Ranolazine and related piperazines for protecting skeletal muscles

ES 2 177 601 T3

DESCRIPTION

Ranolazine and related piperazines for use in the treatment of shock states.

The present invention relates to applications of ranolazine or another compound of formula I derived from piperazine, particularly to applications of ranolazine in medicaments for the treatment of tissues suffering physical or chemical damage, and specifically for the treatment of shock states.

Ranolazine, i.e. ± N- (2,6-dimethylphenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1-piperazine-acetamide or 1- [3- (2-methoxyphenoxy) -2-hydroxypropyl] -4 - [(2,6-dimethyl-phenyl) aminocarbonylmethyl] piperazine and the dihydrochloride salt thereof, and the compounds of formula I are described in US Patent No. 4,567,264. Ranolazine is described as a calcium entry blocking compound, useful for the treatment of cardiovascular diseases, such as myocardial infarction, congestive heart failure, angina and arrhythmia.

The anti-ischemic effects of ranolazine have been described in numerous publications, such as Jain et al., "A PRELIMINARY STUDY OF A NEW ANTI-ANGINAL AGENT", Cardiovascular Drugs and Therapy, Vol. 1, N^° 3, p. 252 (October 1987); Allely and Alps, "THE EFFECTS OF THE NOVEL ANTIANGINAL AGENT RANOLAZINE (ID) IN A CANINE MODEL OF TRANSIENT MYOCARDIAL ISCHAEMIA", Br. J. Pharmacol, 1988, 93, 246P; and Ferrandon et al., "PROTECTIVE EFFECTS OF THE NOVEL ANTI-ISCHAEMIC AGENT RANOLAZINE (RS-43285) IN PERFUSED RAT HEARTS", Br. J. Pharmacol, 1988, 93, 247P, in which the usefulness in protecting hearts from life-threatening functional and biochemical lesions produced by ischemia and / or reperfusion has been reported. Tissue protection, however, is not achieved by blocking calcium entry or by a beta-blocking mechanism (Brown et al., Br. J. Pharmacol., 1988, 93, 248P), nor can it be expected that such active agents have a tissue protective effect. In addition, cardiodepression has been identified as a limiting factor for the extensive use of CEB (calcium entry block) in the treatment of cardio-related ischemic conditions (Packer et al., Circn., 75 (V), 56-64, 1987; Barjon et al., J. Am. Coll. Cardiol., 9, 622-630, 1987).

One aspect of the present invention relates to the use of an effective amount of a compound of

<img file="ES2177601T3_D0001.tif" />

and of the osters and salts by addition of acids, pharmacoeutically acceptable, of the same, in which:

R¹, R², R³, R⁴ yR⁵ are each, independently, hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, (lower alkyl) too, (lower alkyl) sulfinyl, (lower alkyl) sulfonyl, optionally N-substituted alkylamido, except when R¹ is methyl, R⁴ it is not methyl; or

R² yR³ together they form -OCH2O-;

R⁶, R⁷, R⁸, R⁹ yR¹⁰ They are each, independently, hydrogenic, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, (lower alkyl) too, (lower alkyl) sulfinyl, (lower alkyl) sulfonyl or di (lower alkyl) amino; or

R⁶ yR⁷ together they form -CH = CH-CH = CH-; or

R⁷ yR⁸ together they form -OCH2O-;

R¹¹ yR¹² are each, independently, hydrogenic or lower alkyl; Y

ES 2 177 601 T3

W is oxygen or sulfur.

In a preferred embodiment, the invention involves the use of the compound of formula I wherein R¹ and R⁵ are methyl, particularly where R², R³, R⁴, R¹¹ and R¹² they are hydrogen, and more particularly where W is oxygen. The most preferred is the use of ranolazine, that is, when R⁶ is methoxy and R⁷, R⁸, R⁹ yR¹⁰ they are hydrogen.

The present invention presents a use for the manufacture of medicaments for the treatment of shock states (including cardiogenic shock), the method of which comprises administering to a subject experiencing shock an effective amount of a compound of formula I, preferably ranolazine.

Another aspect of the invention presents an application by co-administration of a compound of formula I together with another pharmacoeutically active agent, such as thrombolytic agents [especially TPA (Tissue Plasminogen Activator) or streptokinase] or antianginals (such as beta-blockers, including propanolol. and timolol).

Definitions and general parameters

The following definitions are presented to illustrate and define the meaning and scope of the various terms used to describe the present invention.

As used herein, the term "treatment" or "treat" means any treatment of a disease in a mammal, including:

(i) prevent the disease, that is, make the clonic symptoms of the disease not develop;

(ii) inhibit the disease, that is, stop the development of clonic symptoms; and / or (iii) alleviating the disease, that is, causing the clonic symptoms to subside.

As used herein, the term "csp" means adding a sufficient amount to achieve a given function, for example, to make a solution to the desired volume (ie,

100%).

As used herein, the term "effective amount" means a dose sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease, and the treatment being performed.

Preparation of ranolazine

Ranolazine and the piperazone compounds of Formula I can be prepared, for example, as described in US Patent No. 4,567,264.

Utility, trials and administration

Surprisingly, ranolazine has been found to be active in treatment methods unrelated to its initially identified calcium influx blocking mechanism and with cardioselective indications. Particularly interesting is the fact that ranolazine has now been found to protect tissues against ischemia (improving the efficiency of cellular oxygen utilization) at doses that do not produce any cardiodepressant effects (see Allely and Alps, supra and Ferrandon et al., supra).

General utility

The piperazone compounds of formula I, particularly ranolazine and its pharmacoeutically acceptable salts (preferably the dihydrochloride), are useful for treating tissues suffering from a phosphoric or chemical injury. For example, such treatment may be for cardioplegia or for hypoxic reperfusion injury to skeletal or cardiac muscles or brain tissue. The compounds of formula I, particularly ranolazine and its salts, are also useful for preserving (i.e. preventing deterioration of) donor tissues used in transplantation, by administration to the transplant donor or transplant recipient, or by infusion of the tissues to be transplanted, particularly for kidney transplants, skin grafts, heart transplants, lung transplants, kidney transplants

ES 2 177 601 T3 cornea and liver transplants.

essays

Protection of the myocardium against ischemic injury is experimentally demonstrated by inducing infarction in a suitable test animal (eg baboon), followed by examination of injury-induced increases in enzyme levels [particularly creatine kinase "CK" (also known as creatine phosphokinase "CPK") and lactate dehydrogenase "LDH"]. It is accepted that the concentrations of these enzymes increase after myocardial injury (Galen et al., JAMA, 232, 145-147, 1975) and that such enzyme levels can be obtained by an experimental model under conditions that are adapted from that described by Alps et al. [Arzneim, Forsch Drug Res., 33, (1), 6, 868-876, 1983]. The actual measurement of enzyme levels is carried out using the Galen method [Med. Times, 105 (2), 89-99, 1977]. The compounds of formula I, exemplified by ranolazine, are active in reducing the levels of the CK and LDH enzymes determined by this assay.

Protection against myocardial ischemia can also be evaluated by its efficacy in preventing the ischemia-induced increase in the number of alpha-1 adrenoceptors in the myocardium. The alpha-1 adrenoreceptor population is known to increase in the ischemic myocardium (Heathers et al., Circulation Research, 61, 735-746, 1987). Alpha-1 adrenoreceptor antagonists have also been shown to have beneficial effects during ischemia in animal models (Wilbur et al., J. Cardivascular Pharmacol., 10, 96-106, 1987). Thus, agents that prevent ischemia-induced increase in alpha-1 adrenoreceptor density are beneficial during myocardial ischemia. The ability of the compounds of formula I, exemplified by ranolazine, to inhibit the ischemia-induced increase of alpha-1 adrenoreceptors in the myocardium is evaluated in the rat left ventricle using the ischemia model described by Allely et al. Brown (Br. J. Pharmacol., 95, 705P, 1988) and the method of Williams et al. (Cardiovascular Pharmacology, 3, 522, 1981) to measure the density of alpha-1 adrenoceptors. A detailed description is presented in Example 4.

The protection of skeletal muscles against damage resulting, for example, from major surgical practices, was evaluated experimentally in the same model used to evaluate its protective effects at the myocoardic level. To this end, skeletal muscle-specific isoenzymes CPK3 and LDH5 were tested as indications of injured muscle, according to the Galen method (Med. Times, 105 (2), 89-99, 1977).

The protection of the myocardium against the harmful effects of ischemia induced by open heart surgical interventions and by other cardiac surgical procedures, including cardioplegia, was evaluated using a modified method of the Langendorff method, which involves measuring the pH of the coronary effluent and the level lactate. These indicators are recognized as indicative of tissue damage induced by severe reduction of nutrient supply to the heart (Armiger et al., Biochem. Med., 29, 265-267, 1983; van Gilst et al., Archives of Pharmacol., suppl., 330, 161P, 1985). A detailed description is presented in Example 2.

The utility of the compounds of formula I, exemplified by ranolazine, in organ transplants is demonstrated by administering the test compound to pigs before a nephrectomy, and / or adding the compound to the fluid used for washing and storage of the organ and evaluating during a period of 14 days the functionality of transplanted kidneys. The improvement of renal function in treated animals was evaluated by measuring the glomerular filtration rate and also by the maximum levels of creatinine and urea in serum. Glomerular filtration is a well-established indicator of kidney function (see, for example, Mudge and Weiner in The Pharmacological Basis of Therapeutics, Goodman and Gilman, 879, 7th edition, 1985) and is generally evaluated by measuring inulin clearance and / or creatinine (Textbook of Medicine, 1088-93, 14^to edition, 1975 - Beeson and McDermott edition).

Cerebral ischemia is the result of a prolonged, localized or generalized reduction in blood flow to the brain. Such reduced blood flow can result from various pathological conditions, including cerebral venous inflammation and thrombosis, heart disease, changes in the blood (clotting, viscosity, anemia), or cardiac surgery. One of the indications of the lesions produced by cerebral ischemia is the increase of the isoenzyme creatine phosphokinase 1 (CPK1) in the plasma (Rossi et al., Am. J. Cardiol., 58 (13), 1236-1241, 1986) . Inhibition of the peripheral appearance of CPK1 is an indication of reduced injury caused to the brain by ischemia. This is demonstrated by administering a test compound prior to coronary artery ligation in the mandrel, by intravenous injection of a bolus followed by an infusion during the reperfusion period, as described by Alps et al., (Arzneim Forsch Drug Res., 33, (1), 6, 868-876, 1983).

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Administration

The administration of ranolazine in pure form or in an appropriate pharmaceutical composition can be carried out by any of the accepted forms of administration of agents that serve the same purpose. Thus, administration can be, for example, oral, nasal, parenteral or topical, including administration by infusion. Administration can be in the form of a solid, semi-solid or lyophilized powder, or in liquid dosage forms, such as, for example, tablets, suppositories, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments or the like. , preferably in dosage unit forms suitable for simple administration of exact dosages. The compositions will include a conventional pharmaceutical carrier or excipient and an effective amount of ranolazine or a pharmaceutically acceptable salt thereof, and may further include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Slow release and delayed release formulations to maintain constant or prolonged dosage levels are also useful in the present invention. Ranolazine can also be co-administered with other active agents, such as thrombolytic agents [especially TPA (Tissue Plasminogen Activator) or streptokinase] or antianginals (such as beta-blockers, including propanolol and timolol).

The preferred method of administration is parenteral, except for those cases in which the patient must be pretreated before surgery or when the patient must undergo therapy after acute episodes of ischemia (cases in which it may be preferable to administer oral composition).

Generally, depending on the intended mode of administration, pharmaceutically acceptable compositions will contain from about 1% to about 99% by weight of the pharmacoeutically active compound of this invention and 99% to 1% by weight of suitable pharmaceutical excipients. Preferably, the composition contained about 5% to 75% by weight of the pharmacoeutically active compound, with the remainder being suitable pharmaceutical excipients. In liquid and semi-solid formulations, the preferred maximum concentration of active ingredient is approximately 5 mg / ml.

Oral administration involves using a convenient daily dosing regimen that can be adjusted according to the degree of disease. For such oral administration, a pharmacoeutically acceptable, non-toxic composition is formed by incorporating any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, capsules, powders, slow release or delayed release formulations, and the like.

Preferably, the oral compositions will take the form of capsules or tablets and the composition contains, together with the active ingredient, a diluent such as lactose, sucrose, dicaolcium phosphate and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof, and the like.

The active compounds can be formulated into suppositories using, for example, about 0.5% to about 50% of active ingredient disposed in a carrier of polyethylene glycols (PEG) [for example, PEG 1000 (96%) and PEG 4000 (4%) )] or semisyntotic glycerides (Witepsol®, Suppocire®).

Another preferred form of administration is parenteral. Pharmacoeutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc. an active compound (about 0.5% to about 20%), as described above, and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form roast a solution or suspension.

For tissue preservation pending transplantation, an infusion solution is preferred. Such solutions include an active compound in a vehicle such as Eurocollins Solution (Fresenius, AG, Bad Homburg, vdH, Germany), University of Wisconsin Fluid (Kalayoglu, M. et al., The Lancet, 1988 i, 617), buffered sucrose with phosphate (see, for example, Example 7E) and hyperosmolar citrate (Ross et al. Transplantation, 1976, 498-501).

If desired, the pharmaceutical composition to be administered may also contain quantity5

ES 2 177 601 T3 des minors of non-toxic auxiliary substances, such as emulsifying or wetting agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art; See, for example, Remington's Pharmaceutical Sciences, 16th edition, (Mack Publishing Company, Easton, Pennsylvania, 1980). The composition to be administered may, in any case, contain an amount of active compound (s) in a pharmaceutically effective amount for the relief of the particular condition being treated when administered in accordance with the teachings of this invention.

Example 5 describes parenteral and oral formulations containing ranolazine. Such formulations should not be construed as limiting the invention. In particular, parenteral formulations can be provided as dilutions with perfusion fluids, dialysis fluids and / or fluids used to wash and store organs. The invention is also intended to encompass the possibility of associating ranolazine with other pharmaceutical agents, as co-prescription or by concomitant dissolution in fluids.

Dosage

Generally, ranolazine is administered in a therapeutically effective amount, that is, in a dose sufficient to effect treatment. The amount of active compound administered will, of course, depend on the patient treated, the patient's weight, the severity of the disease, the route of administration and the judgment of the prescribing physician. However, in the absence of sufficient time to weigh the above-mentioned factors in detail, for example, in emergency situations, effective intravenous dosages range from about 0.05 to about 5 mg / kg for bolus injection followed by an infusion that It ranges from about 0.3 to about 30 mg / kg.hour. Preferably, the intravenous bolus dosage ranges from about 0.1 to about 2.5 mg / kg and the infusion dosage ranges from about 1.5 to about 15 mg / kg.hour. For an average 70 kg man, the intravenous bolus will range from about 3.5 to about 350 mg, or preferably, from about 15 to about 105 mg. In other situations, the oral dosage is in the range of about 35 to about 1,400 mg per day, preferably about 70 to about 700 mg / day, for an average 70 kg man. For administration by infusion fluid, a concentration of about 0.001 to about 5 g per liter is used, preferably about 0.005 to about 2.5 g per liter, and most preferably about 0.005 to about 0.1 g per liter. ; The perfusion can continue from the donor tissue removal until it is used for transplantation. Examples

The following preparations and examples are provided to facilitate a more clear understanding and practice of the present invention by those skilled in the art. These should not be considered as a limitation of the scope of the invention, but merely as illustrative and representative thereof.

Example 1

Protection against cardiac ischemia

It is an adaptation of the model described by Alps, et al. (Arzneim. Forsch Drug Res .., 33, (1), 6,868-876, 1983).

Eight male baboons were anesthetized and then randomized into one of the following two groups:

Group A (control group)

Four animals were subjected to left anterior descending coronary artery (LAD) occlusion for 30 minutes, followed by a 5.5 hour reperfusion period. Venous plasma samples were taken before thoracotomy, before LAD ligation and were analyzed every hour during the reperfusion period to determine the levels of CPK2 and LDH1 isoenzymes.

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Group B (treated group)

As in group A, except that animals received a loading dose of ranolazine (500 micrograms / kg) intravenously 10 minutes before LAD ligation, followed by a continuous infusion of 50 micrograms / kg per minute for a 6-hour period from the moment of LAD ligation.

Results

Levels of the CPK2 isoenzyme in plasma remained below detection limits until the first hour after the infarction. The LDH1 levels in plasma were identical in the moments before the surgical intervention and the ligation (period before the infarction). The results, as presented in Table I, are expressed in international units of isoenzyme per liter of plasma.

TABLE I

<td>Group</td><td>Weather</td><td>Pre-Pre- Heart attack</td><td>1 hour after reperfusion</td><td>6 hours after reperfusion</td>

<td>Group of</td><td>CPK2</td><td>ND</td><td> 10,5</td><td> 232,8</td>

<td>control</td><td>LDH1</td><td> 52,7</td><td> -</td><td> 333,8</td>

<td>Group</td><td>CPK2</td><td>ND</td><td> 11,0</td><td> 28,5</td>

<td>rehearsed</td><td>LDH1</td><td> 53,0</td><td> -</td><td> 85,8</td>

As shown above, ranolazine strongly inhibited the release of CPK2 and LDH1, such a result being indicative of an effective protection of myocardial tissue against the damaging effects of ischemia.

Example 2

Protection of the myocardium during cardioplegia

This method has been described by Ferrandon et al., Br. J. Pharmacol., 93, 247P, 1988.

Male Sprague-Dawley rats were anesthetized with sodium pentobarbitone (50 mg / kg, intraperitoneally). After injecting heparin (200 units intravenously), the thorax was opened, the heart was removed with a section of the aorta attached to it, and then it was immersed in an ice-cold Krebs solution (118 mM NaCl, 4.55 KCl mM, 1.2 mM KH2SO4, 1.2 mM MgSO4, 11.0 mM glucose, 20.0 mM NaHCO3, 1.35 mM CaCl2, pH7.4). The heart was gently palpated to expel the blood. The hearts were then perfused with the above solution heated to 37 ° C and gassed with 95% O2 and 5% CO2 through the aorta (Langendorff model), using a peristaltic pump set to deliver 14 ml per minute. A microelectrode was inserted into the wall of the ventricular muscle and a reference electrode was placed in contact with the perfusion fluid 3 cm above the heart. The two electrodes were connected to a pH meter.

The hearts were perfused at 14 ml per minute for a period of 15 minutes to obtain a stable basal ventricular pH value. The aortic flow was then reduced to 1 ml per minute for 15 minutes, by decreasing the pumping speed. Then it went back to starting speed for 15 minutes. Coronary flow and ventricular pH values ​​were measured at 5 minute intervals. After returning to the initial flow rate, measurements were made at 30 seconds, one minute and 5 minutes. Coronary effluent samples were collected and stored on ice. Infusions of ranolazine (1 micromole) were started 10 minutes before reducing the flow rate, and continued with them for the rest of the experiment. At the end of the experiment, the aureicles were removed and the hearts were dried at 75 ° C for 2 days.

The biochemic determination of the released lactate in the coronary effluent was done using a spectrophotometric method. The amount of lactate contained in the samples was obtained by reference to a standard curve. Lactate release from the heart mass was calculated using the following formula:

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[lactate] (micromol / ml) x coronary flow (ml / min) heart dry weight (g)

The results are presented in Tables 2 and 3.

TABLE 2

PH modifications

<td></td><td>Before ischemia</td><td>After 10 minutes of perfusion low</td><td>PH drop</td>

<td>Controls</td><td> 7,36</td><td> 6,77</td><td> 0,59</td>

<td>Ranolazine</td><td> 7,38</td><td> 7,10</td><td> 0,28</td>

Thus, ranolazine inhibits ischemia-induced drop in pH by approximately 50%.

TABLE 3

Changes in lactate release *

<td>Group</td><td>2 min. before perfusion low</td><td>5 min. after perfusion low</td><td>15 min. after low perfusion</td><td>1 min. after reperfusion</td>

<td>Controls</td><td> 0,6</td><td> 3,34</td><td> 5,0</td><td> 17,4</td>

<td>1 micromole of</td><td></td><td></td><td></td><td></td>

<td>ranolazine</td><td> 1,2</td><td> 2,45</td><td> 2,5</td><td> 8,0</td>

* The values ​​are expressed in micromoles of lactate released per minute in the coronary effluent per 1 g of dried heart.

Thus, the compounds belonging to this invention clearly decreased the sequelae of low-flow perfusion.

Example 3

Protection against cerebral ischemia

The appearance of isoenzymes in the peripheral venous blood was determined according to experimental conditions according to example 1, except that the plasma samples were tested for the presence of CPK1. The results are shown in Table 4.

TABLE 4

CPK1 levels

<td>Group</td><td>Before surgery</td><td>6 hours after the heart attack</td>

<td>Control group</td><td> 18,8</td><td> 85,7</td>

<td>Treated group</td><td></td><td></td>

<td>with ranolazine</td><td> 19,9</td><td> 19,3</td>

The results are expressed in international units per liter of plasma, and clearly demonstrate the protective role played by ranolazine in cerebral ischemia.

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Example 4

Protection against myocardial ischemia

Sprague-Dawley rats were anesthetized with pentobarbitone and assisted by mechanical breathing with room air. A left lateral thoracotomy was then performed and the left anterior descending coronary artery (LAD) was occluded for a period of 30 minutes. Control animals held the ligation in place, but not tied.

Compounds (500 micrograms of ranolazine per kg, in saline vehicle) were administered intraperitoneally for 3 days (twice a day) plus 15 minutes before occlusion.

At the end of the ischemic period, the ischemic area of ​​the left ventricle was removed and analyzed to determine the density of the alpha-1-adrenoceptor according to the method described by Williams et al. (Cardiovascular Pharmacology, 3, 522, 1981). The apparent density of alpha-1-adrenoceptor was calculated in [³H] -prazosin 0.1 nM and the results were expressed in femtomols of receptors per mg of proteon, as shown in Table 5. These results demonstrate that ranolazine inhibits the increase in the density of alpha-1-adrenoceptor, induced by ischemia, in the left ventrocle of rats, and is therefore useful in preventing tissue damage resulting from myocardial ischemia.

TABLE 5

<td>Group</td><td>Vóa</td><td>Nuóm. of animals</td><td>density alpha-1</td>

<td>Control</td><td></td><td> 12</td><td> 8,65</td>

<td>Ischemia / Treated only with</td><td></td><td></td><td></td>

<td>saline vehicle</td><td></td><td> 12</td><td> 16,30</td>

<td>Ischemia / Treated with ranolazine</td><td>ip</td><td> 13</td><td> 11,20</td>

<td>Ischemia / Treated with ranolazine</td><td>iv</td><td> 9</td><td> 9,71</td>

<td>Ischemia / Treated with ranolazine</td><td>ip 3 days</td><td> 9</td><td> 8,33</td>

Example 5

Formulations

The following example illustrates the preparation of representative pharmaceutical formulations containing a compound of formula I, exemplified by ranolazine.

A. Intravenous formulation (low concentration)

<td>(Ranolazine)</td><td>5.0 mg</td><td>0.5 g</td>

<td>Dextrose monohydrate</td><td>51.2 mg</td><td>5.1 g</td>

<td>Sodium hydroxide csp</td><td>pH 4</td><td>pH 4</td>

<td>Water for injections up to</td><td>1.0 ml</td><td>100 ml</td>

B. Intravenous formulation (high concentration)

<td>(Ranolazine)</td><td>20.0 mg</td><td>2 g</td>

<td>Dextrose monohydrate</td><td>39.4 mg</td><td>4 g</td>

<td>Sodium hydroxide csp</td><td>pH 4</td><td>pH 4</td>

<td>Water for injections up to</td><td>1.0 ml</td><td>100 ml</td>

ES 2 177 601 T3

To prepare intravenous formulations, ranolazine and dextrose monohydrate are dissolved in water (70 percent of the desired final volume), then sodium hydroxide (10N solution) is added, with stirring, to pH 4, and the volume is made up to 100 ml with water. The medium is filtered through a 0.2 micrometer membrane filter and packaged in ampoules or vials under sterile conditions. Alternatively, the medium can be filtered under non-sterile conditions, packaged in ampoules, and then sterilized in an autoclave.

C. Formulation of film-coated tablets

<td>Ingredients</td><td>Parts by weight</td>

<td>Ranolazine HCl (A)</td><td> 80,0</td>

<td>Microcrystalline cellulose (B)</td><td> 16,5</td>

<td>Polyvinylpyrrolidone (C)</td><td> 1,0</td>

<td>Croscaramellose sodium (D)</td><td> 2,0</td>

<td>Magnesium stearate (E)</td><td> 0,5</td>

(A), (B) and half of (D) are mixed and then (C) and water are added to allow wet granulation. Finally (E) and the remaining part of (D) are added. After careful mixing, the granulated mixture is dried and tableted containing up to 250 mg of active compound, and the tablets are film coated using White Opadry® following suitable techniques.

D. Controlled release formulation

<td>Ingredients</td><td>Parts by weight</td>

<td>Ranolazine base (A)</td><td> 90</td>

<td>Microcrystalline cellulose (B)</td><td> 10</td>

The two aforementioned ingredients are dry mixed and then water is added to form a suitable huomer mass for extrusion and subsequent spheronization (0.5 to 1.4 mm). The microspheres are coated with appropriate release controlling polyomers and then packed into hard capsules containing up to 250 mg of active ingredient per unit.

E. Perfusion fluid

<td>Ingredients</td><td>Parts by weight</td>

<td>Ranolazine</td><td>20 mg</td>

<td>Phosphate Buffered Sucrose</td><td></td>

<td>Saccharose</td><td>48.0 g</td>

<td>Sodium dihydrogen phosphate</td><td>4.59 g</td>

<td>Sodium monohydrogen phosphate</td><td>6.53 g</td>

<td>Water for injections (USP)</td><td>qs 1,000 ml</td>

The ingredients are dissolved in a portion of water for injections and, once dissolved, the remaining volume is made up with water for injections.