MXPA06005247A - Pharmaceutical composition for oral administration of a pyrazol-3-carboxamide derivative - Google Patents

Abstract

A pharmaceutical composition in a liquid or semi-solid form which is self-emulsionable or self-emulsionable in an aqueous medium, for oral administration of a pyrazol-3-carboxamide derivative, wherein said derivative is solubilized in an amphiphilic mixture containing one or several lipidic solvents and a non-ionic hydrophilic surfactant.

Description

PHARMACEUTICAL COMPOSITION INTENDED FOR THE ORAL ADMINISTRATION OF A PIRAZOL-3- CARBOXAMIDE DERIVATIVE The present invention relates to a pharmaceutical composition intended for the oral administration of a pyrazole-3-carboxamide derivative as well as its pharmaceutically acceptable salts and solvates thereof. By pyrazole-3-carboxamide derivative is meant a compound chosen from N-piperidin-5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide and N-piperidin-5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide. In the present description, these compounds are referred to as "active ingredients according to the invention". N-piperidin-5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide, hereinafter referred to as compound A, is described in European patent EP-B-1 150961 The N-piperidin-5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methylpyrazo-3-carboxamide, hereinafter referred to as compound B, whose international naming is rimonobant, is described in European patent EP-B-656354. These compounds are antagonists of the CB Í receptors of cannabinoids. These compounds are very poorly soluble molecules in water, respectively: 0.1 μg / ml and 1 μg / l at pH = 6.5. In addition, these compounds have high membrane permeability coefficients: respectively 78.10"7 cm / s and 96.10" 7 cm / s on the CaCO2 cell model as described by M. C. Gres et al. in Pharmaceutical Research, 1 198, 15 (5), 726-7333. In European Patent EP-B-969832 a pharmaceutical composition containing a pyrazole-3-carboxamide derivative in micronized form and a surfactant wetting agent has been described. In international application WO 98/43635 a pharmaceutical composition containing compound B mixed with Poloxamer 127 and a macrogolglyceride has been described. Patent application WO 2004/009057 describes a process for preparing a dispersion of crystalline nanoparticles in an aqueous medium and the use of surfactant at a low concentration, which makes it possible to avoid the solubilization of said nanoparticles; The examples of embodiments relate in particular to compound A and compound B. Pharmaceutical compositions containing a pyrazole-3-carboxamide derivative according to the invention have now been found which make it possible to improve the solubilization of the active principles according to the invention and the bioavailability thereof. the man fasting. These pharmaceutical compositions are constituted by a homogeneous, water-dispersible mixture, in which the active principle according to the invention is solubilized in a lipid solvent to which a hydrophilic surfactant is added in order to spontaneously form a fine emulsion or a microemulsion during its dilution in aqueous medium; it is said that these compositions are self-emulsifiable or self-micro-emulsifiable. A microemulsion is a thermodynamically stable transparent system (Microemulsion and related system in Surfactant Sciences Series, Marcel Dekker Inc., 1988, 30, pp. 25-26). By "fine emulsion" is meant an emulsion in which the size of the dispersed beads is less than 5 μm. This fine emulsion is characterized in that it is sufficiently stable to last in the gastro-intestinal tract up to the site of absorption, ie the intestine. Thus, the present invention relates to a pharmaceutical composition in liquid or semi-solid form, self-emulsifiable or self-microemulsifiable in aqueous medium, for the oral administration of a pyrazole-3-carboxamide derivative selected from the N-piperidine- 5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) -4-ethylpyrazole-3-carboxamide and the N-piperidin-5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4- methylpyrazole-3-carboxamide, wherein said pyrazole-3-carboxamide derivative is solubilized in a mixture containing one or more lipidyl solvents of the pyrazole-3-carboxamide derivative and a hydrophilic nonionic surfactant whose hydrophilic-lipophilic balance is greater than 10 and is preferably between 10 and 18. According to the present invention, the weight proportion of the active principle is comprised between 0, 1 and 6%, preferably between 0, 1 and 5%. In the pharmaceutical composition according to the invention, the weight ratio of the lipid solvent or the mixture of lipidyl solvents is from 35 to 75%, preferably from 35 to 55%. Preferably, the mixture of the pharmaceutical composition according to the invention also contains an amphiphilic cosolvent or a mixture of amphiphilic cosolvents. The presence of such an amphiphilic cosolvent favors the solubilization of the active principle according to the invention and the subsequent emulsification of the pharmaceutical composition in aqueous medium. When present, the amphiphilic cosolvent, or each of the amphiphilic cosolvents, is in a weight ratio of less than 30%. When 2 amphiphilic solvents are present, they are in a total weight ratio of less than 50%, preferably less than 45%. Thus, the pharmaceutical composition according to the present invention preferably contains from 10 to 50% of amphiphilic cosolvent (s), more particularly from 10 to 45%. Preferably, the nonionic hydrophilic surface active agent is constituted either by a single surfactant whose hydrophilic-lipophilic balance is greater than 10, or by a mixture of surfactants, the hydrophilic-lipophilic balance of said mixture being greater than 10. According to the present invention, the surfactant is in a weight ratio of 5 to 50%, preferably 5 to 25% and optimally 5 to 15%. Thus, the concentration of surfactant used according to the present invention is clearly higher than the critical micelle concentration (CMC), so that the solubilization capacity of said surfactant is introduced under the conditions of the present invention. The pharmaceutical compositions according to the present invention can be administered in soft gelatin capsules or in sealed or embedded hard gelatin capsules. According to the present invention, the nonionic surfactants such as: Polyoxyethylene hydrogenated castor oil: Cremophor® EL, Polyoxyethylene 40 hydrogenated castor oil: Cremophor® RH40, both marketed by BASF. Polyoxyethylene polysorbate: Tween® 80, Tween® 20, Tween® 60, Tween® 85, marketed by ICI. Mono sorbitol laurate: Span 20, Sorbitan monooleate: Span 80, both marketed by ICI. Vitamin E / TPGS: Propylene glycol tocopherol succinate 1000, marketed by Eastman. Polyethylene glycol hydroxy stearate 15: Solutol® HS 15, marketed by BASF. The preferred hydrophilic surfactants, alone or in mixture, are Cremophor® RH40, Cremophor® EL, vitamin E TPGS, Tween 80. Surfactants such as Span, being hydrophilic, are used in admixture with other surfactants so that the hydrophilic balance lipophilic of the surfactant mixture is greater than 10. By lipid solvents and amphiphilic cosolvents, it is meant natural fatty acid derivatives, preferably of vegetable origin, obtained by esterification with an alcohol: either glycerol (mono-, di-, tri-glycerides) ), either a glycol, optionally long chain (macrogolglycerides). According to the length of the fatty acid chain and according to the nature of the alcohol, these solvents have a more or less amphiphilic character. According to the present invention, lipid solvents such as: Oleoyl Macrogol 6 glycerides (polyglycosylated unsaturated glycerides) can be used: Labrafl® 1944 CS, marketed by Gattefossé. Caprileate propylene glycol caprate: Labrafac®PG, marketed by Gattefossé. Mono caprylic acid ester. and propylene glycol: Capmul® PG-8, marketed by Abitec. Glyceryl Oleate: Peceol® marketed by Gattefossé. Mono and diglyceride of medium chain (capric caprylic): Capmul® MCM, marketed by Abitec. Polyglycerol oleate: Plurol® oleic, marketed by Gattefossé. Caprylic / capric triglyceride: Miglyol® 812, marketed by Dynamit Nobel, Labrafac® CC, marketed by Gattefossé. Preferred lipid solvents, alone or as a mixture, are Labrafil® 1 944 CS and Miglyol® 812 or Labrafac® CC or Capmul® MCM. According to the present invention, amphiphilic cosolvents can be used such as: propylene glycol monolaurate: Capmul® PG12, marketed by Abitec. Propylene glycol monolaurate: Lauroglycol® 90, marketed by Gattefossé. Caprilocaproil Macrogol 8 glycerides: (ethyldiglycosylated saturated glycerides) Labrasol®, Gélucire 44-14 marketed by Gattefossé, Diethylene glycol mono ethyl ether: Transcutol®, marketed by Gattefossé. PEG 400: Polyethylene glycol .400, marketed by Huís or ICI. Preferred amphiphilic solvents alone or in a mixture are Labrasol and Gellucire 44-14, Capmul® PG12 or Lauroglycol® 90. EXAMPLES Several pharmaceutical compositions according to the invention are prepared using the following procedure: the solvent (s) is mixed ( s) lipid (s) chosen as well as the surfactant agent at a temperature comprised between 30 and 65 ° C, preferably between 40 and 45 ° C, with agitation; and this after having melted the different solvents if necessary. The active principle is incorporated maintaining the stirring the time necessary for the solubilization of said active principle, then the formulation thus obtained is transferred to the encapsulation post.

EXAMPLE 1: Formulations with lipid solvent (s) and surfactant.

EXAMPLE 2: Formulations with lipid solvent, surfactant and amphiphilic cosolvent (s).

The ability to form a fine and stable emulsion is evaluated for each of the above formulations by diluting these 10: 1 in a simulated intestinal medium of pH 6. On the one hand is observed the decantation start time that marks the stability of the emulsion and, on the other hand, with the microscope, the size of the oily globules dispersed in the aqueous phase to control their fineness. In all cases, the decantation start time exceeds 24 hours. The globules that are visible under the optical microscope are often of a diameter of around 1 micrometer, being able to reach the largest 5 micrometers. In vitro kinetics of dissolution kinetics: The kinetics of dissolution are studied in the blade apparatus (apparatus no. 2 of the Pharmacopoeia) in a simulated physiological medium of pH 6. at 37 ° C, and with an agitation of 75 turns / min. The capsule formulation is introduced into the dissolution apparatus at a time 0 and the percentage of finely emulsified product is determined at times of 15, 30, 60 minutes, then 2, 3 and 4 hours by HPLC dosage (from English High Performance Liquid Chromatography = high performance liquid chromatography) of the dissolution medium, then filtration over 5 μm.

(This way it is well assured of not dosing more than the active principle that is in the form of a sufficiently fine emulsion because it is not retained by the 5 μm filter). The experiment time is longer than necessary to reach the intestine (2 to 3 hours), which is the main absorption site. By way of comparison, the same dissolution test was carried out with a reference formulation, described below: Reference formulation: Compositions mg / unit Compound A 10 Corn starch 80 Lactase monohydrate 200 mesh 274 Hypromellose 10 Sodium lauryl sulphate 2 Purified water CS Croscarmellose sodium 20 Magnesium stearate 4 Pill size 0 pill filled with 400 mg The experiment is carried out with the same initial concentration of compound A in the medium for each dissolution test. A) Yes. in 250 ml of dissolution medium, 1 reference capsule containing 10 mg of compound A, or 10 mg of compound A, which comes from a capsule prepared either from formulation 1.1, or from formulation 2.1, is well placed. Table 1 In-vitro dissolution It is found that the formulations according to the invention allow more than 80% of the compound according to the invention to be solubilized by fine emulsion in 30 minutes and that this solubilized state persists for at least 4 hours, on the contrary, the reference formulation does not allow solubilization more than about 25% of the active ingredient. Measures of bioavailability in man: The pharmaceutical compositions according to the invention have also been evaluated in-vivo in man in order to study the influence of the formulation according to the invention on the bioavailability of the active principle in the fasting state and after eating . In a first test, the bioavailability of the active principle in fasting versus after eating has been compared for the reference formulation described above. In this trial, a dose of 50 mg of compound A is administered orally, in one dose, to 12 healthy volunteers and the two administrations fasting and after eating are carried out randomly and with 21 days of interval. Blood extractions are taken after administration at times: 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 120 hours and 168 hours. The different pharmacokinetic parameters that allow establishing the bioavailability of the active principle are measured.

TABLE 2 Bioavailability of compound A with the reference formulation With the reference formulation, it is observed that the Cmax and AUC values (area under the curve) are respectively 4.3 and 3.5 times larger for subjects after eating than for fasting subjects. In a second test, the bioavailability of the active principle was evaluated with the formulations according to the present invention. In this trial, a dose of 10 mg of compound A has been administered to 12 healthy volunteers, fasting, orally taken, either the reference formulation, or the 1 .1 formulation in hard gelatin capsules, well of the formulation 2.1 in soft gelatine capsules. The administrations are carried out randomly, with 8 days of interval. Blood samples are taken as in the previous test, and the pharmacokinetic parameters are measured. The results show an improvement of the bioavailability of the active principle in fasting in relation to the results obtained with the reference formulation.

After a period of 15 days, formulation 2.1 was administered under the same conditions, to the same patients after eating and the pharmacokinetic parameters were measured. TABLE 3 Absorption of compound A in subjects after eating and fasting . Í The values in parentheses () indicate the standard deviations. With the formulations according to the invention, it is found that the Cmax and AUC values are close regardless of the formulation when fasted. The improvement of the bioavailability in the fasting state, based on the increase of the AUC is respectively 165% and 152% for the formulation 2.1 and 1.1 with respect to the reference formulation.

In addition, with the formulation 2.1, it is seen that the difference of bioavailability between the state in fasting and after eating is not more significant. Thus, the formulations according to the invention make it possible to significantly improve the bioavailability in the fasting state, which thus leads to suppressing the difference in bioavailability between the state of after eating and fasting.

Claims (9)

1. CLAIMS 1. Pharmaceutical composition in liquid or semi-solid form. self-emulsifiable or self-microemulsifiable in aqueous medium, for the oral administration of a pyrazole-3-carboxamide derivative selected from: N-piperidin-5- (4-bromophenyl) -1 - (2,4-dichlorophenyl) - 4- etiIpyrazole-3-carboxamide and N-piperidin-5- (4-chlorophenyl) -1 - (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide, wherein said pyrazole-3-carboxamide derivative is solubilized in a mixture containing one or more lipidyl solvents of the pyrazole-3-carboxamide derivative and a hydrophilic nonionic surfactant whose hydrophilic-lipophilic balance is greater than 10.
2. 2. Pharmaceutical composition according to claim 1, which contains among others an amphiphilic co-solvent or a mixture of amphiphilic cosolvents.
3. 3. The pharmaceutical composition according to claim 2, wherein the amphiphilic cosolvent or each of the amphiphilic cosolvents present is in a proportion by weight of less than 30%.
4. 4. Pharmaceutical composition according to any of claims 2 or 3, wherein the amphiphilic cosolvent or the mixture of amphiphilic cosolvents is in a weight ratio comprised between 10 and 50%.
5. 5. Pharmaceutical composition according to any of claims 1 to 4, wherein the lipid solvent or the mixture of lipid solvents is in a weight ratio of 35 to 75%.
6. 6. The pharmaceutical composition according to any of claims 1 to 5, wherein the lipid solvent or the mixture of lipid solvents is in a weight ratio of 35 to 55%.
7. 7. Pharmaceutical composition according to any of claims 1 to 6, wherein the surfactant is constituted by a single surfactant or by a mixture of surfactants, whose hydrophilic-lipophilic balance is between 10 and 1
8. 8. 8. Pharmaceutical composition according to any of claims 1 to 7, wherein the surfactant is in a weight ratio of 5 to 50%.
9. 9. The pharmaceutical composition according to claim 8, wherein the surfactant is in a weight ratio of 5 to 15%. 1 0. Pharmaceutical composition according to any of claims 1 to 9, wherein the pyrazole-3-carboxamide derivative is in a weight ratio of 0.1 to 6%. eleven . Pharmaceutical composition according to any of claims 1 to 1 0 administrable in soft gelatine capsules. 12. Pharmaceutical composition according to any of claims 1 to 10, which can be administered in sealed or embedded hard gelatin capsules.