ringer's solution (sodium, chloride, lactate, potassium, calcium), normal saline (sodium chloride). This may be formulated in the bag, or injected into the bag immediately prior to administration.

[00141] Patients suffering from cardiovascular disease, particularly for heart failure and atrial fibrillation, and less often for stable angina, often have to receive emergency room treatment, which may be followed by hospitalization. The present invention provides pharmaceutical formulations and treatment methods ideal for these patients. In accordance with the invention, a cardiovascular disease patient in need of treatment would receive intravenous treatment with YM758 in the emergency room. This treatment would last minutes to hours, i.e., for up to about eight hours (e.g. by continuous infusion). The intravenous treatment with YM758 can be continued in accordance with the invention in the hospital setting (non-emergency room) for as long as the treating physician deems appropriate, which may be the duration of the hospital stay (usually a few days to a week, and typically less than about two weeks). Upon discontinuance of the intravenous administration, the patient is then administered an oral formulation of YM758 in accordance with the invention, and that treatment is continued for as long as there is therapeutic benefit, which may be for days, one to three weeks, one to ten months, a year, or longer, e.g. for up to two years or longer.

V. Unit Dose Forms

[00142] The present invention provides unit dose forms of the pharmaceutical formulations of YM758 provided herein. In various embodiments, the unit dose form contains about 5 mg to about 80 mg of YM758. In various embodiments, the unit dose form contains about 5 mg to about 50 mg of YM758. In various embodiments, the unit dose form contains 5, 10, 20, 25, or 50 mg YM758. In each of these various embodiments, the YM758 may be formulated for immediate release, sustained release, or a combination thereof. In each of these various embodiments, the YM758 may be the only active pharmaceutical ingredient (API) or a second API may be present. When a second API is present, it is present in an amount approved for human use.

[00143] In one embodiment of the methods of the invention, the unit dose form is administered once a day. In another embodiment of the methods of the invention, the unit dose form is administered twice per day.

EXAMPLES

[00144] Example 1. The superior effect of YM758 (Figure 1A) in comparison with metoprolol (Figure IB) on survival rates of rats after myocardial infarction (MI) using Kaplan Meier curve analysis. The present invention arose in part from the discovery that YM758 has anti-heart failure effects as demonstrated in a rat model using rats with myocardial infarction-induced heart failure. The MI rats used in this demonstration were CHF, as determined by the cardiac dysfunction indicated by left ventricular contractility (+dP/dt_max) and observed dilatility decrease (-dP/dt_max) and increased preload indicated by LVEDP (left ventricular end diastolic pressure) elevation. The rat model was prepared by heart surgery and suture of the left coronary descending artery. The sham was prepared by a similar technique but the suture was not placed in such a way as to suture the artery. YM758 (3 mg/kg BID) or a β-blocker, metoprolol (100 mg/kg BID) was orally administered to rats for 6 weeks except for sham and control groups that received distilled water. The doses of YM758 and metoprolol were shown to lower heart rate by about 20% on average from results of previous studies. The results of this animal model study are summarized in Figures 1 and 2 and Tables 2 and 3. Table 2. Mortality of Sham Operated Rats and Myocardial infarction (MI) Rats after 6 Weeks Treatment with Vehicle, YM758 or Metoprolol.

^, Shara ^' YM758

[00145] The post-operative mortality rate was about 63%. Rats were then randomly assigned to control and treatment arms. Treatment arms started 2 weeks after surgery. The top row in Table 2 represents deaths following commencement of treatment over the initial number of animals treated (with % mortality given in the lower row). Although the effect on cardiac function (Figure 2) is similar between treatments (both show improved cardiac function), survival was higher in the YM758 arm.

[00146] Plasma brain natriuretic peptide (BNP) is secreted from atrium and ventricle in

CHF so that plasma BNP levels are elevated (see control in Table 3). Table 3 shows the results of measuring plasma BNP levels in this study.

Table 3. Plasma BNP Levels.

Sham Control Y 758 Metoprolol (n - 6) (» = 10) (n ^ 6} (ft = 5)

B P ( / S) 572.2 ± 63.1 816.3 ± 175.1 615.5 sb ¾Q J ?3&6 ± 4LI _^_

[00147] BNP levels both in animals and clinical studies are correlated with cardiac function impairment and decrease as this impairment improves with treatment. Plasma BNP is used to judge the severity of ischemic heart disease. In this study, in the MI rats (control), BNP tended to increase in comparison with sham, and both YM758 and metoprolol tended to reduce BNP levels. However, YM758 reduced the BNP levels more than metoprolol. YM758 appears to improve cardiac dysfunction in CHF at least as well as the β-blocker.

Example 2. Use of YM758 in patients with stable angina in a proof of concept Phase 2 clinical study.

[00148] Patients selected through criteria for stable angina were entered into a study and randomized between placebo and different doses of YM758. The treatment period was preceded by a single blind, placebo run-in period of one week to assess variability of the exercise tolerance test performance and protocol compliance. Thereafter, a double blind, placebo controlled, randomized design was applied to objectively assess the safety, tolerability, and efficacy of YM758. A treatment period of four weeks was applied to obtain reliable data on safety and tolerability parameters.

[00149] Patient groups received 5 mg QD (once daily, also described as OD), 10 mg

QD and 20 mg QD, respectively. Another patient group received 40 mg YM758 QD based on ability to receive the higher dose. The final dosing group was assigned to 20 mg BID (twice daily).

[00150] As shown in Figures 3 and 4, YM758 gives a dose-dependent reduction in heart rate both at baseline and with exertion. Dosing at 20 mg BID vs 40 mg OD does not significantly change the trough characteristics but does reduce the peak characteristics in this study.

Example 3. Use of YM758 in combination with beta blockers in animal models reduced heart rate without affecting blood pressure.

[00151] As described in Figure 5 and shown in Figures 6, 7, and 8, to demonstrate the benefit of administering YM758 in combination with β-b lockers, anesthetized dogs that had been administered β-blockers with and without YM758 were subjected to a variety of tests. In addition to heart rate and diastolic (DBP) and systolic blood pressure (SBP), mean blood pressure (MBP) and rate pressure product (RPP), the latter a measure of myocardial oxygen consumption, were measured. RPP was calculated by multiplying heart rate (HR) by SBP. MBP was calculated as follows: (SBP-DBP)/3 + DBP. The results of these studies are summarized in Figures 6, 7, and 8.

[00152] The design of the testing as shown in Figure 5 that produced the results shown in Figure 6 was to give one or more of the following: vehicle, YM758, and atenolol (a beta- blocker). Atenolol was given by continuous infusion and YM758 was given by iv injection in anesthetized dogs for the test results provided in Figures 6, 7, and 8.

[00153] These dog studies demonstrate use of an iv formulation for effective and rapid decrease in heart rate. Figures 7 and 8 show the additive effect of YM758 on heart rate lowering when injected 30 minutes into atenolol infusion.

Example 4. Dose escalation study in humans.

[00154] Figure 9 shows the mean YM758 concentration (in plasma) versus time profiles in a dose escalation study, which was a single dose-escalation design in which 54 healthy male subjects received YM758 at doses ranging from 0.5 mg to 90 mg (9 groups, N=6/YM758 dosage, 8 subjects received placebo).

[00155] This, other studies, and Table 4 below show that YM758 is rapidly absorbed

(T_max of about 1 hour) with a variable half-life (15.1 hr to 18.2 hr for females; and 12.4 hr to 18.9 hr for males) and expected peak plasma concentrations about 2.4 fold to about 3.7 fold higher than trough levels. The half- life above 10 mg no longer shows dose proportionality (see Table 4, below). These properties make it difficult to maintain efficacious levels of the drug over a 24 hour period with once daily dosing without nearing or exceeding peak plasma concentrations associated with potentially undesirable side effects (visual side effects at moderate to high dose and bradycardia at high dose). Table 4, below, shows the PK data collected in the human dose escalation study of YM758 fast acting tablets. The terms on the left are defined as follows: t_max = time at which the maximum concentration in a plasma concentration observed; C_max = maximum concentration in a plasma concentration versus time profile; AUCi_ast = area under the plasma concentration versus time profile from t = 0 up to the last quantifiable sample; AUCo-inf = area under the plasma concentration versus time profile from t = 0 to infinity; CL/F = apparent total body plasma clearance; t _½ = terminal elimination half-life; SD = standard deviation; CV = coefficient of variation (SD related to mean).

Table 4. PK Data.

Example 5. YM758 sustained release (SR) tablets.

[00156] A. A YM758 sustained release formulation is prepared in unit dose form as tablets for oral administration of various strengths, containing between 10 mg to 50 mg YM758. The formulation is enclosed within a coated tablet and contains silicon dioxide, microcrystalline cellulose, calcium phosphate, polyacrylic/methacrylic copolymer, magnesium stearate, stearic acid, hydroxypropyl methylcellulose, glyceryl palmitostearate, talc, titanium dioxide, polysorbate and coloring agents.

[00157] B. A YM758 sustained release formulation is prepared in unit dose form as tablets for oral administration of various strengths, containing between 10 mg to 50 mg YM758. The formulation is enclosed within a coated tablets and contains carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide, and coloring agents.

[00158] C. A YM758 sustained release formulation is prepared in unit dose form as tablets for oral administration of various strengths, containing between 5 mg to 80 mg YM758. The formulation is a tablet and contains polyvinylpyrolidone, microcrystalline cellulose, carbosil, carbomer, citric acid, carboxymethyl cellulose (cellulose gum), co- processed starch, talc and magnesium stearate. As described in the studies in Table 5 and Figure 10 below, a 100 mg SR tablet was prepared as described with the following contents: 40 mg YM758, 5 mg polyvinylpyrrolidone, 32 mg microcrystalline cellulose, 1 mg cabosil, 6 mg carbomer, 6 mg citric acid, 4 mg cellulose gum, 4 mg co-processed starch, 1 mg talc, and 1 mg magnesium stearate. For forming the granules, the YM758 is first granulated, for example, with a solution binder (e.g. polyvinylpyrrolidone) and excipients (e.g., 10 mg microcrystalline cellulose and 1 mg cabosil) in a granulator. Suitable apparatus for wet granulation include low shear mixers (e.g., planetary mixers), high shear mixers, and fluid beds (including rotary fluid beds). The resulting granulated material may then be sieved, dried, and optionally dry-blended with further ingredients (e.g., excipients such as, for example, lubricants, colorants, and the like). In certain embodiments, the granules are blended with 22 mg microcrystalline cellulose, 6 mg carbomer, 6 mg citric acid, 4 mg cellulose gum, 4 mg co-processed starch, 1 mg talc, and 1 mg magnesium stearate. The final dry blend is then suitable for compression.

[00159] Wet granulation improved the content uniformity of the tablet. Tablets were of acceptable hardness.

[00160] Table 5, below, and Figure 10 summarize data from a study of sustained release tablets prepared in accordance with Example 5C and containing 40 mg YM758.

Figure 10 shows dissolution in 0.1N HC1 and acetate buffer at pH 4.5 over 10 hours at 50 rpm. Complete dissolution is achieved after 10 hours in 0.1N HC1 and complete dissolution is after greater than 12 hours in acetate buffer, pH 4.5. Table 6 shows the average % released with respect to time. The immediate release formulation shows 97% to 100% release within 15 minutes under the same conditions. The objective achieved with the sustained release formulation is to reduce the short-term spikes in plasma concentration and to provide a longer therapeutic effect with fewer side effects. Thus, in contrast to immediate release tablets where YM758 is released within 15 minutes, YM758 is slowly released over greater than 10 hours with this sustained release formulation.

[00161] The content uniformity of the tablets was measured by high performance liquid chromatography using a Betabasic CI 8 column under isocratic conditions at 1 mL/min with ultraviolet detection at 230 nm. The release of YM758 was measured using a standard USP Dissolution Apparatus 2 (paddle) at 50 RPM at 1, 2, 4, 6 and 10 hours by UV

spectroscopy at 230 nm.

[00162] Table 5. Percent dissolution of a sustained release formulation of YM758 in tablet form.

Example 6. YM758 plus metoprolol in SR tablets

[00163] A. A YM758 sustained release oral formulation is prepared in unit dose form as tablets for oral administration of various strengths, containing between 10 mg to 50 mg YM758, and also containing between 25 mg to 100 mg of metoprolol, a beta-blocker. The formulation is enclosed within a coated tablet and contains silicon dioxide,

microcrystalline cellulose, calcium phosphate, polyacrylic/methacrylic copolymer, magnesium stearate, stearic acid, hydroxypropyl methylcellulose, glyceryl palmitostearate, talc, titanium dioxide, polysorbate and coloring agents.

[00164] B. A YM758 sustained release oral formulation is prepared in unit dose form as tablets for oral administration of various strengths, containing between 10 mg to 50 mg YM758, and also containing between 25 mg to 100 mg of metoprolol, a beta-blocker. The formulation is enclosed within a coated tablet and contains carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide and coloring agents.

[00165] C. A YM758 sustained release oral formulation is prepared as described in Example 6A or 6B with the metoprolol replaced with another beta-blocker or anti- arrhythmia agent used for the treatment of heart failure, atrial fibrillation, and angina. In one embodiment, the beta blocker is carvedilol, present in an amount between 3 mg and 25 mg, and in another emdodiment, the beta blocker is atenolol, present in an amount between 10 mg and 50 mg, and in another embodiment, the beta blocker is bisoprolol, present in an amount between 5 and 10 mg.

Example 7. YM758 SR capsules.

[00166] A. A YM758 sustained release formulation is prepared in unit dose form as capsules for oral administration of various strengths, containing between 10 mg to 50 mg YM758. The formulation is enclosed within prolonged release microgranules, which are in turn enclosed within a capsule. The microgranules are composed of YM758, and sucrose, and/or maize starch and/or a polymer. The capsules contain the SP microgranules and ethylcellulose, talc, a coating agent such as Aquacoat ECD 30, dibutyl sebacate, and coloring agents.

[00167] B. A YM758 sustained release formulation is prepared in unit dose form as capsules for oral administration of various strengths, containing between 10 mg to 50 mg YM758. The formulation is enclosed within prolonged release spheres, which are in turn enclosed within a capsule. The spheres are composed of YM758, and sucrose, and/or maize starch and/or a polymer. The capsules contain the prolonged release spheres and gelatin and coloring agents.

Example 8. YM758 with metoprolol in SR capsules.

[00168] A. A YM758 sustained release formulation is prepared in unit dose form as capsules for oral administration of various strengths, containing between 10 mg to 50 mg YM758, and also containing between 25 mg to 100 mg of metoprolol, a beta-blocker. The YM758 is in sustained release microgranules, which are in turn in a capsule. The

microgranules are composed of YM758, metropolol, and sucrose, and/or maize starch and/or a polymer. The capsules may contain the SP microgranules and ethylcellulose, talc, a coating agent such as Aquacoat ECD 30, dibutyl sebacate and coloring agents.

[00169] B. A YM758 sustained release formulation is prepared in unit dose form as capsules for oral administration of various strengths, containing between 10 mg to 50 mg YM758, and also containing between 25 mg to 100 mg of metoprolol, a beta-blocker. The YM758 is in sustained release spheres, which are in turn in a capsule. The spheres are composed of YM758, metropolol, and sucrose, and/or maize starch and/or a polymer. The capsules may contain the prolonged release spheres and gelatin and coloring agents.

[00170] C. A YM758 sustained release formulation as described in Example 8 A and 8B, except the metoprolol is replaced in the sustained release capsule with another beta- blocker or anti-arrhythmia agent used for the treatment of heart failure, atrial fibrillation and angina. In various embodiments, the metropolol is replaced with either between 3 mg and 25 mg of carvediol, between 10 mg and 50 mg of atenolol, or between 5 and 10 mg of bisoprolol.

Claims

1. A pharmaceutical formulation comprising YM758, wherein the formulation is a

sustained release formulation suitable for oral administration.

2. The sustained release formulation of claim 1 that comprises microparticles.

3. The sustained release formulation of claim 1 that is a controlled release matrix.

4. A unit dose form of the pharmaceutical formulation of any of claims 1-3 that

comprises 5 mg to 80 mg of YM758.

5. A unit dose form of the pharmaceutical formulation of any of claims 1-3 that

comprises 5 mg to 40 mg of YM758.

6. The unit dose form of claim 4 or 5 that is a tablet or capsule.

7. The unit dose form of claim 6 that is a tablet that comprises a core.

8. The unit dose form of claim 6 that is a tablet that comprises a coat.

9. The tablet of claim 8, wherein the coat is a controlled release coat.

10. The tablet of claim 8, wherein the coat is a moisture barrier coat.

11. The sustained release formulation of any one of claims 1-3, further comprising an additive, an anti-foaming agent, a binder, a chemical stabilizer, a coloring agent, a diluent, a disintegrating agent, an emulsifying agent, a filler, a flavoring agent, a thickening agent, a glidant, a lubricant, a pH modifier, a plasticizer, a solubilizer, a swelling enhancer, a spheronization aid, a solubility enhancer, or a suspending agent.

12. The unit dose form of claim 6 that shows a pulsatile YM758 release profile.

13. A pharmaceutical formulation suitable for oral administration that comprises YM758 and an excipient in nanoparticles.

14. A gelatin capsule comprising a sustained release formulation of YM758.

15. A unit dose form of a pharmaceutical formulation of YM758, wherein the formulation is a solution that contains from 5 to 80 mg of YM758, and the solution is in a vial or bag.

16. A method for treating a patient with stable angina, atrial fibrillation, heart failure or other cardiovascular disease, said method comprising administering to said patient a pharmaceutical formulation of claim 1 or claim 15 alone or in combination with another drug selected from the group of drugs consisting of beta-blockers, anti- arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine and digitalis.

17. A method for treating a patient with stable angina, atrial fibrillation, heart failure or other cardiovascular disease, said method comprising administering to said patient a pharmaceutical formulation of claim 1 or claim 15 in combination with another drug selected from the group of drugs consisting of beta-blockers.

18. A method for treating a patient with stable angina, atrial fibrillation, heart failure or other cardiovascular disease, said method comprising first intravenously

administering to said patient a pharmaceutical formulation of YM758 for a period of less than about two weeks and then orally administering a pharmaceutical formulation of YM758 for a period of at least a week.

19. The method of claim 18, wherein said patient is also administered a beta-blocker.

20. The method of claim 18 or 19, wherein said pharmaceutical formulation orally

administered to said patient is a sustained release formulation.