Ranolazine enantiomer for use in cancer treatment

Abstract

The present disclosure relates to non-racemic compositions of ranolazine and enantiomerically pure formulations and pharmaceutical compositions of ranolazine that are used in the treatment of diseases wherein the pathology of the disease includes a contribution from VGSC mediated late sodium currents, such as e.g., heart diseases and various types of metastatic cancers.

Description

[0001] RANOLAZINE ENANTIOMER FOR USE IN CANCER TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to cancer therapy. In particular, the present invention relates to therapy of cancer by administering an enantiomer of ranolazine, i.e., the (S)-enantiomer or (R)-enantiomer of ranolazine in an effective amount.

[0004] BACKGROUND OF THE INVENTION

[0005] Ranolazine is a small molecule of a pharmacological class which have been shown to have its anti-ischaemic and antianginal effects via inhibition of the late sodium current resulting from voltage-gated sodium channels ("VGSCs") in cardiac cells with a resultant reduction of intracellular sodium and intracellular calcium overload. The clinical development programme for ranolazine commenced in 1985 with initial studies using intravenous (IV) and immediate release (IR) formulations. In order to maintain an effective plasma concentration, an extended release (ER) formulation and prolonged release (PR) formulations have been developed. Ranolazine (sold under the tradename Ranexa) is a well-established drug used in the treatment of heart diseases, such as chronic angina and arrythmia.

[0006] Ranolazine has the following formula, where the dashed circle indicates the molecule's asymmetric carbon atom:

[0007] While the exact mechanism of action in relation to ranolazine has not yet been fully established, there is emerging evidence that the pharmacological effect of ranolazine is a result of inhibition of the late or persistent current of particular VGSCs. VGSCs are integral membrane proteins containing a pore-forming alpha subunit and smaller non-pore-forming beta subunits, conducting sodium ions (Na+) through a cell's plasma membrane. In humans, there are nine different VGSC alpha subunits or "Nav" proteins (Navl.l to Navi.9), encoded by the genes SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A respectively. The alpha subunit of VGSCs is a transmembrane protein with 4 repetitive transmembrane domains (termed DI, DII, Dill, and DIV), which each contains 6 transmembrane spanning sections that are termed S1-S6. Na+ions flow through a pore formed by S5 and S6 of all 4 domains. The S4 segment plays a central role in voltage sensing. The smaller beta subunits contain an N-term extracellular immunoglobulin (Ig) loop, a transmembrane domain and an intracellular domain.

[0008] Recent structures of the Navi.5 VGSC with ranolazine shows that ranolazine positions itself in the sodium pore of the channel in the traditional class I antiarrhythmic drugs (ADD) receptor site, however forming a number of non-conventional contacts in especially the DI-S6 segment of the channel, providing ranolazine with a distinct binding mode in comparison with classical class I and III AADs that do not make similar molecular contacts (see Lenaeus et al., Nat Cardiovasc Res. 2023 June ; 2(6): 587-594).

[0009] Besides the involvement in cardiac indications, VGSCs are expressed in invasive, aggressive, and / or metastatic cells from a number of cancers, potentiating invasive and metastatic behaviour. In some cancers, the dominant VGSC expressed is a neonatal splice variant of a VGSC.

[0010] For example, more than 10 different splice isoforms have been described for SCN5A (Navi.5), of which several harbour different functional properties, and different isoforms are expressed during neonatal and adult life. The neonatal and adult forms of the Navi.5 protein are the results of alternative splicing of exon 6, and have several amino acid differences in, e.g., the DI:S3-S4 region of the channel protein (Figure 1). In particular, at position 211, the conserved aspartate (Asp or D) residue (negative) in adult Navi.5 is switched to a lysine (Lys or K) residue (positive) in neonatal Navi.5.

[0011] Human Navi.7 is encoded by the gene SCN9A. The neonatal form of Navi.7 (nNavl.7) is a splice variant of exon 6, similar to nNavl.5, resulting, e.g., in the amino acid aligning with residue 211 of human Navi.5 being switched from a conserved aspartate (Asp or D) in all VGSCs (Navl.l-Navl.9) to an asparagine (Asn or N).

[0012] Human Navi.6 is encoded by the gene SCN8A. The neonatal form is spliced similar to Navi.7 (i.e., a D to N substitution in the residue aligning with residue 211 in Navi.5). WO 2012 / 049440 relates to methods of inhibiting or reducing metastatic behaviour in cancer by administering certain drugs including ranolazine.

[0013] However, there remains a need for improved methods of treating both heart diseases such as arrythmia and angina as well as cancer, including methods that prevent, reduce or inhibit metastatic and / or invasive behaviour of tumour cells.

[0014] OBJECT OF THE INVENTION

[0015] It is an object of embodiments of the invention to provide a treatment of heart diseases and cancer based on administration of non-racemic ranolazine with an improved activity profile compared to the existing methods.

[0016] SUMMARY OF THE INVENTION

[0017] It has surprisingly been found that non-racemic compositions of ranolazine are more potent than racemic composition of ranolazine in terms of inhibition of the late currents in VGSCs, and that the enantiomers of ranolazine have a lower potency towards inhibition of the transient current in VGSCs.

[0018] Accordingly, the present disclosure provides optimized compositions of ranolazine that are more potent than previously known compositions, and which are suggested to have a better side-effect profile due to the lower activity towards the transient current in VGSCs.

[0019] An aspect of the present invention relates to a pharmaceutical composition comprising a mixture of (R)-ranolazine and (S)-ranolazine in a molar ratio different from 1 : 1 and a pharmaceutically acceptable excipient and / or adjuvant.

[0020] A mixture of (R)-ranolazine and (S)-ranolazine comprising the two enantiomers of ranolazine in a 1 : 1 ratio, is also referred to as a "racemic composition" or the "racemate" of ranolazine or "racemic ranolazine". The marketed formulation of ranolazine, e.g., marketed as Ranexa, comprise racemic ranolazine, i.e., ranolazine with a molar 1 : 1 ratio of the two enantiomers of ranolazine.

[0021] The enantiomers of ranolazine may be obtained by either purification from the racemate or by stereospecific synthesis. In the stereospecific synthesis only (R)-ranolazine or (S)- ranolazine is obtained, while in the purification trace amounts of the undesired enantiomer may be present. It is to be understood that where a composition consists essentially of (R)-or (S)-ranolazine, what is meant is that trace amounts of the undesired enantiomer may be present but in an amount / concentration that does not impede the activity of the desired enantiomer. As such it is preferable that less than 10%, such as less than 5%, such as less than 1%, preferably less than 0.5% of the molar content of ranolazine in the composition is the unwanted enantiomer. In other words, it is preferable that more than 90%, such as more than 95%, such as more than 99.5%, more preferably more than 99.5% of the molar content of ranolazine in a composition is the intended enantiomer. The chiral purification and evaluation of enantiomeric purity may e.g., be addressed using HPLC or UPLC using chiral resins functionalized by chiral molecules. Examples of stationary phases e.g., involved functionalization of resins with chiral molecules such as e.g., tris(3,5- dimethylphenylcarbamate), tris-4-methyl-benzoate, or tris(3-chloro-4- methylphenylcarbamate), (R)- or (S)-N-(3,5-dinitrobenzoyl)phenylglycine, or (R,R)-Whelk-O. Commonly such functional stationary phases are packed as columns such as e.g., Chiralpak or Chirex HPLC columns or similar chiral columns.

[0022] A further aspect of the present disclosure relates to a pharmaceutical composition comprising ranolazine and a pharmaceutically acceptable excipient / adjuvant, wherein the ranolazine consist essentially of (R)-ranolazine.

[0023] A further aspect of the present disclosure relates to a pharmaceutical composition comprising ranolazine and a pharmaceutically acceptable excipient / adjuvant, wherein the ranolazine consist essentially of (S)-ranolazine.

[0024] The invention further relates to a method of treating a disease, the method comprising administering an effective amount of a pharmaceutical composition according to the aspects of the invention to a patient in the need thereof.

[0025] In some embodiments, the patient suffers from a heart disease. In other embodiments, the patients suffer from a cancer.

[0026] The present invention also relates to a pharmaceutical composition of ranolazine as disclosed herein, for use in a method of treating a disease as defined herein.

[0027] In an aspect the present invention relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (S)- ranolazine. In an additional and closely related aspect the present invention relates to (S)-ranolazine for use in a method of treating a malignant neoplasm.

[0028] In an aspect the present invention relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (R)- ranolazine.

[0029] In an additional and closely related aspect the present invention relates to (R)-ranolazine for use in a method of treating a malignant neoplasm.

[0030] It is believed that it has not previously been suggested to utilise the purified / isolated enantiomers of ranolazine of mixtures thereof where their molar ratio differs from 1 :1 as a pharmaceutical product. Hence, the present invention also provides purified or isolated (S)- or (R)-ranolazine for use as a medicament and also provides a mixture of (S)- and (R)- ranolazine, where the molar ratio between the enantiomers differs from 1 : 1, for use as a medicament.

[0031] BRIEF DESCRIPTION OF THE FIGURES

[0032] Figure 1. Shows the inhibition of the (A) late current and (B) transient current, using a 25 pM racemic composition of ranolazine comprising both (R)- and (S)-ranolazine (denoted ranolazine), predominantly (S)-ranolazine (denoted CL-S03-A1), or predominantly (R)- ranolazine (denoted CL-S03-A2), measured using whole-cell patch clamp.

[0033] Figure 2. Circular dichroism spectrum of (S)-ranolazine (denoted (S)-(-)-ranolazine) and (R)- ranolazine (denoted (R)-(+)-ranolazine) as used herein, with the optical activity indicated for each compound.

[0034] Figure 3. HPLC chromatogram showing separation of ranolazine as (R)-ranolazine and (S)- ranolazine in methanol using a chiral solid support (Amylose tris(3-chloro-5- methylphenylcarbamate). DETAILED DISCLOSURE OF THE INVENTION

[0035] Ranolazine has been known for decades and is being prescribed for treatment of several heart related indications and have over the recent years been suggested for cancer treatment.

[0036] The inventors herein surprisingly found that the individual enantiomers of ranolazine are each more potent than the combined racemic composition of ranolazine. The surprising finding suggests that Ranolazine may preferably be formulated as enantiomerically pure compositions, or almost enantiomerically pure compositions.

[0037] As can be seen from Figure 1, (R)-Ranolazine (denoted as CL-S03-A2 in the figure) shows a more potent effect than (S)-ranolazine (denoted as CL-S03-A1 in the figure) with respect to inhibition of the late current, but also with respect to lower tendency towards inhibition of the transient current. However, both enantiomers outperformed the racemic composition of ranolazine, thereby showing that both enantiomers have a clear potential for further development as individual drug for treatment of VGSC late current related diseases.

[0038] The present disclosure provides new paradigms for treatment of such diseases, using non- racemic compositions of ranolazine or enantiomerically pure formulations to treat VGSC late current related diseases.

[0039] A pharmaceutical composition comprising ranolazine

[0040] Pharmaceutical compositions comprising ranolazine has been known for decades, and intravenous (IV) and immediate release (IR) formulations are well known in the art. Additionally, extended release (ER) formulation and prolonged release (PR) formulations have been developed. Means to provide such formulations of the racemic ranolazine are therefore well known to the skilled person.

[0041] The aspects that the inventors have herein envisioned is that there is a surprising effect of each of the enantiomers of ranolazine, different from the effect of the racemate. (R)- and (S)-ranolazine has previously been tested in in vitro pharmacological assays, without giving rise to substantial differences in the effect on late currents in an ATX-II induced late current in cardiac myocytes and HEK293. In that light the data presented in the examples is especially surprising. In the examples of the present disclosure the inventors have shown that a more potent inhibition of the VGSC current can be obtained when ranolazine is administered as either the (R)- or (S)-enantiomer compared to administration of the racemic composition of the two enantiomers.

[0042] Ranolazine, e.g., sold under the tradename Ranexa is currently marketed as the racemate, i.e., comprising equal molar amounts of the (R)- and (S)-enantiomer.

[0043] The present disclosure both relates to the composition comprising both the (R)- and (S)- enantiomers of ranolazine but also relates to the situation where only one of the two enantiomers is present i.e., (R)- or (S)-ranolazine i.e., a racemic pure or almost racemic pure composition.

[0044] In an aspect the present invention therefore relates to a pharmaceutical composition comprising a mixture of (R)-ranolazine and (S)-ranolazine in a molar ratio different from 1:1. Such composition may comprise a pharmaceutically acceptable excipient and / or adjuvant.

[0045] In embodiments, the molar ratio between (R)-ranolazine and (S)-ranolazine is at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 100:1, at least 150:1; at least 200:1, at least 250:1. In other embodiments, the molar ratio between (R)-ranolazine and (S)-ranolazine is at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, at least 1:20, at least 1:25, at least 1:30, at least 1:40, at least 1:50, at least 1:60, at least 1:70, at least 1:80, at least 1:90, at least 1:95, at least 1:100, at least 1:150; at least 1:200 or at least 1:250.

[0046] In some aspects, the invention relates to a pharmaceutical composition comprising ranolazine, wherein the ranolazine consist essentially of (R)-ranolazine.

[0047] In other aspects of the invention, the pharmaceutical composition comprises ranolazine, wherein the ranolazine consist essentially of (S)-ranolazine.

[0048] In some embodiments, the composition is a racemic pure composition, such that it contains only a single enantiomer, or essentially a single enantiomer of ranolazine.

[0049] As such a racemic pure composition is to be understood as a composition comprising predominantly one enantiomer of ranolazine, such as at least 80 % of either the (S)- or (R)- enantiomer of ranolazine, preferably at least 90%, such as 95%, 98%, or at least 99% of either the (S)- or (R)-enantiomer of ranolazine.

[0050] In the examples the inventions have shown that (S)-ranolazine is more effective at inhibiting the late currents than the combined (R)- and (S)-enantiomer mixture i.e., the racemate, when (S)-ranolazine is provided at the same concentration as the (R)- and (S)-enantiomer mixture. This is for example shown in figure 1A which shows that (S)-ranolazine (denoted CL-S03-A1 in the figure) is more effective at inhibiting the late current at 25uM compared to the (R)- and (S)-enantiomer mixture (denoted ranolazine in the figure). An explanation for the difference in the function of the two enantiomers compared to the racemate can be due to differences in the binding to the VGSC channel, and since ranolazine was found to have a number of non-canonical interactions compared to other ADDs Lenaeus et al., Nat Cardiovasc Res. 2023 June ; 2(6): 587-594}. It is likely that the exact interaction pattern between the (R)- and the (S)-enantiomer and the VGSC differ slightly, thereby explaining the different properties of the two enantiomers. Along the same lines, such differences in binding patterns may also explain why the individual enantiomers are more potent than the racemate, since the enantiomers may compete for similar but not identical binding sites, thereby reducing the overall occupancy of each of the biding modes thereby potentially reducing the overall effect when administered as the racemate.

[0051] In embodiments, the active pharmaceutical ingredient in the pharmaceutical composition is (S)-ranolazine.

[0052] In the examples the inventions have shown that (R)-ranolazine is more effective at inhibiting the late currents than the combined (R)- and (S)-enantiomer mixture, when (R)-ranolazine is provided at the same concentration as the (R)- and (S)-enantiomer mixture. This is for example shown in figure 1A which shows that (R)-ranolazine (denoted CL-S03-A2 in the figure) is more effective at inhibiting the late current at 25uM compared to the (R)- and (S)- enantiomer mixture (denoted ranolazine in the figure), but also more effective in at inhibiting the late current then (S)-ranolazine.

[0053] In embodiments, the active pharmaceutical ingredient in the pharmaceutical composition is (R)-ranolazine.

[0054] The pharmaceutical compositions may be formulated as an immediate release, extended release or prolonged release formulation for oral administration or intravenous administration. When formulated for oral administration the pharmaceutical composition as disclosed herein may comprise one or more excipients selected from the group consisting of lactose, microcrystalline cellulose, starch, croscarmellose sodium, magnesium stearate, silicon dioxide, talc, hydroxypropyl methylcellulose, sodium starch glycolate, polyethylene glycol, stearic acid, povidone, calcium phosphate, sucrose and mannitol.

[0055] When formulated for oral administration the pharmaceutical composition as disclosed herein may comprise one or more adjuvants selected from the group consisting of citric acid, sodium citrate, sodium bicarbonate, flavouring agents, colouring agents, sweeteners, preservatives, surfactants, pH modifiers and taste-masking agents.

[0056] Where formulated for intravenous (IV) administration the pharmaceutical composition as disclosed herein may comprise one or more excipients selected from the group consisting of water for injection, sodium chloride, dextrose, glycerine, polyethylene glycol, propylene glycol, ethanol, polysorbate 80, sodium hydroxide, hydrochloric acid, phosphate buffer, citrate buffer, mannitol, EDTA and sodium acetate.

[0057] Where formulated for IV administration the pharmaceutical composition as disclosed herein may comprise one or more adjuvants selected from the group consisting of immunostimulants, aluminium salts (e.g., aluminium hydroxide), MPL (monophosphoryl lipid A), liposomes, saponins (e.g., QS-21), cytokines, CpG oligonucleotides, emulsifiers, preservatives (e.g., benzyl alcohol) and stabilizers.

[0058] In some embodiments, the pharmaceutical composition comprises in addition to ranolazine, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, sodium hydroxide, polyethylene glycol, titanium dioxide, carnauba wax and / or colloidal silicon dioxide.

[0059] In some embodiment, the pharmaceutical composition is formulated for nasal administration. In additional embodiments, the pharmaceutical composition is aerosolized, or in a droplet or powder form suitable for nasal administration or inhalation.

[0060] In some embodiments, the pharmaceutical composition comprises in addition to ranolazine, on or more of a solvent, a vehicle, a buffering agent, a preservative, a stabilizer, an antioxidant, a viscosity enhancer, a mucoadhesive, a permeation enhancer, a surfactant and a solubilizer.

[0061] In embodiments, the solvent is selected from the group consisting of water for injection, saline (sodium chloride) and ethanol. In embodiments, the vehicle is selected from the group consisting of propylene glycol and polyethylene glycol. In embodiments, the buffer is selected from the group consisting of sodium phosphate, sodium citrate and citric acid. In embodiments, the preservatives is / are selected from the group consisting of benzalkonium chloride, phenyl ethyl alcohol, chlorobutanol, thimerosal and parabens.

[0062] In embodiments, the stabilizer or antioxidant is selected from the group consisting of EDTA (disodium edetate), ascorbic acid, sodium metabisulfite and tocopherol.

[0063] In embodiments, the viscosity enhancer or mucoadhesive is selected from the group consisting of carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC), xanthan gum, chitosan and polyvinyl alcohol.

[0064] In embodiments, the permeation enhancer is selected from the group consisting of polysorbate 80, bile salts, cyclodextrins (e.g., hydroxypropyl-p-cyclodextrin), laureth-9 nad oleic acid.

[0065] In embodiments, the permeation surfactant or solubilizer is selected from the group consisting of polysorbate 80, sorbitan monolaurate and cremophor EL.

[0066] Since it was shown in the examples, that both the (R)-enantiomer and the (S)-enantiomer were more efficient at alleviating the late current than the racemate ranolazine, at equimolar concentrations it is considered that both species are more potent than the racemate.

[0067] Therefore, in some embodiments, the compositions disclosed herein preferably, has a more potent inhibition of the persistent part of the voltage gated sodium channel (VGSC) current than a composition comprising a racemic composition of (R)- and (S)-ranolazine with a ratio of 1 : 1.

[0068] Additionally, it is preferable that the composition has a less potent inhibition of the transient part of the voltage gated sodium channel (VGSC) current than a composition comprising a racemic composition of (R)- and (S)-ranolazine with a ratio of 1 : 1.

[0069] The terms "persistent part of the voltage gated sodium channel (VGSC) current", "persistent current" and "late currents" or "INa,L" are used interchangeably.

[0070] As used herein "potency" relates to the efficacy of ranolazine in inhibiting the persistent or transient current of a VGSC. Potency may be evaluated on the basis of the EC50 or IC50 as is well known in the art. In examples the EC5o or IC5o may be evaluated on the basis of the conductance of an VGSC measured in an in vitro assay, where the current of the VGSC is measure such that both the transient and persistent current may be evaluated, and plotted against a series of concentrations of ranolazine. Assays establishing the EC5o or IC5o of an inhibition of VGSC current are well known in the art. In vivo assays to measure the late current from VGSCs may e.g., include optogenetics, such as e.g. cardiac optogenetics.

[0071] In embodiments, the VGSC is selected from VGSCs encoded by genes selected from SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A.

[0072] In further embodiments, the VGSC is selected from NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 and NaV1.9. In some embodiments, the VGSC is one or more of Navi.5, Navi.6, and Navi.7. In some embodiments, the VGSC selected from the group consisting of Navi.5, Navi.6 and Navi.7. In preferred embodiments the VGSC is Navi.5.

[0073] Alternative splicing of VGSC genes, such as SCN1A-SCN11A, generates splice variants that diversify their expression, gating properties, and drug sensitivity. In particular, splice variants of Navi.5 (SC / V5A) influence cardiac conduction and are linked to arrhythmias. Navi.6 (SC / V8A) variants affect neuronal excitability and are associated with epilepsy and neurodevelopmental disorders. Navi.7 (SC / V9A) splice forms modulate pain thresholds and contribute to conditions like inherited erythromelalgia and congenital insensitivity to pain. These variants alter channel kinetics, trafficking, and pharmacology, making them important targets for precision therapies in neurology and cardiology. In the present case, it is well known the specific splice variants have a tendency to generate late currents. An example is the Exon 6A (foetal) variant of Navi.5, which have an increased late current, linked to arrhythmogenic potential and cancer. Another example is the Navi.5 AQ1077 variant, which is associated with altered inactivation and increased INa,L in cardiac tissue.

[0074] Another example is the Exon 18A variant (neuronal) of Navi.6 (SCN8A) which generates a persistent current contributing to excitability and has been linked to epileptic phenotypes

[0075] Yet another example is e.g. exon 5 or 11 variants of Navi.7 (SCN9A) which have been shown to be cancer-associated variants or variants with altered exon usage, that may show increased persistent or resurgent currents.

[0076] VGSC splice variants, particularly of Navi.5 and Navi.7, are implicated in cancer progression. The neonatal splice form of Navi.5 enhances metastatic potential in breast and colon cancers by promoting cell migration and invasion. In some embodiments, the VGSC expressed is a splice variant. In other embodiments, the VGSC is neonatal Navi.5.

[0077] Method of treatment

[0078] The present disclosure also relates to methods of treating patients in the need thereof with the pharmaceutical compositions disclosed herein.

[0079] An aspect of the disclosure therefore relates to a method of treating a disease, the method comprising administering an effective amount of a pharmaceutical composition disclosed herein to a patient in the need thereof.

[0080] As mentioned herein, a common denominator of some heart diseases and certain types of cancers is the late sodium currents driven by VGSCs, leading to hyperpolarization of the cells, activating numerous pathways leading to the disease state. Accordingly, inhibiting the VGSC late current may be preferable when treating patients suffering from such diseases.

[0081] Voltage-gated sodium channels (VGSCs), especially Navi.5, are essential for cardiac action potential initiation and propagation. In heart diseases, such as arrhythmias, heart failure, and Brugada syndrome, VGSC dysfunction or altered expression contributes to electrical instability. Mutations, post-translational modifications, or altered trafficking of VGSCs can lead to impaired conduction, increased risk of arrhythmias, or sudden cardiac death. Abnormal late sodium current (INa,i_) is particularly implicated in heart failure and long QT syndrome. Thus, VGSCs are critical not only for normal cardiac electrophysiology but also as therapeutic targets for anti-arrhythmic drugs and treatment of related cardiac pathologies.

[0082] In an embodiment, the method comprises alleviating / reducing late sodium currents in the patient. Preferably, the method comprises alleviating / reducing late sodium currents in the patient without materially affecting the transient current. The presence of late sodium currents in patients may e.g., be found by ECG, and the effect of the treatment may be followed by following the symptoms of the patient along with monitoring of the heart function by ECG.

[0083] In some embodiments, the pathology of the disease to be treated includes a contribution from late sodium currents. In some embodiments, the disease is a heart related disorder. Racemic ranolazine has been used for decades in the treatment of heart disorders, in particular in its use in alleviating chronic angina is well known.

[0084] In some embodiments, the heart related disorder is a late current related heart condition or long Q interval heart disorder. In some embodiments, the heart related disorder is a late current related heart disorder, or long Q interval heart disorder. In other embodiments, the heart disorder is chronic stable angina, microvascular angina, chronic coronary syndrome and / or arrhythmias.

[0085] In some embodiments, ranolazine, predominantly as (S)-ranolazine or (R)-ranolazine is administered in a dose of 0.1-10.000 mg / day, preferably at a dose of 750-2000 mg / daily.

[0086] In some embodiments, the present invention relates to enantiomerically pure ranolazine for use in a method of treating a heart disease. Since both enantiomers of ranolazine are more effective than the racemate either of the enantiomers may preferably be used in the treatment of heart diseases. Nevertheless, (R)-ranolazine has proven to be more efficacious than (S)-ranolazine, wherefore it is preferred that (R)-ranolazine is used in the treatment of heart diseases.

[0087] Since the recommended dose of racemate ranolazine is 375-1000 mg twice daily, it is expected that a lower dose of enantiomerically pure ranolazine can be equally effective in the treatment of e.g., chronic angina. Therefore, it is expected that the dose of (R)- or (S)- ranolazine, when administered orally, can be 100-500 mg twice daily. More so, it may be expected that (R)-ranolazine may be administered at even lower dosages than (S)- ranolazine, such as e.g., 50-500 mg twice daily.

[0088] The limiting factor in the daily ranolazine dosage is due to the onset of side effects at higher dosages than the 2000 mg / daily. Therefore, when treating heart diseases, it is especially relevant that especially the enantiomers of ranolazine, in particular (R)-ranolazine shows a much-improved ratio between inhibition of the late current and the transient current, since the main source of side effects from ranolazine is related to its inhibition of the transient currents. Also, the fact that not only the ratio but also the actual lower inhibition of the transient current strongly supports this. Therefore, it is expected that the enantiomers but in particular (R)-ranolazine may be administered in even higher dosages than racemic ranolazine, without inducing further side effects, thereby providing a more efficient treatment, since higher dosages may be used. Accordingly, in some embodiments, (R)- ranolazine is administered at dosages of up to 10.000 mg / daily over a period of 2-4 weeks. The pharmaceutical composition may also be used in the treatment of a patient suffering from cancer. As such the composition may be used to prevent the cancer from becoming invasive or metastatic i.e., as a prophylactic treatment in an early stage of cancer.

[0089] The composition may also be used in the treatment of cancer treatment induced comorbidities, such as cancer therapy induced heart conditions.

[0090] Treatment of a malignant neoplasm in a patient

[0091] In recent years, ranolazine has been shown to have a positive effect on metastatic cancers, where the underlying mechanism of the metastasis is largely driven by an enhanced sodium influx through the late sodium current.

[0092] In some aspects, it is preferable to use the pharmaceutical compositions of the present disclosure in the treatment of cancer patients. The invention in particular relates to the treatment of a malignant neoplasm.

[0093] Where the treatment provided is used in the treatment of patients suffering from cancer, the treatment may be use specifically to treat the cancer as a treatment with an anti-metastatic effect or treatment that inhibits the invasiveness of the cancer, or it may be used to treat comorbidities, resulting from the cancer or from treatment of the cancer with antineoplastic agents such as chemotherapy, or radiation, affecting the heart of the patient, such as e.g., anthracyclines, HER2-targeted therapies, tyrosine kinase inhibitors or alkylating agents. Accordingly, in some embodiments, the pharmaceutical compositions of the present disclosure are for use in the treatment of cancer therapy induced heart disorders. In other the pharmaceutical compositions of the present disclosure are for use in the treatment of the malignant neoplasms.

[0094] While many anti-cancer therapies used in the clinic today are efficient since they kill the cancer cells, such as e.g., chemotherapy and radioembolization, they often also kill surrounding tissue or has systemic effects on non-cancerous cells. Ranolazine provides an effect which is different from the classical dogma in cancer therapy, where the effect is not cytotoxic or cytostatic, since - when dosed correctly - is not directly lethal to the cancer cells and normally allows cancer cells to proliferate. By restoring the sodium current in the cancer cells to that of a normal healthy cell, the treatment may also restore the normal cell cycle, due to the downstream effects of a normalized current, such as a normalized Ca2+ level in the cells, leading to a more normal signalling via. the Ca2+ coupled pathways, such as e.g., K-Ras, ERK1 / 2 etc. In simpler terms, the malignant cells are converted to a benign neoplastic phenotype; the aggressiveness of the cancer is halted, by inhibiting the mechanisms responsible for the aggressiveness of the cancer driven by the late sodium influx mediated by the VGSCs. It is preferable that the effective amount of ranolazine administered is hence not lethal for the malignant cells of the malignant neoplasm and is typically also permissive for the cancer cells' ability to proliferate.

[0095] As mentioned, the present invention in an aspect relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (S)- ranolazine.

[0096] The present invention in another aspect relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (R)- ranolazine.

[0097] It is preferred that the treatment comprises or consists of reducing or abolishing the metastatic or invasive activity of malignant cells of the malignant neoplasm - i.e. relying on the effect described above and utilised initially in WO 2012 / 049440, where it was demonstrated that this effect could be attained in cultures of malignant cells without killing the cells and without impeding their proliferation. Hence, also according to the present invention it is preferred that the effective amount of ranolazine is not lethal for the malignant cells of the malignant neoplasm. Also, in line with the findings in WO 2012 / 049440, the treatment is designed to target malignant cells that express at least one active voltage gated sodium channel (VGSC); in other words, the malignant cells of the malignant neoplasm express at least one active voltage gated sodium channel (VGSC). Such VGSC is typically encoded by a gene selected from SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A. The expression product, i.e. the active VGSC can be any of the possible splice forms encoded by these genes; it is known that some malignant neoplasms express VGSC in the form of a neonatal splice variant, so in specific embodiments, the target for the present treatment is such a neonatal splice variant.

[0098] In order to safely administer a VGSC blocker it is imperative that the transient current in VGSCs are not blocked completely - since excitable tissues such as heart muscle express VGSCs, a substantial or complete block of the transient VGSC current would lead to fatal heart failure due to blocking of the heart muscle action So according to preferred embodiments of the first aspect of the invention, the effective amount of ranolazine blocks persistent current in the VGSC without completely blocking the transient current in the VGSC. Until now, the use of ranolazine has been in the form of a racemic composition, which typically has to be present in tumour tissue to exert the antimetastatic antiinvasive effects in a concentration of between 1 and 10 pM. It is hence contemplated that the effective amount is such that it can establish a concentration of (S)-ranolazine in the malignant neoplasm of between 0.5 and 5 pM and still provide for the same efficacy. Accordingly, in some embodiments, the effective amount is effective in establishing a concentration of (S)- ranolazine or (R)-ranolazine in the malignant neoplasm of between 0.5 and 5 pM.

[0099] It is also contemplated that the effective amount is such that it can establish a concentration of (R)-ranolazine in the malignant neoplasm of between 0.5 and 5 pM and still provide for the same efficacy.

[0100] Therefore, in some embodiments, the effective amount of ranolazine is not lethal for the malignant cells of the malignant neoplasm.

[0101] In some embodiments, the effective amount is effective in establishing a concentration of ranolazine in the malignant neoplasm of between 0.5 and 5 pM.

[0102] In principle, any type of malignant neoplasm can be treated according to the present invention, but since metastatic behaviour and invasive growth are of particular relevance for solid or semi-solid tumours, these are the primary targets. At any rate, the malignant neoplasm is typically a tumour from the group consisting of an epithelial tumour, a non- epithelial tumour, and a mixed tumour.

[0103] Examples of an epithelial tumour is a carcinoma or an adenocarcinoma, and examples of a non-epithelial tumour or mixed tumour is a liposarcoma, a fibrosarcoma, a chondrosarcoma, an osteosarcoma, a leiomyosarcoma, a rhabdomyosarcoma, a glioma, a neuroblastoma, a medulloblastoma, a malignant melanoma, a malignant meningioma, a neurofibrosarcoma, a leukaemia, a myeloproliferative disorder, a lymphoma, a hemangiosarcoma, a Kaposi's sarcoma, a malignant teratoma, a dysgerminoma, a seminoma, or a choriocarcinoma.

[0104] Also, the anatomic location of the malignant neoplasm can vary: it is typically selected from the eye, the nose, the mouth, the tongue, the pharynx, the oesophagus, the stomach, the colon, the rectum, the bladder, the ureter, the urethra, the kidney, the liver, the pancreas, the thyroid gland, the adrenal gland, the breast, the skin, the central nervous system, the peripheral nervous system, the meninges, the vascular system, the testes, the ovaries, the uterus, the uterine cervix, the spleen, bone, and cartilage. As noted above, ranolazine has an active (S)-enantiomer and an active (R)-enantiomer, which is the main compounds responsible for the anti-cancer effects described above. Ranolazine (or rather: 1-Piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2- methoxyphenoxy)propyl]-,(±)-) is a molecule currently used for treating angina pectoris. Racemate ranolazine has the following structural formula.

[0105] The molecule has a chiral centre:

[0106] For pharmaceutical treatment of Angina Pectoris a racemic solution is being used, and it was generally believed that both enantiomers are considered equally pharmaceutically active.

[0107] As is shown herein, both enantiomers are more potent than the racemate, and have less side effects, but the results indicate that (R)-ranolazine is the most efficacious of the enantiomers.

[0108] As used herein, S-ranolazine is defined as the compound which has a negative optical activity when assayed using circular dichroism, i.e., (S)-(-)-Ranolazine, as shown in figure 2. As used herein, R-ranolazine is defined as the compound which has a positive optical activity when assayed using circular dichroism, i.e., (R)-(+)-Ranolazine, as shown in figure 2, as is described further in Luo et al., J. Sep. Sci. 2006, 29, 164 - 171, e.g., Figure 5 of Luo et al. (R)- and (S)-ranolazine may be separated by chiral purification, such as e.g., HPLC using a chiral solid phase, such as e.g., an Amylose tris(3-chloro-phenylcarbamate) resin or Amylose tris(3-chloro-5-methylphenylcarbamate) resin. Typically, using such resins, (S)-(-)-ranolazine will elute earliest and (R)-(+)-ranolazine will elute later as described further in Luo et al., J. Sep. Sci. 2006, 29, 164 - 171, e.g., Figure 1 of Luo et al.

[0109] As noted above, the present inventors have found that the (R)-enantiomer is the most potent form of the enantiomers. This warrants treatment with either a pure (R)-enantiomer or a composition enriched for the (R)-enantiomer. On the other hand, also (S)-ranolazine was found to be more potent then the racemate. Which also warrants treatment with either a pure (S)-enantiomer or a composition enriched for the (S)-enantiomer.

[0110] Effective methods for separation and purification of ranolazine enantiomers have been published in Luo et al., J. Sep. Sci. 2006, 29, 164 - 171 and stereoselective synthesis of ranolazine is also a viable option. It is hence possible to treat patients with (S)-ranolazine alone or at least with compositions that contain a very high fraction of (S). It is also possible to treat patients with (R)-ranolazine alone or at least with compositions that contain a very high fraction of (R)-ranolazine.

[0111] An aspect of the invention therefore relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (S)- ranolazine.

[0112] Hence, it is preferred that the ranolazine administered comprises a ratio between (S)- ranolazine and (R)-ranolazine of at least 2: 1. This ratio can be much higher: at least 3: 1, at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 15: 1, at least 20: 1, at least 25 : 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80: 1, at least 90: 1, at least 95: 1, at least 100: 1, at least 150 : 1; at least 200: 1, and at least 250: 1. In a particular preferred embodiment, the ranolazine administered is essentially free from (R)-ranolazine.

[0113] An aspect of the present invention entails (S)-ranolazine for use in a method of treating a malignant neoplasm; this is in line with the other aspects of the invention, meaning that each and every feature disclosed above in the context of the other aspects and the embodiments thereof apply mutatis mutandis to the current aspect.

[0114] The present disclosure therefore also relates to (S)-ranolazine for use in a method of treating a malignant neoplasm, preferably, wherein the method for treatment of the malignant neoplasm is as defined herein.

[0115] Another aspect of the invention relates to a method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (R)-ranolazine.

[0116] Hence, it is preferred that the ranolazine administered comprises a ratio between (R)- ranolazine and (S)-ranolazine of at least 2: 1. This ratio can be much higher: at least 3: 1, at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 15: 1, at least 20 : 1, at least 25: 1, at least 30: 1, at least 40 : 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80 : 1, at least 90: 1, at least 95: 1, at least 100 : 1, at least 150: 1; at least 200: 1, and at least 250: 1. In a particular preferred embodiment, the ranolazine administered is essentially free from (S)-ranolazine.

[0117] An aspect of the present invention entails (R)-ranolazine for use in a method of treating a malignant neoplasm; this is in line with the other aspects of the invention, meaning that each and every feature disclosed above in the context of the other aspects and the embodiments thereof apply mutatis mutandis to the current aspect.

[0118] The present disclosure therefore also relates to (R)-ranolazine for use in a method of treating a malignant neoplasm, preferably, wherein the method for treatment of the malignant neoplasm is as defined herein.

[0119] As such the treatment of a malignant neoplasm in a patient, in some embodiments entails reducing or abolishing the metastatic or invasive activity of malignant cells of the malignant neoplasm.

[0120] The invention also relates to pharmaceutical compositions of ranolazine as disclosed herein, for use in a method of treating a disease as defined in the above sections.

[0121] As described above Voltage-gated sodium channels (VGSCs), typically involved in electrical signalling in excitable cells, and have been implicated in cancer progression. In malignant neoplasms, VGSCs are aberrantly expressed and contribute to increased invasiveness and metastatic potential of cancer cells. Their activity enhances cellular motility, invasion through extracellular matrices, and formation of metastases by regulating processes like pH balance, cytoskeletal dynamics, and cell adhesion. VGSC expression correlates with poor prognosis in several cancers, including breast, prostate, pancreatic, endometrial and colon carcinomas as well as glioblastoma. As a result, VGSCs are being explored as potential biomarkers for cancer aggressiveness and as therapeutic targets to inhibit metastasis and improve patient outcomes.

[0122] Accordingly, in some embodiments, the malignant cells of the malignant neoplasm express at least one active voltage gated sodium channel (VGSC).

[0123] In malignant neoplasms, splice variants of voltage-gated sodium channels (VGSCs) are frequently overexpressed and play a key role in cancer progression. These alternatively spliced isoforms, particularly of the Navi.5 channel (e.g., the neonatal variant) and Navi.7, are associated with enhanced metastatic behaviour. Splice variants often show altered gating properties, increased sodium influx, and greater interaction with pro-metastatic signalling pathways. Their expression is often tumour-specific and correlates with invasiveness, particularly in breast and colon cancers.

[0124] Accordingly, in some embodiments, the malignant cells express VGSC in the form of a neonatal splice variant.

[0125] Since complete blockade of the transient current is associated with several side effects including death, it is highly preferable not to entirely block the transient current, while effectively blocking the persistent current. The most preferable scenario is to completely block the persistent current while not affecting the transient current.

[0126] Accordingly, it is preferable to administer an effective amount of ranolazine, which inhibits or blocks the persistent current without completely blocking the transient current in the VGSC.

[0127] It is shown in the examples, that one of the main benefits of the enantiomers of ranolazine is that both enantiomers provide a more specific inhibition of the late current versus the transient current than the racemate. The examples shows that the transient current is inhibited more in the case of racemate ranolazine, compared to the enantiomers.

[0128] Additionally, both enantiomers have an improved ratio between inhibition of the late current inhibition and the inhibition of the transient current. Especially (R)-ranolazine provides a more specific inhibition of the late current, by having a higher reduction of the late current than the reduction in the transient current i.e., improving the ratio of the currents.

[0129] It is also shown in the examples, that one of the main benefits of the enantiomers of ranolazine is that both enantiomers provide a more specific inhibition of the late current versus the transient current than the racemate.

[0130] In some embodiments, the effective amount of ranolazine administered, predominantly as (S)-ranolazine, inhibits or blocks the persistent current without completely blocking the transient current in the VGSC, preferably the VGSC being Navi.5, Navi.6 and / or Nav 1.7, more preferably the VGSC being Navi.5.

[0131] In some embodiments, the effective amount of ranolazine administered, predominantly as (S)-ranolazine, inhibits or blocks the persistent current without completely blocking the transient current in the VGSC, preferably being Navi.5. In some embodiments, the effective amount of ranolazine administered, predominantly as (R)-ranolazine, inhibits or blocks the persistent current without completely blocking the transient current in the VGSC, preferably the GBSC being Navi.5, Navi.6 and / or Nav 1.7, more preferably the VGSC being Navi.5. In some embodiments, the effective amount of ranolazine administered, predominantly as (R)-ranolazine, inhibits or blocks the persistent current without completely blocking the transient current in the VGSC, preferably being Navi.5.

[0132] EXAMPLES

[0133] Example 1 - inhibition of late currents in VGSC expressing cells

[0134] Methods

[0135] Ranolazine enantiomer purification

[0136] Racemic ranolazine was dissolved in methanol and the enantiomers of ranolazine e.g., in methanol were separated by HPLC using a Chirapak IG column with detection at 210 nm. The ranolazine enantiomers were collected and purified using HPLC and each enantiomer was purified to >99% purity. The resulting chromatogram showing the separation of ranolazine is shown in figure 3. It is evident from figure 3 that the first elution peak is (S)-ranolazine and the second elution peak is (R)-ranolazine. The identity of the enantiomer was assigned based on the optical activity as measured by circular dichroism (CD). The CD spectra obtained (see Figure 2) from the two fraction shows a negative optical activity for the first peak eluting which is therefore assigned as S-(-)-ranolazine and a positive optical activity for the second peak elution, which is assigned to R-(+)-ranolazine, in accordance with annotation used in Luo et al., J. Sep. Sci. 2006, 29, 164 - 171 and Zhu & al New J Chem. 2022, 46, 16547- 16555

[0137] Cell Culture

[0138] MDA-MB-231 cells endogenously or de-novo expressing Nav1.5 were grown in Dulbecco's modified eagle medium supplemented with 5% FBS and 4 mM L-glutamine. Molecular identity of the MDA-MB-231 cells was confirmed by short tandem repeat analysis. Cells were confirmed as mycoplasma-free using the DAPI method. Cells were seeded onto glass coverslips 48 h before electrophysiological recording.

[0139] Electrophysiology

[0140] Plasma membrane Na+currents were recorded using the whole-cell patch clamp technique. Patch pipettes made of borosilicate glass were pulled using a P-97 pipette puller (Sutter Instrument) and fire-polished to a resistance of 3-5 MQ when filled with intracellular recording solution. The extracellular recording solution for MDA-MB-231 cells contained (in mM) : 144 NaCI, 5.4 KCI, 1 MgCI2, 2.5 CaCI2, 5.6 D-glucose, and 5 HEPES (adjusted to pH 7.2 with NaOH). The intracellular recording solution contained (in mM) : 5 NaCI, 145 CsCI, 2 MgCh, 1 CaCh, 10 HEPES, 11 EGTA, (adjusted to pH 7.4 with CsOH). Voltage clamp recordings were made at room temperature using a Multiclamp 700B or Axopatch 200B amplifier (Molecular Devices) compensating for series resistance by 40-60%. Currents were digitized using a Digidata interface (Molecular Devices), low pass filtered at 10 kHz, sampled at 50 kHz and analysed using pCLAMP 10.7 software (Molecular Devices). Leak current was subtracted using a P / 6 protocol. Extracellular recording solution ± drugs (Ranolazine, CL- S03-A1 or CL-S03-A2 each at 25 pM) was applied to the recording bath at a rate of ~1.5 ml / min using a ValveLink 4-channel gravity perfusion controller (AutoMate Scientific). Each new solution was allowed to equilibrate in the bath for ~4 min following switching prior to recording at steady state.

[0141] Voltage Clamp Protocols

[0142] Cells were clamped at a holding potential of -120 mV for >250 ms, dependent on experiment. The following voltage clamp protocols were used:

[0143] 1. To assess the effect of drug perfusion and wash-out on peak current in real time, a simple one-step protocol was used where cells were held at -120 mV for 250 ms and then depolarised to -10 mV for 50 ms.

[0144] 2. The late or persistent current was measured as the average inward current between 20-25 ms following depolarisation.

[0145] The data were analysed and datapoints obtained from cells with a patch-seal resistance of less than 1GQ were omitted.

[0146] The resulting currents obtained for the transient area and the persistent area was normalized to the physiological saline solution (PSS) baseline, and the normalized values are reported in table 1.

[0147] Results

[0148] The results of the patch clamp experiments are reported in figure 1 and table 1. Table 1 - Normalized currents

[0149] It was observed that both CL-S03-A1 and CL-S03-A2 had a more profound effect on the late current compared to the racemate ranolazine when administered at equimolar amounts (see Figure 1A and table 1). Accordingly, both enantiomers are more potent than racemate ranolazine, with respect to the inhibition of the late current. From the results it can further be seen that CL-S03-2A impacted the late current more than CL-S03-1A and racemic ranolazine.

[0150] It was further observed that both CL-S03-A1 and CL-S03-A2 had a less pronounced effect on the transient current compared to the racemate ranolazine when administered at equimolar amounts. Accordingly, both enantiomers are more selective towards inhibition of the late current over the transient current than racemic ranolazine. From table 1 it can further be seen that CL-S03-2A impacted the transient current even less than CL-S03-1A.

[0151] The presented results shows that there is a difference between the inhibitory potential of the different enantiomers with respect to the inhibition of the late current of VGSCs. This suggests that the dose required to obtain the same effect from the treatment i.e., the effective dosage of the enantiomers can be lower than the racemic ranolazine, which is highly beneficial from an on-target side-effect point of view.

[0152] Additionally, the results suggests that the separated enantiomers exhibit less side effects than the racemic ranolazine since both enantiomers block the transient current to a lesser degree than the racemate, suggesting that the enantiomers can be provided at higher dosages than racemic ranolazine without incurring a higher risk of side effects.

Claims

CLAIMS1. A pharmaceutical composition comprising a mixture of (R)-ranolazine and (S)- ranolazine in a molar ratio different from 1:1 and a pharmaceutically acceptable excipient and / or adjuvant.

2. The pharmaceutical composition according to any one of the preceding claims, wherein the ratio is selected from at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 100:1, at least 150:1; at least 200:1, at least 250:1, least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, at least 1:20, at least 1:25, at least 1:30, at least 1:40, at least 1:50, at least 1:60, at least 1:70, at least 1:80, at least 1:90, at least 1:95, at least 1:100, at least 1:150; at least 1:200 and at least 1:250.

3. A pharmaceutical composition comprising ranolazine and a pharmaceutically acceptable excipient / adjuvant, wherein the ranolazine consist essentially of (R)-ranolazine4. A pharmaceutical composition comprising ranolazine and a pharmaceutically acceptable excipient / adjuvant, wherein the ranolazine consist essentially of (S)-ranolazine5. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated as an immediate release, extended release or prolonged release formulation for oral administration or formulated for intravenous administration.

6. A method of treating a disease, the method comprising administering an effective amount of a pharmaceutical composition according to any claim claims 1-5 to a patient in the need thereof.

7. The method according to claim 6, wherein method comprises alleviating / reducing late sodium currents in voltage gated sodium channels (VGSCs) of the patient's cells.

8. The method according to claim 6 or 7, wherein the pathology of the disease includes a contribution from late sodium currents in VGSCs.

9. The method according to any one of claims 1-6, wherein the disease is a heart related disorder.

10. The method according to claim 9, wherein the heart related disorder is a late current related heart condition or long Q interval heart disorder.

11. The method according to any one of claims 9 or 10, wherein the heart related disorder is a late VGSC current related heart disorder.

12. The method according to any one of claims 9-11, wherein the heart disorder is chronic stable angina, microvascular angina, chronic coronary syndrome and / or arrhythmias.

13. The method according to any one of claims 6-8, wherein the patient suffers from a cancer.

14. The method according to claim according to any one of claims 6-8, wherein the treatment comprises treatment of a malignant neoplasm.

15. The method according to claim 14, wherein the effective amount of ranolazine is not lethal for the malignant cells of the malignant neoplasm, and which optionally permits the malignant cells ability to proliferate.

16. The method according to claim 14 or 15, wherein the effective amount is effective in establishing a concentration of ranolazine in the malignant neoplasm of between 0.5 and 5 pM.

17. The method according to any one of claims 14-16, wherein the malignant neoplasm is a tumour from the group consisting of an epithelial tumour, a non-epithelial tumour, and a mixed tumour.

18. The method according to claim 17, wherein the epithelial tumour is a carcinoma or an adenocarcinoma, and wherein the non-epithelial tumour or mixed tumour is a liposarcoma, a fibrosarcoma, a chondrosarcoma, an osteosarcoma, a leiomyosarcoma, a rhabdomyosarcoma, a glioma, a neuroblastoma, a medulloblastoma, a malignant melanoma, a malignant meningioma, a neurofibrosarcoma, a leukaemia, a myeloproliferative disorder, a lymphoma, a hemangiosarcoma, a Kaposi's sarcoma, a malignant teratoma, a dysgerminoma, a seminoma, or a choriocarcinoma.

19. The method according to any one of claims 14-18, wherein the anatomic location of the malignant neoplasm is selected from the eye, the nose, the mouth, the tongue, the pharynx, the oesophagus, the stomach, the colon, the rectum, the bladder, the ureter, the urethra, the kidney, the liver, the pancreas, the thyroid gland, the adrenal gland, the breast, the skin, the central nervous system, the peripheral nervous system, the meninges, the vascular system, the testes, the ovaries, the uterus, the uterine cervix, the spleen, bone, and cartilage.

20. A pharmaceutical composition of ranolazine according to any one of claims 1-5, for use in a method of treating a disease as defined in any one of claims 6-19.

21. The pharmaceutical composition for use according to claim 20, wherein the composition has a more potent inhibition of the persistent part of the voltage gated sodium channel (VGSC) current than a composition comprising a mixture of (R)- and (S)-ranolazine with a ratio of 1 : 1.

22. The pharmaceutical composition for use according to any one of claims 20 or 21, wherein the composition has a less potent inhibition of the transient part of the voltage gated sodium channel (VGSC) current than a composition comprising a mixture of (R)- and (S)- ranolazine with a ratio of 1 : 1.

23. The pharmaceutical composition for use according to any one of claims 20-22, wherein the VGSC is selected from VGSCs encoded by genes selected from SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A.

24. The pharmaceutical composition for use according to any one of claims 20-23, wherein the VGSC is selected from NaVl.l, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 and NaV1.9.

25. The pharmaceutical composition for use according to any one of claims 20-23, wherein the VGSC is NaV1.5, Navi.6 or Navi.7, preferably Navi.5, such as the neonatal NaV1.5 (nNaV1.5).

26. A method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (S)-ranolazine.

27. The method according to claim 26, wherein the ranolazine administered comprises a ratio between (S)-ranolazine and (R)-ranolazine of at least 2: 1.

28. The method according to claim 27, wherein the ratio is selected from at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 100:1, at least 150:1; at least 200:1, and at least 250:1.

29. The method according to any one of claims 26-28, wherein the ranolazine administered is essentially free from (R)-ranolazine.

30. A method for treatment of a malignant neoplasm in a patient, the method comprising administering an effective amount of ranolazine to the patient, wherein the majority of the ranolazine administered is (R)-ranolazine.

31. The method according to claim 30, wherein the ranolazine administered comprises a ratio between (R)-ranolazine and (S)-ranolazine of at least 2:1.

32. The method according to claim 31, wherein the ratio is selected from at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 100:1, at least 150:1; at least 200:1, and at least 250:1.

33. The method according to any one of claims 30-32, wherein the ranolazine administered is essentially free from (S)-ranolazine.

34. The method according to any one of claims 26-33, wherein the treatment comprises or consists of reducing or abolishing the metastatic or invasive activity of malignant cells of the malignant neoplasm.

35. The method according to any one of claims 26-34, wherein the malignant cells of the malignant neoplasm express at least one active voltage gated sodium channel (VGSC).

36. The method according to claims 35, wherein the VGSC is encoded by a gene selected from SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SCN10A, and SCN11A.

37. The method according to claim 35 or 36, wherein the malignant cells express VGSC in the form of a neonatal splice variant.

38. The method according to any one of claims 35-37, wherein the effective amount blocks persistent current in the VGSC without completely blocking the transient current in the VGSC.

39. The method according to any one of claims 26-38, wherein the effective amount is not lethal for the malignant cells of the malignant neoplasm.

40. The method according to any one of claims 26-39, wherein the effective amount is effective in establishing a concentration of (S)-ranolazine or (R)-ranolazine in the malignant neoplasm of between 0.5 and 5 pM.

41. The method according to any one of claims 26-40, wherein the malignant neoplasm is a tumour from the group consisting of an epithelial tumour, a non-epithelial tumour, and a mixed tumour.

42. The method according to claim 41, wherein the epithelial tumour is a carcinoma or an adenocarcinoma, and wherein the non-epithelial tumour or mixed tumour is a liposarcoma, a fibrosarcoma, a chondrosarcoma, an osteosarcoma, a leiomyosarcoma, a rhabdomyosarcoma, a glioma, a neuroblastoma, a medulloblastoma, a malignant melanoma, a malignant meningioma, a neurofibrosarcoma, a leukaemia, a myeloproliferative disorder, a lymphoma, a hemangiosarcoma, a Kaposi's sarcoma, a malignant teratoma, a dysgerminoma, a seminoma, or a choriocarcinoma.

43. The method according to any one of claims 26-42, wherein the anatomic location of the malignant neoplasm is selected from the eye, the nose, the mouth, the tongue, the pharynx, the oesophagus, the stomach, the colon, the rectum, the bladder, the ureter, the urethra, the kidney, the liver, the pancreas, the thyroid gland, the adrenal gland, the breast, the skin, the central nervous system, the peripheral nervous system, the meninges, the vascular system, the testes, the ovaries, the uterus, the uterine cervix, the spleen, bone, and cartilage.

44. The method according to any one of claims 26-43, wherein ranolazine is administered in a dose of 0.1-10.000 mg / day.

45. (S)-ranolazine for use in a method of treating a malignant neoplasm.

46. (S)-ranolazine for the use according to claim 45, wherein the method for treatment of the malignant neoplasm is as defined in any one of claims 26-29 or 34-44.

47. (R)-ranolazine for use in a method of treating a malignant neoplasm.

48. (R)-ranolazine for the use according to claim 47, wherein the method for treatment of the malignant neoplasm is as defined in any one of claims 30-44.

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