Parenteral formulations of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine

Abstract: A pharmaceutical formulation suitable for parenteral (preferably intravenous) administration includes an effective amount of 1-diphenylmethyl-4-[(2-(4-methyl­ phenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine and a suitable amount of an acid to generate a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4.0 mg/ml. The intravenous formulation optionally includes a suitable tonicifier in a quantity sufficient to achieve isotonicity with body fluids. The salt is formed in situ during the formulation process. The salt of tartaric acid is preferred; suitable salts for lower concentration dosages are the citric acid and methane sulphonic acid salts.

Description: The present invention relates to parenteral formulations of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine as a pharmaceutically acceptable salt, particularly to intravenous formulations with the tartrate salt thereof. The formulations are suitable for treating mammals having any of a variety of disease states including: diseases treated by direct neuronal protection via inhibition of sodium ion and/or by type 3-specific calcium channel antagonists, such as ischemia including focal and global ischemia, spinal injuries, head trauma, and neurological diseases such as Alzheimer's and Huntington's chorea; diseases treated by inhibition of sodium ion such as uraemic and hyponatraemic encephalopathy; and diseases treated with calcium channel antagonists, including: diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and ischemia of lower legs due to peripheral vascular disease, e.g., intermittent claudication; spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis and irritable bowel syndrome; and uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis or post operative hypertension, by parenteral administration of a formulation of the invention. 1-Diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, is a potent calcium channel antagonist, having activity for treating a variety of disease states in mammals. It is often preferred to administer such active agents via the parenteral route. However, when initial attempts were made to prepare formulations suitable for intravenous administration, it was discovered that this compound exhibited significant solubility problems, particularly at physiological pH, both in the formulation process and upon administration to test animals. It was, therefore, desired to develop a stable, soluble, physiologically and clinically acceptable solution containing 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine or a pharmaceutically acceptable salt thereof, suitable for administration by intravenous or other parenteral routes, and compatible with a wide variety of infusion fluids. In animal testing with a 8 mg/ml solution of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, trihydrochloride, adjusted to a pH of about 3 to 3.5 with sodium hydroxide, compound precipitation was observed in rat tail veins shortly after injection. This was evidenced by bruising of the vein, hardening of the tail and other signs of pain upon injection. This finding was verified by slowly dropping approximately 1 ml of the injectable formulation into 50 ml of 0.1M pH 7.4 phosphate buffer, whereupon a white precipitate was observed immediately at the interface between the two liquids. Experiments with a variety of aqueous miscible cosolvents commonly used to improve the solubility of parenteral products [for example, various mixtures of polyethylene glycol (PEG 300), propylene glycol (PG) and ethanol], achieved limited increase in the solubility of the active agent. However, all of the resulting solutions showed excessive irritation upon tail vein injection in rats. The tartrate salt proved to be a deliquescent compound, thus making it less than optimum to use the salt of the compound itself in the preparation of the formulation. Other salts were investigated with the aim of producing adequate solubility at a physiologically acceptable pH and a reduction in irritancy upon administration. The aspartic, fumaric, phosphoric and glutamic acid salts showed only moderate changes in properties, and were quite difficult to prepare. Acetic, maleic, malonic, oxalic and succinic acid salts did not have adequate solubility. The ascorbic acid salt was also relatively insoluble, and solutions showed rapid discolouration upon standing. The sulfuric acid salt was tried, but rejected as physiologically unacceptable due to its low pH (1.76) in solution. The citric and methanesulphonic acid salts were tested, showing better solubilities (in excess of about 4 mg/ml) but minor irritation upon tail vein injection. These formulations were outside the optimum pH range for physiological compatibility when prepared at the desired concentrations. The citrate and methanesulphonate salts are acceptable for lower concentrations than those optimally preferred for the present invention. Surprisingly, it was discovered that only the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine provides the full combination of properties desired in such a parenteral formulation. It gives a pH of greater than about 3.0, and has a solubility of greater than 4.0 mg/ml. The solution is physically and chemically stable over at least 12 months storage at 25°C and is compatible with a wide range of commercially available infusion fluids. Acceptable irritancy levels were demonstrated over a one week tail vein injection trial, and successful administration to both rats and baboons has been demonstrated over 28 days. The problem is to prepare a formulation containing the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine which provides a pH greater than about 3.0, a solubility of greater than 4.0 mg/ml, a low irritancy level, and is physically and chemically stable. One aspect of the present invention is a parenteral formulation containing the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)- methyl]piperazine which provides a pH greater than about 3.0, a solubility of greater than 4.0 mg/ml, a low irritancy level, and is physically and chemically stable. Another aspect of the present invention is a parenteral formulation of the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine made by mixing 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine , tartaric acid, a tonicifier, and water. The formulations are suitable for treating mammals having any of a variety of disease states including: diseases treated by direct neuronal protection via inhibition of sodium ion and/or by type 3-specific calcium channel antagonists, such as ischemia including focal and global ischemia, spinal injuries, head trauma, and neurological diseases such as Alzheimer's and Huntington's chorea; diseases treated by inhibition of sodium ion such as uraemic and hyponatraemic encephalopathy; and diseases treated with calcium channel antagonists, including: diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and ischemia of lower legs due to peripheral vascular disease, e.g., intermittent claudication; spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis and irritable bowel syndrome; and uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis or post operative hypertension, especially for treating ischemia in a mammal, by parenteral (particularly intravenous) administration, to a mammal in need of such treatment, of a therapeutically effective amount of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine tartrate in a formulation suitable therefor. Still another aspect of the present invention involves a method for preparing the formulations of the present invention by the in situ formation of a pharmaceutically acceptable salt having the desired pH and solubility characteristics for parenteral administration. Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. 1-Diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine has the following formula: As used herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms. As used herein, the term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%). As used herein, the term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected. The Formulations The formulations of the present invention include an effective amount of a pharmaceutically acceptable salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine which has been prepared by mixing an effective amount of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine and a suitable amount of an acid for generating a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4.0 mg/ml. The parenteral formulation optionally includes a suitable tonicifier in a quantity sufficient to achieve isotonicity with body fluids. Other optional pharmaceutically acceptable ingredients, such as stabilizing agents, preservatives, buffers, and the like (all of which are typically commercially available or can be prepared by methods readily known to those skilled in the art) can also be employed. The formulations may include other medicinal and pharmaceutical agents. The balance of the formulation is made up with water. For intravenous administration, the formulation optionally includes an infusion fluid. The infusion fluid is selected from the group consisting of: dextrose 5%, sodium chloride 0.9%, dextrose 5% + sodium chloride 0.9%, sodium chloride 0.9% + potassium chloride 0.3%, dextrose 4% + sodium chloride 0.18% + potassium chloride 0.3%, manitol 20%, half strength compound sodium lactate, ringers, darrows, compound sodium lactate, Gentran 40, Gentran 40 + sodium chloride 0.9%, and Gentran 70 + dextrose 5%. The parenteral formulations are prepared as solutions incorporating the above-described ingredients within the following approximate ranges: the active Compound 0.1 to 10.0 mg/ml Acid 0.05 to 15.0 mg/ml Tonicifier none, or q.s. to achieve isotonicity with physiological fluids Water q.s. to 1 ml In a preferred injectable formulation, the ingredients are incorporated within the following approximate ranges: the active Compound 4.0 to 8.0 mg/ml Tartaric Acid 4.03 to 8.5 mg/ml Sorbitol 35 to 55 mg/ml Water q.s. to 1 ml In the presently preferred formulation, the ingredients are combined as follows: the active Compound 6.0 mg/ml Tartaric Acid 6.19 mg/ml Sorbitol 40.5 mg/ml Water q.s. to 1 ml The Active Agent 1-Diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine (the "compound") is made as described in EP-A-289,227. The Acids Tartaric acid, citric acid and methane sulphonic acid are all commercially available. They are employed in a molar ratio of about 3 parts of the acid to about one part of the compound, to generate, in situ , a pharmaceutically acceptable salt during the formulation process. Preferably, when tartaric acid is used it is used in 1 to 3 molar excess to the concentration of the compound. The product is preferably the di-tartrate or tri-tartrate salt. The Tonicifiers Tonicifiers optionally useful in the formulations of the present invention include, e.g. , dextrose, potassium chloride, sodium chloride, sorbitol, and manitol, preferably sorbitol. Other Optional Ingredients The formulations are water based solutions, and may include other conventional pharmaceutical carriers or excipients, adjuvants, buffers and pH adjusting agents (e.g., NaOH), and in addition, other medicinal and pharmaceutical agents, and the like. For example, in methods of treating stroke, particularly acute ischemic stroke, the active compound can be co-administered with one or more agents active in reducing the risk of stroke, such as aspirin or ticlopidine (preferably ticlopidine, which has been demonstrated to reduce the risk of a second ischemic event). Preparation The formulations of the present invention are prepared by placing an amount of acid calculated to generate a pharmaceutically acceptable salt having the desired pH and solubility characteristics into a suitable vessel and dissolving it with water, adding an amount of the compound sufficient to achieve the desired concentration, adding an amount of tonicifier calculated to render the resulting formulation isotonic with body fluids, adding the amount of water necessary to bring the total volume to the desired concentration, and combining the ingredients. The procedure is carried out from about 15°C to about 50°C, preferably at about room temperature, and at atmospheric pressure. The resulting formulation is transferred to unit dosage containers (such as bottles or ampoules or prefilled syringes) for storage prior to use. The formulations can be used as prepared or are administered by preparing a liquid pharmaceutically administerable composition, for example, by dissolving, dispersing, etc. the formulation (prepared as described above) in a carrier, such as, for example, an infusion fluid. Infusion fluids suitable for use with the formulations of the present invention, and demonstrated to be compatible therewith, include: dextrose 5%; sodium chloride 0.9%; dextrose 5% + sodium chloride 0.9%; sodium chloride 0.9% + potassium chloride 0.3%; dextrose 4% + sodium chloride 0.18% + potassium chloride 0.3%; manitol 20%; half strength compound sodium lactate; ringers; darrows; compound sodium lactate; Gentran 40; Gentran 40 + sodium chloride 0.9%; and Gentran 70 + dextrose 5%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pennsylvania, 16th Ed., 1980. The composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated in accordance with the teachings of this invention. Administration 1-Diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine is administered at a therapeutically effective dosage, i.e., a dosage sufficient to provide treatment for the disease states previously described. Administration of the formulations of the present invention is by parenteral route, preferably intravenous injection. If by intravenous injection, the formulation is preferably dispersed in an acceptable infusion fluid. Dosage Generally, a daily dose of from 0.02 to 50 mg/kg of body weight per day of the compound. Most conditions respond to treatment comprising a dosage level in the order of 0.1 to 4 mg/kilogram of body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 1.4 to 3500 mg per day, preferably about 7.0 to 280 mg per day. In the formulation of the present invention, the amount of the pharmaceutically acceptable salt administered is sufficient to provide the above daily dose of the compound. Utility, Testing and Administration General Utility The formulations of the present invention are useful for treating mammals having a variety of disease states including: diseases treated by direct neuronal protection via inhibition of sodium ion and/or by type 3-specific calcium channel antagonists, such as ischemia including focal and global ischemia, spinal injuries, head trauma, and neurological diseases such as Alzheimer's and Huntington's chorea; diseases treated by inhibition of sodium ion such as uraemic and hyponatraemic encephalopathy; and diseases treated with calcium channel antagonists, including: diseases treated by inhibiting cerebrovascular vasospasm and by cerebrovascular vasodilation, such as migraine, stroke, vasospasm due to subarachnoid hemorrhage, epilepsy or epileptic psychotic symptoms, and cerebrovascular ischemia induced by cocaine abuse; and cardiovascular diseases, such as hypertension, angina, stable and unstable angina, Prinzmetal angina, arrhythmia, thrombosis, embolism, and congestive heart failure such as chronic or acute cardiac failure; and ischemia of lower legs due to peripheral vascular disease, e.g. , intermittent claudication; spasms of smooth muscle: such as the ureter, the bladder, uterine cramps, diuresis and irritable bowel syndrome; and uses during surgery: such as bypass grafts, angiography, angioplasty, organ preservation during transplant, hypertensive crisis or post operative hypertension. Testing The efficacy of the compound is known, as reported in EP-A-289,227. Stability testing of the formulations is done, for example, as described in Remington's Pharmaceutical Sciences , "Stability of Pharmaceutical Products," Chapter 81, Mack Publishing Company, Easton, Pennsylvania, 15th Ed., 1975. A formulation is prepared and placed in a suitable container, storing it at 25°C, and periodically observing the appearance of the samples and removing aliquots to be tested for concentration and pH. Compatibility with infusion fluids is determined by adding a formulation of the invention to an infusion fluid and inspecting the resulting mixture for formation of any precipitate, discoloration, or the appearance of other physical changes, monitoring the solution active ingredient concentration to ensure no loss in potency, which could lead to decreases in efficacy. In vivo acceptability is tested by injecting a small amount of the formulation into the tail vein of a rat or other suitable species, for example, as described by Waynforth, Experimental and Surgical Technique in the Rat , Chapter 2, pages 42-45 (Academic Press, 1980). EXAMPLES The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. EXAMPLE 1 This example illustrates the preparation of a representative pharmaceutical formulation containing a pharmaceutically acceptable salt of 1-diphenylmethyl-4-[(2-(4-methyl-phenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine. An injectable preparation is prepared having the following composition: The acid is added to a vessel and dissolved in water, followed by the addition of the compound, sorbitol, and water sufficient to bring the total volume to 1 ml. EXAMPLE 2 This example illustrates the preparation of a preferred pharmaceutical formulation containing a pharmaceutically acceptable salt of 1-diphenylmethyl-4-[(2-(4-methyl-phenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine as the active compound. An injectable preparation is prepared having the following composition: The acid is added to a vessel and dissolved in water, followed by the addition of the compound, sorbitol, and water sufficient to bring the total volume to 1 ml. Injectable preparations may be prepared containing lower concentrations of the compound by substituting citric acid or methane sulphonic acid for tartaric acid. EXAMPLE 3 Stability Testing This procedure is a modification of a procedure well known to those skilled in the art, for example, as described in Remington's Pharmaceutical Sciences , "Stability of Pharmaceutical Products," Chapter 81, Mack Publishing Company, Easton, Pennsylvania, 15th Ed., 1975. A formulation prepared in accordance with the teachings of Example 2 was transferred to 1ml glass ampoules and placed in an incubator at 25°C. At periodic intervals, the appearance of the samples was noted, and aliquots were withdrawn and assayed for compound concentration and pH. The results are reported below: The formulations of the present invention show acceptable stability when tested by this method. EXAMPLE 4 Determination of Irritation Utilizing The Rat Tail Vein Injection This procedure is a modification of a procedure described by Waynforth in Experimental and Surgical Technique in the Rat , Chapter 2, pages 42-45 (Academic Press, 1980). The rat tail vein is dilated by warming, and a test formulation administered by injection, using a 25G needle, with the rat held in a restrainer, and a heat source close enough to keep the tail warm during injection. The tail is observed for signs of irritation, which are outwardly apparent and can be detected by the presence of bruising, swelling, lack of flexibility, lumps, or by observation of distress in the animal upon subsequent administration. The formulations of the present invention show acceptable levels of irritation when tested by this method, as shown in the below table. The terms "Gentran 40" and "Gentran 70" one trade marks.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A pharmaceutical formulation suitable for parenteral administration, comprising: 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, tartaric acid, a tonicifier, and water. The formulation of Claim 1 wherein said tonicifier is sorbitol. The formulation of Claim 1 comprising a therapeutically effective amount of a second compound, said second compound being active in reducing the risk of stroke. The formulation of Claim 3 wherein said second compound is aspirin or ticlopidine. The formulation of Claim 4 wherein said second compound is ticlopidine. A pharmaceutical formulation suitable for parenteral administration, comprising: an effective amount of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, an acid, selected from tartaric acid, citric acid, or methane sulphonic acid, in an amount suitable for generating a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4.0 mg/ml, water, and optionally, a tonicifier in a quantity of a sufficient to achieve isotonicity with body fluids. The formulation of Claim 6 wherein said acid is tartaric acid. The formulation of Claim 6 wherein said tonicifier is sorbitol. The formulation of Claim 7 wherein said tonicifier is sorbitol. The formulation of Claim 6, comprising: the active Compound 0.1 to 10.0 mg/ml, Acid 0.05 to 15.0 mg/ml, Tonicifier none, or q.s. to achieve isotonicity with physiological fluids, and Water q.s. to 1 ml. The formulation of Claim 6, comprising: the active Compound 4.0 to 8.0 mg/ml, Tartaric Acid 4.03 to 8.05 mg/ml, Sorbitol 35 to 55 mg/ml, and Water q.s. to 1 ml. The formulation of Claim 6, comprising: the active Compound 6.0 mg/ml, Tartaric Acid 6.19 mg/ml, Sorbitol 40.5 mg/ml, and Water q.s. to 1 ml. The formulation of Claim 6 comprising an infusion fluid suitable for intravenous administration. The formulation of Claim 13 wherein said infusion fluid is selected from the group consisting of: dextrose 5%, sodium chloride 0.9%, dextrose 5% + sodium chloride 0.9%, sodium chloride 0.9% + potassium chloride 0.3%, dextrose 4% + sodium chloride 0.18% + potassium chloride 0.3%, manitol 20%, half strength compound sodium lactate, ringers, darrows, compound sodium lactate, Gentran 40, Gentran 40 + sodium chloride 0.9%, and Gentran 70 + dextrose 5%. A pharmaceutical formulation suitable for parenteral administration and which exhibits low irritancy comprising an effective amount of a pharmaceutically acceptable salt selected from tartrate, citrate, or methanesulphonate of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, a tonicifier, and water, the solubility of said salt being above about 4 mg/ml. The formulation of Claim 15 wherein the said formulation has a pH above about 3. The formulation of Claim 15 wherein the said pharmaceutically acceptable salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine is generated in the process of formulation by mixing 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine and tartaric acid, citric acid, or methanesulphonic acid. The formulation of Claim 15 wherein the said tonicifier is selected from dextrose, potassium chloride, sodium chloride, sorbitol, and manitol. The formulation of Claim 18 wherein the said tonicifier is sorbitol. The formulation of Claim 15 comprising an infusion fluid suitable for intravenous administration. The formulation of Claim 20 wherein said infusion fluid is selected from the group consisting of: dextrose 5%, sodium chloride 0.9%, dextrose 5% + sodium chloride 0.9%, sodium chloride 0.9% + potassium chloride 0.3%, dextrose 4% + sodium chloride 0.18% + potassium chloride 0.3%, manitol 20%, half strength compound sodium lactate, ringers, darrows, compound sodium lactate, Gentran 40, Gentran 40 + sodium chloride 0.9%, and Gentran 70 + dextrose 5%. Use of a pharmaceutically acceptable salt selected from tartrate, citrate or methanesulphonate of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 -yl)methyl]piperazine in the manufacture of a medicament for parenteral administration to treat diseases by direct neuronal protection via inhibition of sodium ion and/or type 3-specific calcium channel antagonists. Use of: 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine; an acid, selected from tartaric acid, citric acid, or methane sulphonic acid, in an amount suitable for generating a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4 mg/ml; water; and, optionally, a tonicifier in a quantity sufficient to achieve isotonicity with body fluids; in the manufacture of a medicament for parenteral administration for treatment of stroke in a mammal. A use according to claim 23 wherein the medicament is for parenteral administration by intravenous injection. A use according to claim 23 further comprising use of an additional compound active in reducing the risk of stroke. Use according to claim 25 wherein said additional compound is aspirin or ticlopidine. Use according to claim 26 wherein said second compound is ticlopidine. A method of producing a stable, soluble physiologically and clinically acceptable solution of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine, suitable for parenteral administration, comprising: placing an excess of tartaric acid to a vessel, and dissolving it with water; adding 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine to the vessel, in an amount calculated to give a desired concentration; optionally, adding an amount of a tonicifier suitable to render the resulting solution isotonic with physiological fluids; and adding water in a quantity sufficient to achieve the desired concentration; thereby generating, in situ , a solution of the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine. The process of Claim 28 wherein the said tartaric acid is used in 1 to 3 molar excess to the concentration of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]-piperazine. The process of Claim 28 wherein the said tartrate salt prepared is the di-tartrate salt. The process of Claim 28 wherein the said tartrate salt prepared is the tri-tartrate salt. Claims for the following Contracting States : ES, GR A method for preparing a pharmaceutical composition comprising a pharmaceutically acceptable salt, selected from tartrate, citrate or methane sulphonate, of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, a tonicifier, and water, the method comprising generating the salt by reacting 1-diphenylmethyl -4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine with tartaric, citric or methane sulphonic acid, and formulating the composition. A method according to claim 1 wherein said acid is tartaric acid. The method of claim 1 or claim 2 wherein said tonicifier is sorbitol. The method of claim 2 further comprising including a therapeutically effective amount of a second compound, said second compound being active in reducing the risk of stroke. A method of claim 4 wherein said second compound is aspirin or ticlopidine. The method of claim 5 wherein said second compound is ticlopidine. A method of production of a pharmaceutical formulation suitable for parenteral administration, comprising combining: an effective amount of the compound 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl )methyl]piperazine, an acid, selected from tartaric acid, citric acid, or methane sulphonic acid, in an amount suitable for generating a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4.0 mg/ml, water, and optionally, a tonicifier in a quantity sufficient to achieve isotonicity with body fluids. The method of claim 7 wherein said acid is tartaric acid. The method of claim 7 wherein said tonicifier is sorbitol. The method of claim 8 wherein said tonicifier is sorbitol. The method of claim 7, wherein the formulation comprises the active Compound 0.1 to 10.0 mg/ml, Acid 0.05 to 15.0 mg/ml, Tonicifier none, or q.s. to achieve isotonicity with physiological fluids, and Water q.s. to 1 ml. The method of claim 7 wherein the formulation comprises the active Compound 4.0 to 8.0 mg/ml, Tartaric Acid 4.03 to 8.05 mg/ml, Sorbitol 35 to 55 mg/ml, and Water q.s. to 1 ml. The method of claim 7 wherein the formulation comprises the active Compound 6.0 mg/ml, Tartaric Acid 6.19 mg/ml, Sorbitol 40.5 mg/ml, and Water q.s. to 1 ml. The method of claim 1 or claim 7 wherein the formulation further comprises an infusion fluid for intravenous administration. The method of claim 14 wherein said infusion fluid is selected from the group consisting of: dextrose 5%, sodium chloride 0.9%, dextrose 5% + sodium chloride 0.9%, sodium chloride 0.9% + potassium chloride 0.3%, dextrose 4% + sodium chloride 0.18% + potassium chloride 0.3%, manitol 20%, half strength compound sodium lactate, ringers, darrows, compound sodium lactate, Gentran 40, Gentran 40 + sodium chloride 0.9%, and Gentran 70 + dextrose 5%. The method of claim 1 wherein the said tonicifier is selected from dextrose, potassium chloride, sodium chloride, sorbitol, and manitol. Use of a pharmaceutically acceptable salt selected from tartrate, citrate, or methanesulphonate of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine in the manufacture of a medicament for parenteral administration to treat diseases by direct neuronal protection via inhibition of sodium ion and/or type 3-specific calcium channel antagonists. Use of: 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine; an acid, selected from tartaric acid, citric acid, or methane sulphonic acid, in an amount suitable for generating a pharmaceutically acceptable salt having a pH above about 3.0 and a solubility above about 4 mg/ml; water; and, optionally, a tonicifier in a quantity sufficient to achieve isotonicity with body fluids; in the manufacture of a medicament for parenteral administration for treatment of stroke in a mammal. A use according to claim 18 wherein the medicament is for parenteral administration by intravenous injection. A use according to claim 18 further comprising use of an additional compound active in reducing the risk of stroke. Use according to claim 20 wherein said additional compound is aspirin or ticlopidine. Use according to claim 21 wherein said second compound is ticlopidine. A method of producing a stable, soluble physiologically and clinically acceptable solution of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine, suitable for parenteral administration, comprising: placing an excess of tartaric acid to a vessel, and dissolving it with water; adding 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine to the vessel, in an amount calculated to give a desired concentration; optionally, adding an amount of a tonicifier suitable to render the resulting solution isotonic with physiological fluids; and adding water in a quantity sufficient to achieve the desired concentration; thereby generating, in situ , a solution of the tartrate salt of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine. The process of claim 23 wherein the said tartaric acid is used in 1 to 3 molar excess to the concentration of 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine. The process of claim 23 wherein the said tartrate salt prepared is the di-tartrate salt. The process of claim 23 wherein the said tartrate salt prepared is the tri-tartrate salt.

Inventors: DEY, MICHAEL J., SELKIRK, ALASTAIR B.
Applicants: SYNTEX PHARMACEUTICALS LTD.
Application year: 1989
Main classification: A61K47
IPC codes: A61P9, A61K47, A61K31, A61K9, A61P13, A61P25, A61P15