HK1040060B - Sustained release ranolazine formulations - Google Patents

Description

Ranolazine sustained release formulations

This application claims priority to U.S. provisional patent serial No. 60/099804 filed on 9/10/1998.

The present invention relates to a method of maintaining plasma ranolazine levels in humans at therapeutic levels using oral ranolazine sustained release formulations.

U.S. patent No. 4,567,264, the specification of which is incorporated herein by reference, discloses ranolazine (±) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) -propyl ] -1-piperazineacetamide, and pharmaceutically acceptable salts thereof, and their use for the treatment of cardiovascular diseases including arrhythmia, variability and motility-induced angina, and myocardial infarction.

U.S. Pat. No. 5,506,229, which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues that are subject to physical or chemical injury, including cardioplegia, hypoxic or reperfusion injury of cardiac or skeletal muscle or brain tissue, and for transplantation. Conventional oral and parenteral formulations, including controlled release formulations, are disclosed. In particular, example 7D of U.S. patent No. 5,506,229 describes a controlled release formulation in capsule form comprising ranolazine microspheres and microcrystalline cellulose coated with a controlled release polymer.

The presently preferred route of administration of ranolazine and its pharmaceutically acceptable salts and esters is oral. Typical oral dosage forms are compressed tablets, hard gelatin capsules filled with a powder mixture or granules, or soft gelatin capsules (soft gels) filled with a solution or suspension. U.S. patent No. 5,472,707, the specification of which is incorporated herein by reference, discloses high dose oral formulations using ultra-cold liquid ranolazine as a fill solution for hard or soft gelatin capsules.

As described in example 3 of the previous application, ranolazine failed the initial trial on patients with angina. This test used an immediate release ranolazine formulation administered at a dose of 120mg three times per day. From initial experiments, the amount and manner in which ranolazine provides effective antianginal therapy in humans remains uncertain.

One problem with conventional oral formulations is that they are not really suitable for ranolazine and its pharmaceutically acceptable salts because the solubility of ranolazine is relatively high in the low pH stomach. And the plasma half-life of ranolazine is relatively short. The highly acid soluble nature of ranolazine results in rapid absorption and clearance of the drug, causes unnecessarily large fluctuations in plasma ranolazine concentration, and short duration of action, necessitating frequent oral administration in order to obtain adequate treatment.

There is therefore a need for a method of administering ranolazine in an oral dosage form once or twice daily that provides a therapeutically effective plasma ranolazine concentration for the treatment of angina in humans.

In one aspect, the invention relates to a ranolazine sustained release formulation wherein a substantial portion of the formulation comprises active ranolazine.

In another aspect, the invention relates to a method of treating a patient suffering from angina or other coronary artery disease by administering a sustained release formulation of ranolazine to the patient once or twice daily.

In yet another aspect, the invention relates to a method of treating a mammal suffering from a condition for which ranolazine is indicated, comprising administering a sustained release ranolazine formulation of the invention once or twice daily in a manner that achieves a near minimum effective level of ranolazine plasma without peak fluctuations.

In yet another aspect, the invention relates to a method of maintaining useful ranolazine levels in human plasma by administering ranolazine in a dosage form containing only once or twice daily.

The invention includes a method of treating a patient suffering from a cardiovascular disease selected from the group consisting of arrhythmia, variant and kinetic angina, and myocardial infarction. The method comprises administering to the patient a sustained release pharmaceutical dosage form comprising at least 50% by weight ranolazine and no more than two tablets per dose such that the patient's plasma ranolazine levels are maintained at about 550 to about 7500ng base/mL for at least 24 hours, wherein the doses are administered at a frequency of once, twice, and three times over 24 hours.

The invention still further includes a method of treating a patient suffering from a cardiovascular disease selected from the group consisting of arrhythmia, variant and kinetic angina, and myocardial infarction. The method comprises administering to the patient a sustained release pharmaceutical dosage form comprising about 70 to about 80% by weight ranolazine and no more than two tablets per dose such that the patient's plasma ranolazine levels are maintained at about 1000 to about 3900ng base/mL for at least 24 hours, wherein the doses are administered at a frequency of one and two times over 24 hours.

The invention also includes pharmaceutical dosage forms comprising at least about 50 wt% ranolazine and at least one pH dependent binder, wherein the pH dependent binder inhibits the release of ranolazine from the sustained release dosage form and promotes the release of a therapeutic amount of ranolazine in an aqueous solution having a pH greater than 4.5 when the sustained release dosage form is used in an aqueous environment having a gastric pH.

"ranolazine" is the compound (±) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) -propyl ] -1-piperazineacetamide, or the enantiomers thereof (R) - (+) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) propyl ] -1-piperazineacetamide, and (S) - (-) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) propyl ] -1-piperazineacetamide, and pharmaceutically acceptable salts thereof, And mixtures thereof. Unless otherwise indicated, the plasma ranolazine concentrations in the specification and examples refer to ranolazine free base.

"optional" and "optionally" mean that the subsequently described result or condition, which may or may not occur, includes instances where the result or condition occurs and instances where it does not. For example, "optional pharmaceutical excipient" means that the formulation includes the presence of an optional excipient and its absence, in addition to those specifically indicated as being present, which may or may not include a pharmaceutical excipient.

"treatment" or "treatment" refers to any treatment of a disease in a mammal, particularly a human, including:

(i) prevention of disease in patients with a pre-existing predisposition to disease, but the disease has not yet been diagnosed;

(ii) inhibiting the disease, i.e. arresting its development; or

(iii) Alleviate the disease, i.e., make the disease less severe.

"immediate release" ("IR") refers to a formulation or dosage unit that dissolves rapidly in vitro and is completely dissolved and absorbed in the stomach or upper gastrointestinal tract. Typically, these formulations release at least 90% of the active ingredient within 30 minutes of administration.

"sustained release" ("SR") refers to a formulation or dosage unit of the invention that dissolves and absorbs slowly and continuously in the stomach and gastrointestinal tract over a period of about 6 hours or more. Preferred sustained release formulations are those having a plasma ranolazine concentration suitable for no more than two administrations per day, two tablets per dose or less as described below.

Plasma ranolazine concentrations are the average concentration determined by analysis of ranolazine concentrations in 5-10 persons using the same dosage regimen. The average ranolazine concentration is important because differences in ranolazine concentration among individuals due to weight, metabolism, or disease state may cause one person to metabolize ranolazine faster or slower than the average person. Plasma ranolazine levels were determined from blood in the drawn heparin.

Other terms used in this application are defined as:

ANOVA ═ Difference analysis

Adenosine Triphosphate (ATP)

ECG (electrocardiogram)

ETT-treadmill exercise test

Pyruvate Dehydrogenase (PDH)

C_maxMaximum concentration

C_troughResidual concentrations 8 hours after dosing with IR formulation and 12 hours after dosing with SR formulation a-C of example 2.

tid is three times a day

bid twice daily

C_xConcentration at time x

T_maxTime to maximum concentration

AUC_xArea under the curve after x hours or time interval

Unless otherwise indicated, the percentages given refer to weight percentages. The invention includes ranolazine sustained release dosage forms and methods of administering ranolazine sustained release dosage forms of the invention to provide therapeutic plasma ranolazine levels.

The sustained release ranolazine formulations of the invention are preferably in the form of compressed tablets comprising an intimate mixture of ranolazine and a partially neutralized pH dependent binder that controls the rate of ranolazine dissolution in aqueous media at a pH in the range of gastric pH (typically about 2) and intestinal pH (typically about 5.5).

To provide sustained release of ranolazine, one or more pH dependent binders are selected to control the dissolution profile of the ranolazine formulation so that it can slowly and continuously release ranolazine as the formulation passes through the stomach and gastrointestinal tract. The ability of the pH-dependent binder to control dissolution is especially important in ranolazine sustained release formulations because if ranolazine is released too quickly ("dose dumping"), administration of a sustained release formulation containing sufficient ranolazine twice daily may result in adverse side effects.

Thus, pH-dependent binders suitable for use in the present invention are those which inhibit the rapid release of drug from the tablet during residence in the stomach (which pH is below about 4.5), and which promote the release of therapeutic amounts of ranolazine from the dosage form in the lower part of the gastrointestinal tract (which pH is typically greater than about 4.5). Many substances known in the pharmaceutical art, such as "enteric" binders and coatings, have the desired pH dissolution characteristics. These include phthalic acid derivatives, such as phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkyl celluloses, alkylcelluloses, cellulose acetates, hydroxyalkyl cellulose acetates, cellulose ethers, alkylcelluloses acetate, and partial esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and partial esters thereof.

A preferred pH-dependent binder material useful in combination with ranolazine to produce sustained release formulations is a methacrylic acid copolymer. Methacrylic acid copolymers are copolymers of methacrylic acid with neutral acrylates or methacrylates, such as ethyl acrylate or methyl methacrylate. The most preferred copolymer is methacrylic acid copolymer type C, USP (which is a copolymer of methacrylic acid and ethyl acrylate having 46.0% to 50.6% methacrylic acid units). Such copolymers may be prepared from

Pharma as Eudragit^*L100-55 (powder) or L30D-55 (30% aqueous suspension) are available under the trade name L100-55. Other pH-dependent binder materials that may be used alone or in combination with the ranolazine sustained release dosage forms include hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone phthalate, and the like. The one or more pH-dependent binders may be present in an amount ranging from about 1 to about 20 wt%More preferably from about 5 to about 12 wt%, and most preferably about 10 wt% is present in the ranolazine dosage forms of the invention.

One or more pH independent binders may be used in the ranolazine sustained release oral dosage form. It should be noted that pH independent binders and viscosity enhancing agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly (meth) acrylates, and the like, by themselves, do not provide the desired dissolution control resulting from a defined pH dependent binder. The pH independent binder may be present in the formulations of the present invention in an amount ranging from about 1 to about 10 wt%, preferably from about 1 to about 3 wt%, most preferably about 2.0 wt%.

As shown in table 1, ranolazine is relatively insoluble in aqueous solutions having a pH greater than about 6.5, while the solubility increases significantly at a pH less than about 6.

TABLE 1

pH of the solution	Solubility (mg/mL)	USP solubility grade
			4.81	161	Readily soluble
4.89	73.8	Soluble in water
			4.90	76.4	Soluble in water
5.04	49.4	Soluble in water
			5.35	16.7	Slightly soluble
5.82	5.48	Slightly soluble
			6.46	1.63	Slightly soluble
6.73	0.83	Extremely sparingly soluble
			7.08	0.39	Extremely sparingly soluble
7.59 (unbuffered water)	0.24	Extremely sparingly soluble
			7.73	0.17	Extremely sparingly soluble
12.66	0.18	Extremely sparingly soluble

Increasing the level of pH-dependent binder in the formulation decreases the rate of release of ranolazine from formulations having a pH below 4.5, particularly as occurs in the stomach. The enteric coating formed by the binder is less soluble and increases the relative release rate at a pH greater than 4.5, while the solubility of ranolazine is lower. Proper selection of the pH-dependent binder allows for faster release of ranolazine from formulations having a pH greater than 4.5, while greatly affecting the release rate at low pH. Partial neutralization of the binder facilitates the conversion of the binder to a film-like latex that forms around the individual ranolazine particles. Thus, the type and amount of pH-dependent binder and the amount of partially neutralized composition are selected to closely control the rate at which ranolazine dissolves from the formulation.

The dosage forms of the present invention should contain a sufficient amount of a pH-dependent binder to produce a sustained release formulation in which the release rate of ranolazine is controlled so that the dissolution rate is significantly slowed at low pH (below about 4.5). In methacrylic acid copolymer type C, USP (Eudragit)^*L100-55), a suitable amount of pH-dependent binder is between 5% and 15%. Typically, the pH-dependent binder contains about 1 to about 20% neutralized carboxy methacrylic acid binder. However, the preferred range of neutralization is about 3 to 6%.

Sustained release formulations may also comprise a pharmaceutical excipient intimately mixed with ranolazine and a pH-dependent binder. Pharmaceutically acceptable excipients may include, for example, pH independent binders or film forming agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly (meth) acrylates (e.g., composed ofPharmal as Eudragit^*Methyl methacrylate/ethyl acrylate copolymers sold under the NE trademark), starch, gelatin, sugars, carboxymethylcellulose, and the like. Other useful pharmaceutical excipients include diluents such as lactose, mannitol, dry starch, microcrystalline cellulose, and the like; surfactants such as polyoxyethylene sorbitan esters, and the like; coloring agents and flavoring agents. Lubricating agents such as talc and magnesium stearate and other tableting aids may also optionally be present.

Ranolazine sustained release formulations of the present invention have ranolazine content of greater than about 50 wt% to about 95 wt% or more, more preferably from about 70% to about 90% by weight, and most preferably from about 70% to about 80% by weight; the content of the pH-dependent binder is 5% to 40%, preferably 5% to 25%, more preferably 5% to 15%; the remainder of the dosage form contains a pH independent binder, a filler and other optional excipients.

Particularly preferred ranolazine sustained release formulations of the present invention consist essentially of:

preferred ranges (%) of component weights (%) most preferred ranges (%)

Ranolazine 50-9570-

Microcrystalline cellulose (filler) 1-355-1510.6

Methacrylic acid copolymer 1-355-12.510.0

Sodium hydroxide 0.1-1.00.2-0.60.4

Hydroxypropyl methylcellulose 0.5-5.01-32.0

Magnesium stearate 0.5-5.01-32.0

The ranolazine sustained release formulations of the present invention are prepared as follows: ranolazine is intimately mixed (dry blended) with the pH-dependent binder and any optional excipients. The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granules are dried, sieved, mixed with an optional lubricant (e.g., talc or magnesium stearate), and compressed into tablets. Preferred aqueous strong bases are aqueous solutions of alkali metal hydroxides (optionally containing up to 25% of a water-miscible solvent such as a lower alcohol), for example sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

The resulting ranolazine-containing tablets may be coated with an optional film forming agent for the purposes of identification, taste masking, and ease of swallowing. The film-forming agent is typically present in an amount ranging from 2% to 4% by weight of the tablet. Suitable film formers are well known to those skilled in the art and include hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/methylbutyl methacrylate copolymer-Eudragit @^*Pharma), and the like. These film formers may optionally contain colorants, plasticizers, and other supplemental ingredients.

The tablet is preferably sufficiently rigid to withstand a pressure of 8 Kp. Tablet size is primarily dependent on the amount of ranolazine in the tablet. The tablets may contain 300-1100mg ranolazine free base. Preferably, the tablets comprise 350-800mg, 400-600mg, 650-850mg and 900-1100mg ranolazine free base.

To vary the dissolution rate, the time for wet mixing the ranolazine-containing powder was controlled. The total powder mixing time, i.e. the time during which the powder is exposed to the sodium hydroxide solution, is preferably 1-10 minutes, more preferably 2-5 minutes. After granulation, the granules were removed from the granulator and placed in a fluid bed dryer for drying at about 60 ℃.

We have surprisingly found that these methods result in sustained release formulations of ranolazine when used as its free base, rather than the more pharmaceutically common ranolazine dihydrochloride or another salt or ester, which provide lower peak plasma ranolazine levels after administration and also maintain effective plasma concentrations of ranolazine for up to 12 hours and longer. There is at least one advantage to using ranolazine free base: because the molecular weight of ranolazine free base is only 85% of that of ranolazine dihydrochloride, the ranolazine ratio in the tablet can be increased. In this method, the effective amount of ranolazine delivered can be achieved while limiting the physical size of the dosage unit.

Another great advantage of the sustained release ranolazine formulations of the present invention is that they can be prepared using essentially only water as the solvent, using standard pharmaceutical processing techniques and equipment.

The ranolazine sustained release formulations of the present invention may be used to treat cardiovascular diseases, including arrhythmia, variability and motility-induced angina, and myocardial infarction; treating tissue that has been physically or chemically damaged, including cardioplegia, hypoxic or reperfusion injury of heart or skeletal muscle or brain tissue, and ischemia; and peripheral artery disease, such as intermittent claudication. Most preferably, the sustained release formulation is used as an anti-angina agent in mammals, more preferably in humans.

The oral ranolazine sustained release formulations of the present invention are administered once, twice or three times over a 24 hour period to maintain the patient's plasma ranolazine levels above the therapeutic threshold and below the maximum tolerable level, i.e., about 550-7500ng base/mL. This is consistent with a range of amounts of ranolazine 2HCl from about 644ng/mL to about 8782 ng/mL. Additionally, the time of oral ingestion of the ranolazine oral dosage form should be controlled to ensure that plasma ranolazine levels do not exceed about 7500ng base/mL, preferably plasma ranolazine levels do not exceed about 5000ng base/mL, and most preferably do not exceed 3800ng base/mL. In some cases, it may be advantageous to define a peak plasma ranolazine of no more than about 3800ng base/mL. Also, the minimum trough (trough) of plasma ranolazine should preferably not be less than about 1000ng base/mL, and in some cases not less than 1700ng base/mL.

To achieve preferred plasma ranolazine levels of about 1000 to about 3800ng base/mL, the ranolazine oral dosage forms described herein should preferably be administered once or twice daily. If the dosage form is administered twice daily, the ranolazine oral dosage forms are preferably administered about 12 hours apart.

In addition to formulating and administering the oral sustained release dosage forms of the present invention in a manner that controls plasma ranolazine levels, it is also important to minimize the peak to trough differences in plasma ranolazine levels. Typically, a peak plasma ranolazine level is reached about 30 minutes to 8 hours or more after the beginning of ingestion of the dosage form, while a trough plasma ranolazine level is reached at about the time of ingestion of the next intended dosage form. The sustained release dosage forms of the invention should be administered in a manner such that the peak ranolazine level is no more than 8 times the trough of ranolazine levels, preferably no more than 4 times the trough of ranolazine, and most preferably no more than 2 times the trough of ranolazine levels.

The sustained release ranolazine formulations of the present invention provide the therapeutic advantages of minimizing changes in ranolazine plasma concentration while allowing up to two administrations per day. If it is desired to achieve a therapeutically effective plasma concentration of ranolazine rapidly, the formulation may be administered alone, or (at least initially) in combination with an immediate release formulation, or via soluble formulation IV and oral dosage forms.

The following examples are representative of the invention and are not intended to limit the scope of the claims.

Examples

These examples detail methods for preparing ranolazine dosage forms and experiments conducted to evaluate the efficacy and effectiveness of ranolazine administration. Note that throughout the examples:

(1) oral doses of Immediate Release (IR) formulations are administered in capsules or tablets of the dihydrochloride salt and are denoted as dihydrochloride salt.

(2) Oral doses of Sustained Release (SR) formulations are administered in the form of tablets of ranolazine base and are expressed as base.

(3) When comparing IR and SR formulations in the same study, the dosage is expressed both as base and dihydrochloride. The conversion factor for conversion of dihydrochloride to base was 0.854 (e.g., 400mg dihydrochloride x 0.854 ═ 342mg free base equivalent).

(4) All plasma levels and pharmacokinetic parameters are expressed as levels of free base.

Example 1

This example describes a method of preparing an Immediate Release (IR) ranolazine formulation. Ranolazine dihydrochloride (4000g), microcrystalline cellulose (650g), polyvinylpyrrolidone (100g) and croscarmellose sodium (100g) powder were intimately mixed together in a Fielder PMA 65 mixer granulator, then sufficient water was added and mixed to form granules. The granules were dried in an aeromatic stream-5 fluid bed dryer, sieved, and mixed with magnesium stearate (100 g). The mixture is filled into hard gelatin capsules to a fill weight of, for example, 500mg per capsule to achieve a 400mg dose per capsule of ranolazine dihydrochloride (equivalent to 342mg ranolazine free base), but may also be added to fill weights of 30-400mg ranolazine dihydrochloride.

Example 2

This example describes a method of preparing a ranolazine Sustained Release (SR) formulation.

By mixing ranolazine (2500g) and methacrylic acid copolymer type C (Eudragit)^*L100-55-Rohm Pharma (1000g), microcrystalline cellulose (Avicel)^*) (100g) and polyvinylpyrrolidone powder (710g) were intimately mixed together in a Fielder PMA 65 mixer-granulator to prepare aOne is called SR formulation A, which includes Sustained Release (SR) formulations of pH-dependent and pH-independent binders. The mixture was granulated with aqueous sodium hydroxide (40g) and a methyl methacrylate/ethyl acrylate copolymer (Eudragit) was added^*NE 30D-Rohm Pharma) (1667g) as a 30% aqueous suspension was added to the wet mass. The resulting granules were dried in an Aeromatic stream-5 fluid bed dryer, sieved, and then mixed with croscarmellose sodium (100g) and magnesium stearate (50 g). The mixture was compressed into 684mg tablets using a Manestry B tablet press so that each tablet contained a dose of 342mg of ranolazine free base. This formulation is called SR formulation A.

Except that Eudragit^*L100-55 was reduced to 500g using a methyl methacrylate/ethyl acrylate copolymer (Eudragit)^*NE 40D- Pharma) (2500g) of a 40% aqueous suspension instead of Eudragit^*In addition to NE 30D, SR preparation B was prepared in the same manner as SR preparation a. The resulting (SR) formulation contained 342mg ranolazine free base per tablet.

In SR formulation C, ranolazine free base (342mg) was mixed with microcrystalline cellulose and polyvinylpyrrolidone K25, granulated with water, dried, and mixed with croscarmellose sodium and magnesium stearate. The mixture is compressed into tablets and coated with an enteric coating.

SR formulation D comprising only pH dependent binder was prepared by mixing ranolazine (7500g), Eudragit^*L100-55 (1000g), hydroxypropyl methylcellulose (Methocel)^*E5-origin) (200g), and microcrystalline cellulose (Avicel)^*) (1060g) were intimately mixed together. The mixed powder was granulated with a solution of sodium hydroxide (40g) in water (1900-2500 g). The granules are dried, sieved, and mixed with magnesium stearate (200g) and compressed into tablets weighing, for example, 667mg, so that each tablet contains 500mg ranolazine free base. At 24 inches Accelacota^*The tablets were sprayed with OPADRY film coating solution in a disk coater, increasing the weight by 2-4%. Various colors are available from Colorcon, WestPoint, PaThe OPADRY film coating solution of (1).

The stepwise preparation of SR formulation D was as follows:

a) mixing together ranolazine, microcrystalline cellulose, methacrylate copolymer (type C) and hydroxypropylmethylcellulose using a suitable blender;

b) dissolving sodium hydroxide in purified water;

c) using appropriate granulation equipment, the sodium hydroxide solution was slowly added to the mixture with continuous stirring. If necessary, adding equal parts of water;

d) mixing was continued to increase aggregation. If necessary, adding equal parts of water;

e) drying and granulating in a fluidized bed dryer;

f) sieving the dried granules through a suitable mill;

g) adding magnesium stearate to the sieved granules and mixing together;

h) passing the particulate matter through a chilsonator, if necessary;

i) compressing the granules into tablets with a cutter of appropriate size;

j) OPADRY powder was dispersed in water and film coated with an appropriately sized coating apparatus to a typical content of 2-4% by weight;

k) a typical content of 0.002-0.003% by weight was used and polished with carnauba wax.

Example 3

This example outlines the information published in circulation 90: 726-734(1994), which demonstrated that ranolazine was not effective as an anti-anginal and anti-ischemic agent when administered with the IR formulation of example 1.

Patients with stable angina were enrolled in the study. Any anti-anginal drugs previously used by the patient were discontinued under medical supervision. 319 patients received single-blind placebo treatment for 18 days, and were randomized to four dosing study groups due to moderate angina, 318 confirmed myocardial ischemia (≧ 1-mm ST-segment hypotension) with cessation of exercise; ranolazine.2hci 30mg, three times daily (n 81); ranolazine.2hci 60mg, three times daily (n 81); ranolazine 2HCl 120mg, three times daily (n-78); and placebo, three times a day (n-79). After three daily doses of 30-, 60-and 120-mg, the mean peak plasma concentrations of ranolazine free base at 1 hour after administration of the dose were 94, 219 and 510ng/mL, respectively, and the mean trough plasma concentrations at 8 hours after administration of the dose were 18, 37 and 90ng/mL, respectively.

After a 4-week double-blind period, the symptom-limiting exercise test was repeated 1 hour (peak test) and 8 hours (trough test) after administration of study drug. The total exercise time at baseline (± SEM) was 5.9 ± 0.2 minutes for the placebo group and 6.4 ± 0.3, 5.9 ± 0.3 and 6.6 ± 0.2 minutes for the ranolazine 30, 60, and 120mg groups, respectively (P ═ NS). After 4 weeks of double-blind treatment, the study drug was administered for 1 hour (peak effect) compared to baseline values, with an increase in total exercise time (± SEM) of 0.45 ± 0.2 minutes for the placebo group and 0.3 ± 0.2, 0.6 ± 0.2 and 0.5 ± 0.2 minutes for the ranolazine 30, 60 and 120mg groups, respectively (placebo vs ranolazine, P ═ NS). The time to 1-mm ST depression at baseline was similar in the four groups, with a significant increase in similar amounts 1 hour after dosing 4 weeks post treatment in each group. Similar changes were seen in the time of angina attack. At 8 hours post-dose (trough effect), no difference in total exercise time or any other exercise variable was observed between placebo and ranolazine groups. Comparing the baseline values, the number of angina attacks per week and the number and duration of ischemic attacks per 48 hours during Holter monitoring were significantly reduced by similar amounts in the placebo and ranolazine groups.

These results indicate that treatment with 30, 60 and 120mg ranolazine.2 HCl three times daily is not superior to placebo. This study also showed that similar doses of ranolazine had no beneficial effect on myocardial ischemia or exercise capacity or angina attack in daily life of patients with angina.

Example 4

In this example, the safety and anti-ischemic effects of high plasma levels of ranolazine in a large group of angina patients were evaluated, and the duration of any effect during the two and three times daily steady state dosing regimen was assessed. In this example, patients with chronic stable angina who are sensitive to conventional antianginal drugs are treated with 3 ranolazine.2 HCl dosing regimens as follows: IR formulation of example 1, 267mg, three times daily; 400mg, twice daily; and 400mg, three times daily. The peak and trough values of the kinetic test parameters and plasma levels of ranolazine free base concentration were determined.

Method of producing a composite material

The study included a double-blind, placebo-controlled randomized treatment period with 4 treatments (placebo, ranolazine.2 HCl 400mg twice daily, ranolazine.2 HCl 267mg three times daily, and ranolazine.2 HCl 400mg three times daily).

Patients with chronic stable angina pectoris lasting at least 3 months and susceptible to conventional anti-angina treatment were considered as psychogenic. In addition, the patient must have a motility-induced ischemic Electrocardiogram (ECG) based on horizontal or downward sloping ST-segment depression ≧ 1mm, which persists over 3 consecutive heartbeats during the exercise stress test and whose ECG pattern is not disturbed by the expression of ST-segment changes. The latter criterion specifically excludes patients with left ventricular hypertrophy, pre-excitation syndrome, conduction abnormalities or pacemaker rhythms. Other additional criteria include unstable angina or myocardial infarction in the previous 3 months, new york heart committee-determined grade III or IV heart failure, uncorrected severe valvular or congenital heart disease requiring digoxin or long-acting nitrate therapy, unstable diabetes, or other serious diseases that may confound subsequent evaluation.

These immediate release ranolazine.2 HCl dosing regimens (267mg, three times daily, 400mg, twice daily, 400mg, three times daily) and placebo were given during treatment. Patients took capsules containing 267mg or 400mg ranolazine dihydrochloride or placebo at 8:00 am, 4:00 pm, 8:00 pm, and 12:00 am. All capsules were identical in appearance. Patients were randomized to one of 4 courses, each course being assigned 25% of patients. One treatment was repeated between 1 week and the 5 th 1 cycle of each treatment administration.

To qualify patients receiving their commonly used anti-angina medication, a treadmill exercise screening test (ETT-1) using the Shuffield modified Bruce protocol was performed. If the angina attack time is more than or equal to 3 minutes and less than or equal to 13 minutes, the anti-angina drug is stopped, and the single-blind placebo treatment is started. After 1-2 weeks, the patient returns to another ETT (ETT-2). If the time to angina pectoris attacks is reduced by 1 minute compared to ETT-1, the patient is considered to have completed the first limiting ETT. If the time to angina attack is not reduced by more than or equal to 1 minute, the second anti-angina drug is discontinued and the process is repeated. If necessary, the third anti-angina agent can be discontinued in accordance with this method in order to qualify the patient. Always the long-acting nitrate is first discontinued; the beta blocker and calcium antagonist may be discontinued in any order from a patient who does not receive long-acting nitrate. After the patient received the first limiting ETT (ETT-2), the second limiting ETT (ETT-3) was performed during which the onset of angina was within 15% of the time that occurred in ETT-2. In addition, each definitive ETT must have ECG evidence of ischemia (ST segment depression greater than or equal to 1mm level or downward slope in 3 consecutive heartbeats). Patients meeting this criteria were available for this study.

After every 1 week, patients returned to the exercise laboratory in the morning and were fed a small amount of breakfast for at least 1 hour for ETT. This is called primary ETT; each patient underwent primary ETT at the same time. After completion of the primary ETT, the patient received the next planned blind dose of medication from the blister pack (blister pack) used in that week. Another such ETT was performed 1 hour after dosing. This is called advanced ETT. Blood samples were obtained from primary (about 8 hours post-dose) and advanced (1 hour post-dose). Other standard laboratory tests were routinely monitored throughout the study.

Blood pressure (through the cuff) and heart rate were monitored before all ETTs, during ETT, the last minute of each phase of the trial, at the onset of angina, at the point of maximal exercise, and during recovery (1 minute off every 4 minutes, then 1 minute off every 5 minutes until the values returned to baseline). The heart rate was also continuously monitored and a standard 12-lead ECG recording was immediately made prior to the patient's exercise standing on the treadmill, at the end of each phase of the exercise, at the time of maximum endurance to the exercise load and at the end of the exercise.

The peak and trough values of mean treadmill movement time for the 3 relevant motor variables during placebo and different ranolazine dosing regimens (ranolazine-placebo) for all patients are summarized in table 2 below.

TABLE 2

Data from motor tests in the peak and valley of all patients

	Treatment of
						Mean motion variable (all patients, min)		Double-blind placebo	Ranolazine 400mg twice daily	(Reynolds)Oxazine 267mg three times daily	Ranolazine 400mg thrice daily
Time of onset of angina pectoris	Peak value	9.01	9.33	9.40	9.33
						Valley value	8.58	8.77	8.78	8.65
	Duration of movement	Peak value	10.67	10.83	10.87						10.84
Valley value						10.50	10.55	10.56	10.60
		Time to onset of 1mm ST depression	Peak value	9.58	9.86					9.99	9.94
Valley value	9.04					9.22	9.22	9.31

At peak ranolazine plasma concentrations, all ETT ischemic parameters were prolonged in the placebo group, and most notably the time to onset of 1-mm ST depression. In the analysis of all patients, the onset of angina in the placebo group increased from 0.32 minutes to 0.39 minutes (p.ltoreq.0.01), while the time to 1-mm ST-segment depression increased from 0.28 to 0.41 minutes (p.ltoreq.0.02) for each of the 3 ranolazine dosing regimens and all combination regimens. Also, the total duration of exercise was significantly increased for all combination regimen groups and similar directional and quantitative trends were found for each dosing regimen group. Each 3ETT parameter was extended (p.ltoreq.0.01) for all combined ranolazine dosing regimens in each protocol analysis. All single ranolazine dosing regimens significantly prolonged periods of 1-mmST segment depression, with no evidence of similar trends in direction and proportion of angina attack times and motor duration. In general, the results of each protocol analysis, except for the magnitude of the effect, appear to be slightly stronger than the monotherapy.

At trough plasma concentrations, ranolazine had less effect on the ETT parameters. The results of all patients and each protocol analysis were consistent, indicating a propensity for increased exercise time. However, only the time to depression of the 1-mm ST segment was statistically significant in all patient analyses for all combined ranolazine administration groups.

In view of the more significant increase in motor parameters observed with ranolazine monotherapy, patients receiving different concomitant anti-angina agents were analyzed for their response to ranolazine. These specific post-hoc analyses were performed on ranolazine peak data as the effect of increasing motion time was most pronounced. Since long-acting nitrate was first discontinued during the course of the single case restriction, no patients participated in double-blind treatment with long-acting nitrate. Of the patients whose efficacy data peaked, 34% (107/312) received the beta blocker and 24% (75/312) received the calcium antagonist during double-blind treatment.

The exercise trial parameters increased whether or not the patient received beta blocker, peak ranolazine concentration (ranolazine-placebo). These increased amounts were slightly greater in 205 patients who did not receive the beta blocker compared to 107 patients who received the beta blocker. However, there is no statistical significance in the difference between any of the kinetic parameters of those patients who received beta blocker versus those who did not. In patients who did not receive the beta blocker, all motor parameters were significantly increased for each of the 3 ranolazine dosing groups, as were all combined ranolazine dosing groups. A similar trend was also observed in the fewer patients receiving the beta blocker. Similar findings were obtained from the analysis of exercise data for patients taking calcium antagonists compared to those who did not receive calcium antagonists.

Table 3 below summarizes the mean plasma ranolazine (relative to ranolazine dihydrochloride salt) peak and trough concentrations for all gender patients and each dosing group.

TABLE 3

Mean (± standard error) plasma ranolazine concentration by dosing

	Ranolazine 400mg twice daily	Ranolazine 267mg thrice daily	Ranolazine 400mg thrice daily
				Peak value (ng/mL)
All patients were treated	1882(1094)	1346(823)	2128(1198)
				Male sex	1762(999)	1261(774)	1917(1046)
Female with a view to preventing the formation of wrinkles	2171(1253)	1594(904)	2654(1385)
				Valley (ng/Ml)
All patients were treated	235(288)	316(336)	514(500)
				Male sex	235(264)	316(336)	518(494)
Female with a view to preventing the formation of wrinkles	235(342)	316(340)	505(517)

The mean plasma ranolazine peak concentration ranged from 1346-2128ng ranolazine free base/mL. The 400mg three times daily dosing group had the highest plasma ranolazine concentration. The mean plasma ranolazine trough concentration range was 235-514 ng/mL. The mean plasma ranolazine peak concentration was slightly higher in women than in men, but there was no significant gender difference in the plasma trough concentrations.

There was no statistically significant difference between any ranolazine dosed group and the placebo group for the double product at the peak plasma ranolazine concentration. Likewise, there was no statistically significant difference between the 3 ranolazine dosing groups and the placebo group in the analysis of each regimen for either the standard or maximal exercise double product at trough plasma ranolazine concentrations.

The results of this study suggest that ranolazine is an effective anti-angina and anti-ischemic compound for patients with chronic stable angina. At peak plasma concentrations, an average prolongation of about 0.33 minutes was observed for angina attack time and duration of exercise and 1-mm ST segment depression time in the 3 ranolazine-dosed groups compared to the placebo group. In this study, not only was an increase in motor parameters observed in patients receiving concomitant anti-angina therapy (e.g., beta blockers and calcium antagonists), but also in a small fraction of patients receiving ranolazine monotherapy. In the latter patients, the therapeutic effect is somewhat greater in magnitude. This suggests that ranolazine may also be used in monotherapy in patients with chronic stable angina.

Hemodynamic observations indicate that the increase in kinetic parameters in peak plasma ranolazine concentrations is not associated with changes in blood pressure or heart rate. Thus, the mechanism of non-hemodynamic effects of ranolazine is different from other anti-angina drugs currently in clinical use.

Most importantly, we demonstrate that the anti-angina and anti-ischemic effects of the immediate release ranolazine formulations studied do not persist throughout the dosing interval. Although the onset of ischemic ST-segment depression was significantly prolonged and no similar directional trend was observed for other ETT parameters, the effect was minimal at the trough plasma ranolazine concentration. The peak concentration of ranolazine free base in the mean plasma ranged from 1346-2128ng/mL, while the trough concentration of ranolazine free base in the mean plasma ranged from 235-514 ng/mL. This appears to confirm that higher mean plasma ranolazine concentrations are associated with clinically significant anti-angina and anti-ischemia effects, whereas the resulting trough concentrations are not.

According to the results of this experiment, the threshold plasma ranolazine free base concentration for anti-ischemic activity measured during ETT may be greater than about 550 ng/mL. Furthermore, the plasma ranolazine concentration must be maintained at or above a threshold throughout the dosing interval to ensure anti-angina and anti-ischemic activity throughout the interval of motion.

Ranolazine was extremely resistant to the plasma concentrations obtained in this study. The rate of side effects in the ranolazine-administered group and placebo group differed and there was no drug-related change in the ECG interval or complex morphology. In addition, there were no clinically significant changes in blood glucose concentration, lipid values, or liver function tests, suggesting that the metabolic effects of ranolazine do not extend to systemic glucose regulation or lipid metabolism.

Ranolazine increased the motor parameters of patients with chronic stable angina without appreciable effects on heart rate and blood pressure. Perhaps the ranolazine plasma concentration threshold must be above about 550ng/mL to test for its anti-angina and anti-ischemic effects. Ranolazine is extremely resistant to a wide range of plasma concentrations. Further studies using larger doses of sustained release formulations were conducted to fully evaluate this new metabolic concept for the treatment of ischemia.

Example 5

I. In vitro comparison of IR and SR formulations

The IR formulation prepared according to example 1 and the SR formulation prepared according to examples 2A-2C were tested in a USP apparatus 2 dissolution tester using 900mL of 0.1M hydrochloric acid as the dissolution liquid to stimulate dissolution in the stomach.

TABLE 4

Percent formulation of time-resolved formulation

(hour) preparation

IR A B C

0.25 88.1

0.5 100.5 13.9 17.6 17.5

1 101.7 19.9 26.0 25.7

2 27.8 47.5 35.9

4 39.0 69.2 48.4

8 52.4 90.1 64.7

12 61.6 99.6 74.2

24 80.8 105.6 95.4

The results in the table show that SR formulations A, B and C show extended dissolution at low pH when the IR formulation is completely dissolved in no more than 0.5 hours (as expected for immediate release formulations), which is required for sustained release formulations.

In vivo comparison of IR and SR formulations A, B and C

11 healthy volunteers were given a single dose of the IR formulation prepared according to example 1 and SR formulations A and B prepared according to example 2 and their plasma ranolazine free base concentrations were determined at 0, 20, 40, 60, 90 and 120 minutes, once to 6 hours per hour, twice to 18 hours per hour, and 24 hours after administration (SR formulation only). The results are shown in Table 5.

TABLE 5

Preparation

IR A B C

C_MAX(ISD)(ng/mL) 1940(807) 753(264) 657(316) 925(747)

C_trough(ISD)(ng/mL) 165(111) 158(114) 182(110) 290(163)

T_MAX(ISD) (hours) 1.27(0.5) 4.09(1.14) 4.05(1.31) 6.55(2.93)

AUC_0-24(ISD) (ng hr/mL) 6530564052805820

It is apparent from table 5 that the SR formulations A, B and C of the present invention have dissolution characteristics that make them suitable for twice daily administration of ranolazine.

Example 6

This example details a single ascending dose, crossover design study to assess the safety and pharmacokinetic profile of the single oral dose ranolazine base SR formulation of example 2D. Human subjects were divided into 3 groups. Group 1 used 500, 750, and 1000mg ranolazine SR. Group 2 used 1250 and 1750mg ranolazine SR. Group 3 used 1500 and 2000mg ranolazine SR. Each group also had a randomized placebo period. The mean pharmacokinetic parameters after administration of a single oral dose of ranolazine SR are detailed in table 6 below:

TABLE 6

Mean ± SD pharmacokinetic parameters (n ═ 8, except for*n＝7)
						Dosage SR (mg)	Group of	Cmax(ng/mL)	Ctrough(ng/mL)	TMAX(hours)	AUC0 to 30 hours(ng. h/mL)
500	1	883±353	382±251	4.63±1.19	9380±4250
						750	1	1300±1060	455±353	4.25±0.886	12500±9000
1000	1*	1610±959	695±438	5.71±2.14	18100±9630
						1250	2	2210±716	943±541	6.21±3.52	25000±8090
1500	3	1980±1050	1070±754	4.75±0.886	25400±16000
						1750	2	3670±1570	2400±1260	5.25±2.31	49200±18200
2000	3	2440±1120	1640±937	5.21±2.30	35400±19100

The pharmacokinetic results shown in Table 6 indicate that ranolazine is released slowly from the SR formulation and thus ranolazine absorption is limited by the dissolution rate. This resulted in an extended plasma drug concentration-time profile observed at all dose levels, reaching peak plasma levels 4-6 hours after administration. Dose range of over 500-2000mg, average C_maxAnd AUC_{0 to 30 hours}Increase in an approximately dose-proportional manner, although this was somewhat different from the proportionality in group 2.

Example 7

To evaluate the twice daily dosing, this example details a double-blind, placebo-controlled, multiple ascending dose, cross-design volunteer study. 6 subjects received ranolazine SR formulation prepared according to example 2D for 4 days at 500, 750, and 1000mg twice daily, followed by administration in the morning of day 5. The pharmacokinetic results are shown in table 7 below.

TABLE 7

Day 5 ranolazine pharmacokinetic parameters (mean. + -. SD)
				Parameter(s)	Ranolazine SR500mg twice daily (n ═ 7)	Ranolazine SR750mg twice daily (n ═ 7)	Ranolazine SR1000mg twice daily (n ═ 7)
CMAX(ng/mL)TMAX(hour) Cmin(ng/mL)	1760±7152.00±1.15585±340	2710±6574.33±1.621260±501	3660±10904.17±2.481960±812

According to Table 7, ranolazine is released slowly from the SR formulation, and thus pharmacokinetics are limited by the dissolution rate. This results in an extended plasma drug concentration-time profile at all dose levels, reaching peak plasma levels 2-4 hours after administration.

These results indicate that useful plasma ranolazine levels can be achieved in humans using a regimen of twice daily administration of this SR formulation.

Example 8

This example evaluates the safety and tolerability of administration of the racemic ranolazine free base formulation of example 2D. Individual and average concentrations of racemic ranolazine and its enantiomers, namely (R) - (+) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) propyl ] -1-piperazineacetamide, (S) - (-) -N- (2, 6-dimethylphenyl) -4- [ 2-hydroxy-3- (2-methoxyphenoxy) propyl ] -1-piperazineacetamide, in human plasma were also determined.

Studies were conducted with ascending doses of ranolazine sustained release formulations. Before, during and after administration, blood samples were drawn for ranolazine determination, blood pressure, heart rate, ECG and symptoms monitored throughout the procedure. After each period, the summary data was reviewed before entering the next study period.

All 8 healthy male volunteers aged 18-40 years were enrolled and completed the study and were available for pharmacokinetic and safety analysis. Each subject was administered a different dose type of ranolazine free base in the form of a sustained release tablet comprising 500mg and 750mg tablets or a matching placebo (2 x 750mg size +1 x 500mg size) as needed to yield unit oral doses of 1500 and 2000 mg.

At each time period: twice daily doses were used for 4 days, and a single dose was used on day 5. On day 5, a comprehensive pharmacokinetic profile was made for each volunteer, including supine and upright Blood Pressure (BP) as well as heart rate, ECG data, side effects, clinical chemistry and hematology results, urinalysis results.

With C_48h、C_72hAnd C_96hAnd log turnsThe data were analyzed for covariance and tested for significant differences in the coefficients from time 0 (referred to as p < 0.05) to determine the steady state for each dose level. These tests were tested using a two-sided t-test to determine the variability of ANOVA type. C was also compared by using a mixed ANOVA type of effect and no transformation data to log transformation data_48h、C_72hAnd C_96hThe steady state was assessed as the average of. For hemodynamic parameters, day 1 pre-dose treatment and day 5 data were compared using a variability measure of mixed ANOVA type effect, cross-treatment by two-sided t-test. Confidence intervals for treatment comparisons were calculated to be 90 and 95%. No judgment was made for the various comparisons.

The mean and standard deviation of the pharmacokinetic parameters of ranolazine free base at day 5 are detailed in table 8 below, and the mean plasma profile is shown. Steady state plasma levels of ranolazine free base were obtained on day 4. Within the dosing interval, T1-6 hours after dosing_maxThe value slowly increased to the maximum level. The level then slowly decreased and small fluctuations in plasma levels occurred between dosing intervals. There appears to be no difference in the pharmacokinetic parameters of the (+) R and (-) S enantiomers of ranolazine after use of multiple doses of the SR formulation.

TABLE 8

5-day Racemic (RS), (+) R and (-) S ranolazine SR pharmacokinetic parameters

Parameter(s)	1500mg SR twice daily			2000mgSR twice a day
					RS ranolazine	(+) R ranolazine	(-) S ranolazine	RS ranolazine
	CMAX(ng/mL)	5284±2434	2909±1308	2944±1426					7281±2700
Cmin(ng/mL)					2932±1918	1436±1046	1514±1201	4149±2228
	Middle tMAX(hours)	4.00	4.00	4.00					4.00
C96h(ng/ml)					3656±1918	2009±1137	2399±1205	5042±1797
	C108h(ng/ml)	2942±1937	1447±1071	1541±1260					4398±2396
AUC96-108h(ng.h/ml)					49516±23945	25731±13385	26407±14849	68459±25842
	CAverage(ng/ml)	4126±1995	2144±1115	2201±1237					5705±2153
Degree of fluctuation					0.664±0.336	0.833±0.402	0.824±0.443	0.591±0.240

Typically, 2-6 hours after administration, some of ranolazine 1500mg (n-3/8) and 2000mg (n-2/8) received that the subject was too heavy to complete the BP assay in a standing position. Statistically significant reductions in upright systolic BP were observed at day 5 in 1500mg (-9.8 mmHg; 4 hours post-dose) and 2000mg (-8.4 mmHg; 6 hours post-dose). Although the types of side effects were similar in ranolazine and placebo, headache, dizziness and nasal congestion are more common in ranolazine.

Claims (18)

1. An oral ranolazine sustained release formulation comprising at least 50 wt% ranolazine free base, 1 to 35 wt% of at least one pH dependent binder, and 0.5 to 5 wt% of one or more pH independent binders, wherein the pH dependent binder inhibits the release of ranolazine from the sustained release formulation and promotes the release of a therapeutic amount of ranolazine in an aqueous solution having a pH greater than 4.5 when the formulation is used in an aqueous environment having a pH of the stomach, the formulation being administered over a 24 hour period and the plasma concentration of ranolazine in the patient remaining at 550 to 7500ng base/ml for at least 24 hours.

2. The formulation according to claim 1, wherein the formulation comprises 50% to 95% by weight ranolazine free base.

3. The formulation according to claim 1, wherein the formulation comprises 70% to 80% by weight ranolazine free base.

4. The formulation according to claim 1, wherein the pH-dependent binder is selected from methacrylic acid copolymers, hydroxypropyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone phthalate and mixtures thereof.

5. The formulation according to claim 1, wherein the pH-dependent binder is a methacrylic acid copolymer.

6. The formulation according to claim 5, wherein the methacrylic acid copolymer is methacrylic acid copolymer type C USP.

7. The formulation according to claim 5, wherein the formulation comprises 5 to 12 wt% methacrylic acid copolymer USP type C.

8. The formulation according to claim 5, wherein the formulation comprises 10 wt% methacrylic acid copolymer.

9. The formulation according to claim 1, wherein the pH independent binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, neutral polyacrylates and/or polymethacrylates, polyvinylpyrrolidone and mixtures thereof.

10. The formulation according to claim 9, wherein the pH independent binder is hydroxypropyl methylcellulose.

11. The formulation of claim 10, wherein the hydroxypropyl methylcellulose is present in an amount of 1-3 wt%.

12. The formulation of claim 11, wherein the hydroxypropyl methylcellulose is present in an amount of 2 wt%.

13. The formulation of claim 1, wherein the formulation comprises 650 to 850mg ranolazine free base.

14. The formulation according to claim 1, wherein the formulation comprises 900 to 1100mg ranolazine free base.

15. The formulation according to claim 1, wherein the formulation comprises 400 to 600mg ranolazine free base.

16. The formulation according to claim 1, wherein the formulation comprises 300 to 1100mg ranolazine free base.

17. The formulation of claim 1, wherein the formulation is a compressed tablet.

18. An oral ranolazine sustained release formulation comprising a compressed tablet comprising 70 to 80 wt% ranolazine free base, 5 to 15 wt% of at least one pH dependent binder selected from methacrylic acid copolymer, hydroxypropyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinylpyrrolidone phthalate and mixtures thereof and 1 to 3 wt% of at least one pH independent binder, wherein the compressed tablet comprises 350 to 800mg ranolazine free base.