Patent Application
20080200479
The invention relates to new salts of ocaperidone and uses thereof, particularly in the pharmaceutical industry. The invention discloses specific salts of ocaperidone having increased water solubilities, as well as therapeutic methods by administering said salts, in particular for treating various diseases of the central or peripheral nervous system, especially central nervous system. It further deals with pharmaceutical compositions comprising said salts and methods for preparing the same.
European patent no 0453042 describes the 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-pyrido-[1,2-a]pyrimidin-4-one also known as ocaperidone, a potent dopaminergic compound having particularly interesting antipsychotic properties. It has been described as an antagonist of neurotransmitters and in particular dopamine and serotonin. Therapeutic indications for using ocaperidone therefore are mainly in the CNS area, particularly as a potent antipsychotic agent and more specifically for treating acute psychoses including schizophrenia, obsessive compulsive disorder (OCD), bipolar depression, and Tourette syndrome. Indeed, its combined dopamine-serotonin antagonism properties are especially interesting as they offer relief of both the positive and negative symptoms of schizophrenia.
Ocaperidone presents the following formula (I):
In view of its useful pharmacological properties, the subject compound is a candidate as a pharmacologically active ingredient. Water solubility is an essential parameter for the absorption of drugs and usually readily solubilized compounds are better absorbed by passive diffusion in the gastro-intestinal track. Unfortunately, ocaperidone as a free base form is poorly soluble in water (0.0007 g/100 ml) and also in acid solution (0.25 g/100 ml at pH=1.3), which may result in variability in bioavailability. Acid addition salts of ocaperidone due to their increased water solubility may be advantageous over the corresponding base form in the preparation of pharmaceutical compositions.
The Applicant has now found that particular salts of ocaperidone can be obtained in well defined reproducible amorphous and/or crystalline forms that especially exhibit valuable characteristics for formulation. The present invention deals with specific salts of ocaperidone which show very interesting water solubilites, in particular of at least 2.5 mg/ml. The use of such a salt form in the formulation of ocaperidone may give rise to a reduction in the variability of bioavailability from an improvement in absorption and less variability in plasma levels.
The present invention relates to unexpected soluble (1:1) salts of ocaperidone in amorphous and/or crystalline forms, including all polymorphs forms of the salts. The salt of the present invention presents an organic acid moiety.
More specifically, the ocaperidone salt according to the invention presents an acid moiety which is selected from pyroglutamic acid, N-(2-carboxyphenyl)-glycine acid, diglycolic acid, orotic acid, galactaric acid, nicotinic acid and hippuric acid. In a preferred embodiment, the acid moiety is selected from pyroglutamic acid, nicotinic acid and hippuric acid.
According to the invention, the acid moiety, in particular pyroglutamic acid, is in the D- or L-form, if existent, or mixture thereof; more particularly the L-form, most preferably L-pyroglutamic acid form.
Ocaperidone salts presenting an acid moiety selected from succinic acid, fumaric acid, tartaric acid, pyroglutamic acid, N-(2-carboxyphenyl)-glycine acid, diglycolic acid, orotic acid, galactaric acid, nicotinic acid and hippuric acid were made for comparison. As shown in more detail below, the ocaperidone salt solubility study shows that L-pyroglutamic acid addition salt is respectively 31.2 times more soluble than the succinic acid addition salt which is again some 357 times more soluble than the ocaperidone free base form.
The compound according to the present invention may be prepared by various methods known to those skilled in the art. However, the ocaperidone salt of the invention is generally prepared by dissolution of ocaperidone and the organic acid as defined above, preferably in stoichiometric proportion, and advantageously in an organic solvent, for example, dichloromethane, methanol, ethanol, tetrahydrofuran, ethyl acetate, ethers or mixture thereof. The temperature of the process can vary over a wide range, preferably between 0° C. and the boiling temperature of the solvents used. When the salt is prepared, after a time comprised between a few seconds and several days, a crystalline product precipitates which can be isolated or collected by filtration, then can be washed with a cold (i.e. from 0° C. to 25° C.) organic solvent (preferably the same used for the crystallization step) and finally dried, preferably under vacuum.
In the crystallisation process according to the invention, it is possible to use the compound of Formula (I), in particular as free base form, obtained by any process. Advantageously, the compound of Formula (I) as a free base form is obtained by the preparation process described in patent specification EP 0453042.
In a particular embodiment of the process according to the invention, the concentration of ocaperidone in the solvent is preferably from 10-200 g/litre. The concentration of ocaperidone is preferably close to saturation.
It should be understood that other methods of producing the compound of the invention may be designed by the skilled person, based on common general knowledge and following guidance contained in this application.
According to a particular embodiment, the present invention relates to L-pyroglutamic acid addition salt of Formula (II). The salt of Formula (II) can be in amorphous and/or crystalline forms including all polymorphs of this compound.
Formula (II) is as follows:
More specifically, the present invention relates to the crystalline form of the compound of formula (II), characterised by the powder X-ray diffraction diagram (see table (1) below), measured using an X-ray diffractometer (DRX) Rigaku Miniflex (copper anticathode) and expressed in terms of inter-planar distance d (Å), Bragg's angle 2 theta (°), intensity (I) and relative intensity (expressed as a percentage of the most intense ray=Io):
In a similar manner, the nicotinic acid addition salt of ocaperidone (Formula (III)) was also prepared. The salt of Formula (III) can be in amorphous and/or crystalline forms including all polymorphs of this compound.
Formula (III) is as follows:
More specifically, the crystalline form of compound of formula (III) is characterised by the powder X-ray diffraction diagram (see table (2) below), measured using an X-ray diffractometer (DRX) Rigaku Miniflex (copper anticathode) and expressed in terms of inter-planar distance d (Å), Bragg's angle 2 theta (°), intensity and relative intensity (expressed as a percentage of the most intense ray):
In a similar manner, the hippuric acid addition salt of ocaperidone (Formula (IV)) was also prepared. The salt of Formula (IV) can be in amorphous and/or crystalline forms including all polymorphs of this compound.
Formula (IV) is as follows:
Accordingly, the N-(2-carboxyphenyl)-glycine acid, diglycolic acid, orotic acid, or galactaric acid addition salts of ocaperidone were also prepared. Said salts can be in amorphous and/or crystalline forms including all polymorphs of this compound.
The present invention also relates to pharmaceutical compositions comprising at least one ocaperidone salt as defined above in a pharmaceutically acceptable vehicle or support, optionally in association with another active agent.
The pharmaceutical composition is more particularly intended to treat diseases of the central or peripheral nervous system, especially central nervous diseases, including psychosis. The present salt is particularly effective in treating acute psychoses including schizophrenia, obsessive compulsive disorder (OCD), bipolar depression, anxiety, mania, and Tourette syndrome. The present salt is more particularly effective in treating schizophrenia, including positive and negative symptoms of schizophrenia, e.g. anergy, apathy, social withdrawal and depressive mood, and also appear to reduce the incidence of extrapyramidal side-effects during maintenance therapy with classical neuroleptics, i.e. dopamine antagonists.
The present invention also relates to the use of an ocaperidone salt as defined above, for the preparation of a pharmaceutical composition for the treatment of diseases of the central or peripheral nervous system, in particular for the treatment of diseases as specified above.
The present invention also includes methods of treating diseases of the central or peripheral nervous system, in particular for the treatment of diseases as specified above, comprising the administration to a subject in need thereof of an effective amount of a ocaperidone salt as defined above.
As indicated above, a further object of this invention relates to a pharmaceutical composition comprising at least one ocaperidone salt as defined above, and a pharmaceutically acceptable vehicle or support.
The compound may be formulated in various forms, including solid and liquid forms, such as tablets, gels, syrups, powders, aerosols, etc. The ocaperidone salt can be formulated either in crystalline and/or amorphous forms.
The compositions of this invention may contain physiologically acceptable diluents, fillers, lubricants, excipients, solvents, binders, stabilizers, and the like. Diluents that may be used in the compositions include but are not limited to dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and for prolonged release tablet-hydroxy propyl methyl cellulose (HPMC). The binders that may be used in the compositions include but are not limited to starch, gelatin and fillers such as sucrose, glucose, dextrose and lactose.
Natural and synthetic gums that may be used in the compositions include but are not limited to sodium alginate, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and veegum. Excipients that may be used in the compositions include but are not limited to microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, and sucrose. Stabilizers that may be used include but are not limited to polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers and carboxymethyl chitin.
Solvents that may be used include but are not limited to Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids.
The dosages and dosage regimen in which the salts of the invention are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through experimentation.
The ocaperidone salt according to the invention can also be used enterally. The required dose can be administered in one or more portions. For oral administration, suitable forms are, for example, tablets, gels, aerosols, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using a suitable form containing approximately from 0.01 mg to about 1 mg of active substance per subject and day.
The compound according to the invention can also be administered parenterally in the form of solutions or suspensions for intradermal, intravenous infusions or intramuscular injections. In case in intravenous infusion, the compound according to the invention is generally administered at the rate of about 80 ng to 1000 ng per day (and to be infused within about an hour) per kg of body weight; a preferred method of administration consists of using i.v. solutions containing approximately from 0.25 μg to 3 μg of active substance per ml. In case of the intramuscular injection, the compound according to the invention is generally administered in a dose of approximately 0.6 μg to 5 μg per day per kg of body weight, a preferred method of administration would be to inject a volume of 1 ml containing approximately 30 μg to 300 μg.
For the compound of this invention, the dose to be administered, whether a single dose, multiple dose, or a daily dose, will of course vary with the chosen route of administration, the size of the recipient, the type of disease and the nature of the patient's condition. The dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects. A doctor skilled in the art for treating the disease will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compound of this present invention, such as by referring to the earlier published studies on compounds found to have effect on the disease to be treated. In general, it is contemplated that an effective antipsychotic amount of the active ingredient would be from about from 0.00002 mg/kg to about 0.009 mg/kg of body weight, in particular from about 0.0001 to about 0.009 mg/kg of body weight, preferably from about 0.0003 mg/kg to about 0.004 mg/kg body weight, more preferably from about 0.0004 mg/kg to about 0.002 mg/kg body weight. The required dose may advantageously be administered as one, two, three or more times at appropriate intervals throughout the day.
According to another aspect, the present invention relates to a method for the treatment of diseases of the central or peripheral nervous system, comprising administering to warm-blooded animals, in particular humans, in need of such treatment an effective amount of the ocaperidone salt as described above.
According to the invention, the term treatment denotes curative, symptomatic, and preventive treatment. Such ocaperidone salts, compositions comprising the same, or treatment can be implemented alone or in combination with other active ingredients, compositions or treatments. Moreover, it can correspond to treatment of chronic or acute disorders.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluents, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parental administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
In a particular embodiment, composition of the invention is suitably formulated for a topical administration in the mouth, for example buccally or sublingually. In this particular embodiment, the ocaperidone salt of the invention can be in a crystalline and/or amorphous form, it is more particularly in an amorphous state. Said buccal or sublingual formulations include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia or any other form adapted to immediate release of the active ingredient in the mouth.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers, such as cocoa butter or polyethylene glycol.
The relatively non-hygroscopic nature and the high solubility of the salts of ocaperidone of the invention render them particularly suitable for administration in liquid and solid form. Preferred unit dosage formulations are those containing an effective dose, as herein before recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may includes flavoring agents.
The invention is illustrated by the following examples. However, they are representative only and should not be construed as being limiting in any respect.
The powder X-ray diffraction spectrum was measured under the following experimental conditions:
Experimental data processed using MiniFlex Program Manager Vers. 3.1
NMR spectra were obtained at 300 MHz on a Bruker AV 300 instrument using deuterated solvents. Chemical shifts are given in ppm relative to an internal standard of the solvent (ex: 4.79 for D2O).
100 mg (0.237 mmol) of ocaperidone and 28 mg of succinic acid were dissolved in 15 ml of an ethanol/THF (9/1) solution. The precipitated crystalline product was filtered, washed with cold ethanol and dried. The ocaperidone succinate salt (1/1) thus obtained melts at 184-185° C. 1H NMR (300 MHz, CD3OD+D2O): 8.83 (d, 1H), 7.90 (dd, 1H), 7.77 (d, 1H), 7.38 (dd, 1H), 7.30-7.15 (m, 2H), 3.82 (brd, 2H), 3.64-3.52 (m, 1H), 3.37-3.29 (m, 3H), 3.23-3.14 (m, 2H), 2.58 (s, 3H), 2.53 (s, 3H), 2.46 (s, 4H), 2.46-2.38 (m, 2H), 2.33-2.18 (m, 2H). Analysis calculated for the formula: C28H31FN4O6: C, 62.44; H, 5.54; N, 11.09. Found: C, 62.24; H, 5.80; N, 11.40.
1 g (2.37 mmol) of ocaperidone and 357 mg of L-pyroglutamic acid were dissolved in 10 ml of boiling THF. The precipitated crystalline product was filtered, washed with cold THF and dried. The ocaperidone pyroglutamate (1/1) thus obtained melts at 173-175° C. 1H NMR (300 MHz, CD3OD+D2O): 8.79 (d, 1H), 7.89 (dd, 1H), 7.74 (d, 1H), 7.35 (dd, 1H), 7.21 (t, 1H), 7.18 (dt, 1H), 4.06 (dd, 1H), 3.82 (brd, 2H), 3.56 (brt, 1H), 3.40-3.25 (m, 4H), 3.20-3.12 (m, 2H), 2.56 (s, 3H), 2.50 (s, 3H), 2.47-2.36 (m, 3H), 2.35-2.20 (m, 3H), 2.08-1.95 (m, 1H). Analysis calculated for the formula C29H32FN5O5: C, 63.37; H, 5.67; N, 12.74. Found: C, 62.98; H, 5.91; N, 12.84.
Following example 1, using fumaric acid instead of succinic acid, ocaperidone fumaric acid salt was isolated. m.p.=204-206° C. 1H NMR (300 MHz, CD3OD+D2O): 8.81 (d, 1H), 7.86 (dd, 1H), 7.74 (d, 1H), 7.36 (d, 1H), 7.25-7.10 (m, 2H), 6.56 (s, 2H), 3.80 (brs, 2H), 3.54 (brs, 1H), 3.35-3.25 (m, 4H), 3.17-3.07 (m, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.46-2.34 (m, 2H), 2.29-2.12 (m, 2H). Analysis calculated for the formula C28H29FN4O6: C, 62.68; H, 5.45; N, 10.44. Found: C, 62.21; H, 5.77; N, 11.25.
Following example 1, using tartaric acid instead of succinic acid, ocaperidone tartaric acid salt was isolated. m.p.=200-202° C. 1H NMR (300 MHz, CD3OD+D2O): 8.79 (d, 1H), 7.83 (m, 1H), 7.75 (d, 1H), 7.36 (d, 1H), 7.25-7.10 (m, 2H), 4.32 (s, 4H), 3.85 (brs, 2H), 3.52 (brs, 2H), 3.35-3.25 (m, 4H), 3.17-3.07 (m, 2H), 2.53 (s, 3H), 2.50 (s, 3H), 2.46-2.34 (m, 2H), 2.29-2.12 (m, 2H).
Following example 2, using N-(2-carboxyphenyl)-glycine acid instead of L-pyroglutamic acid, ocaperidone N-(2-carboxyphenyl)-glycine acid salt was isolated. m.p.=184-186° C. 1H NMR (300 MHz, CD3OD+D2O): 8.80 (d, 1H), 7.86 (dd, 1H), 7.73 (m, 2H), 7.34 (dd, 1H), 7.26-7.10 (m, 3H), 6.54-6.43 (m, 2H), 3.74 (brs, 2H), 3.66 (s, 2H), 3.50 (brs, 1H), 3.17-3.07 (m, 2H), 2.53 (s, 3H), 2.48 (s, 3H), 2.43-2.32 (m, 2H), 2.25-2.13 (m, 2H). Analysis calculated for the formula: C33H34FN5O6: C, 64.38; H, 5.57; N, 11.38. Found: C, 64.10; H, 5.38; N, 12.13.
Following example 2, using diglycolic acid instead of L-pyroglutamic acid, ocaperidone diglycolic acid salt was isolated. m.p.=158-160° C. 1H NMR (300 MHz, CD3OD+D2O): 8.91 (d, 1H), 7.97 (dd, 1H), 7.85 (dd, 1H), 7.35-7.23 (m, 2H), 4.09 (s, 4H), 3.96 (brs, 2H), 3.63 (brs, 1H), 3.43-3.36 (m, 4H), 3.29-3.22 (m, 2H), 2.64 (s, 3H), 2.61 (s, 3H), 2.57-2.46 (m, 2H), 2.37-2.22 (m, 2H). Analysis calculated for the formula C28H31FN4O7: C, 60.64; H, 5.63; N, 10.10. Found: C, 61.26; H, 5.22; N, 10.46.
Following example 2, using galactaric acid instead of L-pyroglutamic acid, ocaperidone galactaric acid salt was isolated. m.p.=180-182° C. 1H NMR (300 MHz, CD3OD+D2O): 8.81 (d, 1H), 7.87 (dd, 1H), 7.76 (d, 1H), 7.38 (dd, 1H), 7.23 (t, 1H), 7.18 (dt, 1H), 4.15 (s, 1H), 3.86 (s, 1H), 3.84 (brs, 2H), 3.55 (brs, 1H), 3.33-3.26 (m, 2H), 3.18-3.10 (m, 2H), 2.56 (s, 3H), 2.51 (s, 3H), 2.46-2.35 (m, 2H), 2.27-2.09 (m, 2H).
Following example 2, using orotic acid instead of L-pyroglutamic acid, ocaperidone orotic acid salt was isolated. m.p.=245-246° C. 1H NMR (300 MHz, CD3OD+D2O): 8.80 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 1H), 7.38 (dd, 1H), 7.25 (t, 1H), 7.18 (brt, 1H), 6.04 (s, 1H), 3.75 (brs, 2H), 3.53 (brs, 1H), 3.18-3.10 (m, 2H), 2.55 (s, 3H), 2.51 (s, 3H), 2.45-2.35 (m, 2H), 2.26-2.10 (m, 2H).
Following example 2, using hippuric acid instead of L-pyroglutamic acid, ocaperidone hippuric acid salt was isolated. m.p.=163-165° C. 1H NMR (300 MHz, CD3OD+D2O): 8.77 (d, 1H), 7.82 (dd, 1H), 7.76 (m, 2H), 7.62 (d, 1H), 7.41 (m, 1H), 7.37-7.29 (m, 3H), 7.13-7.06 (m, 2H), 3.87 (s, 1H), 3.59 (brd, 2H), 3.37 (m, 1H), 3.04 (s, 4H), 2.94 (t, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 2.26 (dd, 2H), 2.20-2.06 (m, 2H).
Following example 2, using nicotinic acid instead of L-pyroglutamic acid, ocaperidone nicotinic acid salt was isolated. m.p.=160-161° C. 1H NMR (300 MHz, CD3OD+D2O): 8.93 (d, 1H), 8.82 (d, 1H), 8.53 (dd, 1H), 8.22 (brd, 1H), 7.92 (dd, 1H), 7.75 (d, 1H), 7.44 (t, 1H), 7.40 (dt, 1H), 7.23 (t, 1H), 7.17 (dt, 1H), 3.89 (brs, 2H), 3.61 (brs, 1H), 3.45-3.33 (m, 3H), 3.26-3.17 (m, 2H), 2.62 (s, 3H), 2.49 (s, 3H), 2.47-2.40 (m, 2H), 2.38-2.23 (m, 2H).
A 1:1 mixture of ocaperidone (0.5 mmol) and the desired acid (0.5 mmol) was added into 8 ml of water and 2 ml of THF to get an homogeneous solution. The obtained mixture was freezed in a cold bath (at −78° C.) and put to lyophilize overnight to obtain a white solid.
Ocaperidone pyroglutamic acid salt of example 2 presents a higher solubility in water than the other salts described in the examples 1, 3-10 and ocaperidone free base. In particular, the solubilities of ocaperidone salts were measured as follows:
UV/visible spectrophotometer: Agilent 8453E
Volumetric flask (5 ml, 10 ml, 20 ml, 100 ml)
Mechanical pipettes: Biohit (m1000, m200)
Magnetic stirrer: Heidolph MR3001K
A suspension of 100 mg of crystalline ocaperidone salt or ocaperidone free base in 1 ml HPLC grade pure water (pH=6) was prepared. The suspension was kept at fixed and controlled temperature (ex: 25° C.) under magnetic stirring for 24 hours. A sample was taken, filtered and the solubility of the ocaperidone salts or ocaperidone free base was measured after 1 h and 24 h. Results are given in g/100 ml.
The obtained results are presented in
| Number | Date | Country | Kind |
|---|---|---|---|
| 05-290428.1 | Feb 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB06/00688 | 2/24/2006 | WO | 00 | 8/19/2007 |
