MXPA99008722A - Pharmaceutical composition for oral administration of a n-piperidino- 3-pyrazolecarboxamide derivative, its salts and their solvates - Google Patents

Abstract

The invention concerns pharmaceutical compositions for oral administration containing 0. 5%to 20%of N-piperidino-5- (4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methylpyrazole-3-carboxamide in microcrystalline form and pharmaceutical vehicles. The compositions are formulated by wet granulation.

Description

PHARMACEUTICAL COMPOSITION FOR THE ORAL ADMINISTRATION OF A DERIVATIVE OF N-PIPERIDINE-3-PIRAZOLCARBOXAMIDE, ITS SALTS AND ITS SOLVATES Field of Invention The subject of the present invention is a pharmaceutical composition for the oral administration of N-piperidino-5- (4-chloro-enyl) -1- (2,4-dichlorophenyl) -4-methypyrazolo-3 -carboxamide of the formula: of its pharmaceutically acceptable salts and solvates thereof, hereinafter referred to as compounds of formula (I).

Ref: 031339 Background of the invention.

The compounds of formula (I) and their mode of preparation are described in European patent application EP 656 354.

N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -methylpyrazolo-3-carboxamide, also known by the codename SR 141716 and designated compound A in the description that follows, it is particularly preferred for the pharmaceutical composition according to the present invention.

The pharmacological properties of the compounds of formula (I), which are selective antagonists of the receptors to the CB1 central cannabinoids, were mentioned above all in the publication by M. Rinaldi-Carmona et al., FEBS Letters, 1994, 240-244 .

To administer such compounds orally, it is necessary that they present a good absorption, which implies both a good solubility in aqueous medium and a good capacity to cross the intestinal membrane (M. Rowland and TN Tozer in Clinical Pharmacokinetics, concepts and applications, Lea and Fehiger ed., 1989, 2nd edition, pages 113-130).

To evaluate the epithelial permeability of the compounds, the Caco-2 cell family is used, which has the distinction of being differentiated in vitro to form an epithelial monolayer (Crit., Rev. Ther, Drug Carrier System, 1991, 8_, (4), 105 -330). On this model, the permeability of compound A solubilized in dimethylsulfoxide (DMSO) is high, which shows its good ability to be absorbed at the intestinal level, when it is solubilized.

In addition, the hydrophobic nature of the compounds of formula (I) is marked very strongly. Thus, it has been observed that compound A does not wet with water and that this compound and its salts are practically insoluble in water, whatever the pH. These compounds are soluble in alcohols and glycols, more particularly in polyethylene glycols (PEG).

However, when the solutions obtained with an alcohol or a glycol are diluted in aqueous medium, the compound of formula (I) precipitates, due to its strong hydrophobic character.

The compounds of formula (I) and in particular compound A are poorly electrostatic. The micronization can be operated with a good performance (approximately 85%) and allows to obtain particles of approximately 1 micron. The analytical controls carried out after micronization show that there is no modification of the crystalline form.

In studying wettability, it has been found that the rate of penetration of water into a bed of powder by wet granulation is much higher than that measured in a bed of powder obtained by dry mixing. The study of the effects of the incorporation of wetting agents showed that a sodium alkyl sulphate with a low concentration clearly increases the wettability.

In addition, it has been found that the presence of a disaggregation agent, such as cross-linked sodium carboxymethyl cellulose, in the formulation allows to improve the dissolution kinetics.

Description of the invention.

Surprisingly, it has been found that by combining in the same formulation a sodium alkyl sulfate and a disaggregation agent, a complete dissolution of the formulation is quickly obtained, and this with a good reproducibility of the results.

Thus, according to one of its aspects, the present invention has as its object a pharmaceutical composition for the oral administration of a compound of formula (I) comprising - 0.5% to 20% by weight of a compound of formula (I) in micronized form, 0.05% to 0.5% by weight of a sodium alkyl sulfate, - 2.5% to 10% by weight of disaggregation agent, and pharmaceutical excipients, said composition being formulated by wet granulation .

Wet granulation is understood to mean the pharmaceutical operation that allows, by means of a granulation liquid, to densify a mixture of powders containing the active principle, said mixture constituting the internal phase of the formulation, the moist mass thus obtained being dried and then calibrated before the addition of the ingredients constituting the external phase of said formulation.

According to the present invention, sodium alkyl sulphate is understood to be a sodium β-C12 alkylsulphate, such as, for example, sodium octyl sulphate or, preferably, sodium lauryl sulfate.

According to the present invention, the term "disaggregation agent" is understood to mean cellulose or cellulose derivatives, such as sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, crospovidone, pregelatinized starch, sodium carboxymethyl starch, with a preferred breakdown agent. crosslinked sodium carboxymethylcellulose.

The pharmaceutical compositions according to the present invention can be presented in the form of dragees, tablets, sachets or powders, preferably in the form of dragees.

The pharmaceutical excipients useful for the pharmaceutical composition according to the present invention comprise in particular a diluent, a binder and a lubricant. A drying agent, a release agent and, optionally, a colorant and / or a flavoring may also be added.

The diluent used in the composition of the present invention may be one or several compounds that are capable of densifying the active ingredient to obtain the desired mass. Preferred diluents are mineral phosphates, such as calcium phosphates; sugars, such as hydrated or anhydrous lactose, mannitol; and cellulose or cellulose derivatives such as, for example, microcrystalline cellulose, starch, corn starch or pregelatinized starch. Particularly preferred are lactose monohydrate, mannitol, microcrystalline cellulose and corn starch used alone or as a mixture, such as, for example, a mixture of lactose monohydrate and corn starch.

The binder employed in the composition of the present invention may be one or more compounds that are capable of densifying a compound of formula (I) by transforming it into thicker and denser particles, with better drainage. Preferred binders are alginic acid, sodium alginate; cellulose and cellulose derivatives, such as sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose or methylcellulose; the gelatin; the acrylic acid polymers; povidone, for example povidone K-30, with povidone K-30 being particularly preferred as a binder. The binder is present in a weight ratio of 1% to 10% in the pharmaceutical composition according to the invention.

The lubricant used in the composition of the present invention can be one or several compounds that are capable of preventing the problems related to the preparation of dry forms, such as the problems of sticking and / or seizing that appear in the machines at the moment of the compression or filling. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl acetate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate or stearic acid; hydrogenated vegetable oils, for example hydrogenated castor oil; polyalkylene glycol, especially polyethylene glycol; Sodium benzoate or talc. According to the present invention, magnesium stearate is preferred. The lubricant is present in a weight ratio of 0.2% to 5% in the pharmaceutical composition according to the invention.

The antiadhesive optionally employed in the composition of the present invention may be one or more compounds which are capable of reducing the stickiness of the formulation, for example preventing adhesion to metal surfaces. Preferred antiadhesives are compounds containing silicon, for example silica or talc. The anti-adherent may be present in a weight ratio of 0 to 5% in the pharmaceutical composition according to the invention.

The run-off agent optionally employed in the composition of the present invention may be one or more compounds which are capable of facilitating the run-off of the prepared formulation. Preferred draining agents are silicon-containing compounds, for example anhydrous colloidal silica or precipitated silica. The run-off agent may be present in a weight ratio of 0 to 15% in the pharmaceutical composition according to the invention.

According to the invention, the pharmaceutical compositions are prepared by a wet granulation process. Thus, for the internal phase, the active principle, the diluent, the binder, the disaggregation agent, the sodium alkyl sulphate, and optionally the dye are mixed at room temperature, then wetted with the granulation liquid. The wet mass obtained is dried, then calibrated. The calibrated dry grains are then added with the external phase ingredient (s), namely the lubricant and, if appropriate, the anti-adhesive, the draining agent and, if necessary, the colorant and / or the flavorant.

The purified water is used as a granulation liquid.

According to a preferred mode of manufacture, the sodium alkyl sulfate is added to the purified water to proceed to the wet granulation.

In particular, the present invention relates to a pharmaceutical composition for oral administration comprising: 0.5% to 20% by weight of compound A in micronized form, -0.05% to 0.5% by weight of lauryl sulfate Sodium fato, - 2.5% to 10% by weight of crosslinked sodium carboxymethylcellulose, and pharmaceutical excipients, said composition being formulated by wet granulation.

Preferentially, the present invention relates to a pharmaceutical composition for oral administration, formulated by wet granulation and containing: - 0.5% to 20% by weight of compound A in micronized form, - 0.1% by weight of sodium lauryl sulfate, 5% by weight of crosslinked sodium carboxymethylcellulose, - 1% to 10% by weight of binder, - 0.2% to 5% by weight of lubricant, and a diluent in sufficient quantity for 100%.

In particular, the present invention relates to pharmaceutical compositions in the form of dragees, prepared by wet granulation, with one of the following formulations expressed in weight percentage: i) Micronized compound internal phase 0, 59% Corn starch 30% lactose monohydrate 200 mesh 60, 78% povidone K 30 A r O "6 crosslinked sodium carboxymethylcellulose Granulation sodium lauryl sulfate 0.1% purified water C. S External phase magnesium stearate ii) Compound internal phase A micronized 5.88-s corn starch 30% lactose monohydrate 200 mesh 55.49% povidone K 30 2.53% cross-linked sodium carboxymethylcellulose 5% Granulation lauryl sulfate 0.1% sodium purified water CS External phase magnesium stearate 1% iii) Internal phase A micronized compound 17.64% corn starch 30% lactose monohydrate 200 mesh 43.73% povidone K 30 2, 53% crosslinked sodium carboxymethylcellulose 5% Granulation sodium lauryl sulphate 0.1% purified water C.S.

External phase magnesium stearate 1% The characteristics and advantages of the compositions according to the invention will emerge more clearly with the description that follows, from the compositions given by way of example.

ESSAYS 1. Study of the solubility of the compounds of formula (I).

The solubilities of the compounds of formula (I) are measured in different aqueous media. The instantaneous solubility is evaluated, at room temperature, by dosing. The results expressed in μg per ml are gathered in table 1 below: TABLE I The solubility of compound A in different solvents was also measured (table 2) and after diluting the solutions formed in water (table 3). TABLE 2 TABLE 3 2. Wettability study.

The wettability of compound A was studied in different formulations using the method of H. Mohamad et al., Labo Pharma. Technical problems, 1984, 32 (346), 284-289. 2. 1. Influence of the granulation process, A formulation (formulation 1) obtained by simple mixing with a formulation (formulation 2) obtained by wet granulation has been compared.

Formulation 1 compound A 30 mg modified corn starch 48 mg lactose monohydrate extra fine crystals 70.1 mg anhydrous colloidal silica 0.4 mg magnesium stearate 1.5 mg Dragee 150 mg Formulation 2 compound A 30 mg modified corn starch 51 mg lactose monohydrate 200 mesh 83 mg povidone K 30 4, 3 mg magnesium stearate 1.7 mg Dragee 170 mg The wettability measured according to the H. Mohamad method is 22 mg2 / s for formulation 1 and 110 mg2 / s for formulation 2.

Thus, the wet granulation process improves the wettability by a factor of 5. 2.2. Influence of the tenor in active principle.

By way of comparison, wet granulation formulations have been prepared in which the tenor in active principle is respectively 10 mg (formulation 3) and 1 mg (formulation 4).

TABLE 4 For formulation 3 the wettability is 500 mg2 / s For formulation 4 the wettability is 1000 mg2 / s.

Thus, the wettability is inversely proportional to the amount of active principle contained in the formula. This illustrates the hydrophobic nature of compound A. 2. 3. Influence of excipients Several formulations have been prepared by wet granulation and compared to a reference formulation also obtained by wet granulation.

TABLE 5 Only 0.5% sodium lauryl sulphate significantly improves wettability.

Wettability measurements are not adapted to study the effect of a disintegrating agent such as crosslinked sodium carboxymethyl cellulose.

Study of the dissolution in gastric medium The dissolution kinetics of different formulations in a gastric medium have been studied: a 37 ° C, in a citrate phosphate buffer with pH 3, for 30 minutes.

When 40 mg of compound A alone are placed in one liter of the dissolution medium, it is observed that no amount has been dissolved.

In order to allow the dissolution of the tested formulations, 0.2% sodium lauryl sulfate was added to the medium as a surfactant.

TABLE 6 TABLE 6 (continued) For each formulation, 6 tests were carried out and the amount of compound A dissolved in the medium was measured every 5 minutes.

Table 7 indicates the average value of the percentage of dissolved compound A and the average difference with respect to this value for the different formulations described in table 6.

TABLE 7 TABLE 7 (continued) For the formulations C and D containing respectively 1% and 5% of polyethylene glycol 6000, it is found that only the maximum dissolution is reached after 30 minutes.

For formulations A and B containing respectively 0.1% and 0.5% sodium lauryl sulphate, it is observed that the maximum value is reached respectively after 20 and 30 minutes.

In addition, the measured results are dispersed for each of the formulations A, B, C or D.

The results observed with the formulations E, F, G show the interest of the presence of crosslinked sodium carboxymethyl cellulose to favor the dissolution.

With the formulations E and G containing respectively 5% and 2.5% of cross-linked sodium carboxymethylcellulose, it is observed that 100% of the compound A is dissolved respectively after 20 or 15 minutes and that the results are relatively dispersed in the first 15 minutes. minutes Formulation F containing both 0.1% sodium lauryl sulfate and 5% cross-linked sodium carboxymethylcellulose yields the best results. In effect, after 15 minutes the entire compound A is dissolved, and the difference between the results of the different tests is very low (difference of 2.3 to 1.5 between 15 and 30 minutes).

. Evaluation of the intestinal transept telial passage of compound A.

On microporous polycarbonate filters coated with collagen, Caco-2 cells are grown. The cell monolayer formed on the filter thus allows to separate an apical compartment (which mimics the intestinal lumen) from a basal compartment (which imitates blood circulation).

The composition containing the compound to be studied is placed on the apical side and the passage of this compound, dispersed or solubilized in Hank's medium, is evaluated through this cellular barrier, measuring its kinetics of appearance of the basal side. This aqueous medium, pH = 6; 5, has the following composition: NaCl = 8.0 g / 1; KCl = 0.4 g / 1; CaCl 2 = 0.19 g / 1; MgCl2 = 0.1 g / 1; MgSO4 = 0.1 g / 1; Na2HP04 = 0.09 g / 1; KH2P04 = 0.06 g / 1; NaHCO 3 = 0.35 g / 1; glucose = 1 g / 1; phenol red = 0.01 g / 1.

The coefficient of permeability P, in cm / s, which characterizes the speed of passage of the molecule through the membrane, is then determined, namely: »P = (da / dt). (1 / A.Co) in which: da / dt = variation of the amount of compound tested that passes through the cell monolayer as a function of time (mol / s) A = surface of the monolayer (cm2) Co = initial concentration of the Tested compound (mol / 1) 3. 1. Coefficient of permeability of compound A introduced in Hank's medium dissolved in DMSO. P = 96.10"7 cm / s The permeability of compound A thus measured in solution (in DMSO) indicates an intrinsic characteristic of this compound. This result indicates the very good aptitude of compound A for the transept telial passage when it is dissolved. 3. 2. Relative velocity of the intestinal transept telial passage of compound A The rate of passage of compound A in formulation X was measured and compared to that of compound A in suspension.

Formulation X compound A 30 mg modified corn starch 51 mg lactose monohydrate 200 mesh 83 mg povidone K 30 4.3 mg sodium lauryl sulfate 0.17 mg cross-linked sodium carboxymethylcellulose 8.5 mg magnesium stearate 1.7 mg Dragee 178.67 mg EXAMPLE 1: 1 mg Dragee A tablet prepared by wet granulation with the following composition: Internal phase compound A micronized 1 mg corn starch 51 mg lactose monohydrate 200 mesh 103, 33 mg povidone K 30 4, 3 mg cross-linked sodium carboxymethylcellulose, 5 mg Granulation sodium laurilsulphate 0.17 mg purified water C.S.

External phase magnesium stearate 1.7 mg For an opaque white tablet of size 3 finished with 170 mg EXAMPLE 2: 10 mg tablet A tablet prepared by wet granulation with the following composition: Internal phase compound A micronized 10 mg corn starch 51 mg lactose monohydrate 200 mesh 9, 33 mg povidone K 30 4, 3 mg cross-linked sodium carboxymethylcellulose, 5 mg Granulation sodium laurilsulphate 0.17 mg purified water C.S.

External phase magnesium stearate 1.7 mg For an opaque white tablet of size 3 finished with 170 mg EXAMPLE 3: 30 mg tablet A tablet prepared by wet granulation with the following composition: Internal phase A micronized compound 30 mg corn starch 51 mg lactose monohydrate 200 mesh 74.33 mg povidone K 30 4, 3 mg cross-linked sodium carboxymethylcellulose, 5 mg Granulation lauryl sulphide sodium 0.17 mg purified water C.S.

External phase magnesium stearate 1.7 mg For an opaque white tablet of size 3 finished with 170 - mg EXAMPLE 4: 30 mg tablet A tablet prepared by wet granulation with the following composition: Internal phase A micronized compound 30 mg corn starch 51 mg lactose monohydrate 200 mesh 73.65 mg povidone K 30 4, 3 mg cross-linked sodium carboxymethylcellulose, 5 mg Granulation lauryl sulphonate sodium 0.85 mg purified water C.S.

External phase magnesium stearate 1.7 mg For an opaque white tablet of size 3 finished with 170 mg EXAMPLE 5: 1 mg tablet Internal phase A micronized compound 1 mg corn starch 50 mg lactose monohydrate 200 mesh 130 mg hydroxypropylmethylcellulose 6 cP 6 mg crosslinked sodium carboxymethylcellulose 10 mg Granulation sodium laurilsulphate 1 mg purified water C.S.

External phase magnesium stearate 2 mg For a tablet finished with 200 mg EXAMPLE 6: 10 mg tablet Internal phase compound A micronized 10 mg corn starch 50 mg lactose monohydrate 200 mesh 211.5 mg hydroxypropylmethylcellulose 6 cP 9 mg carboxymethylstarch sodium 15 mg sodium lauryl sulfate 1.5 mg Granulation purified water C. S External phase magnesium stearate 3 mg For a tablet finished with 300 mg EXAMPLE 7: 30 mg tablet Internal phase A micronized compound 30 mg corn starch 80 mg lactose monohydrate 200 mesh 252 mg povidone K 30 12 mg crosslinked sodium carboxymethylcellulose 20 mg sodium lauryl sulfate 2 mg Granulation purified water C. S External phase magnesium stearate 4 mg For a tablet finished with 400 mg It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (10)

Claims

1. A pharmaceutical composition for the oral administration of N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazolo-3-carboxamide of the formula: of one of its pharmaceutically acceptable salts or one of its solvates (hereinafter active ingredient), characterized in that it comprises: - 0.5% to 20% by weight of active ingredient in micronized form, 0.05% to 0.5 % by weight of a sodium alkyl sulfate, - 2.5% to 10% by weight of disaggregation agent, and pharmaceutical excipients, said composition being formulated by wet granulation.

2. The pharmaceutical composition according to claim 1, characterized in that it comprises: - 0.5% to 20% by weight of N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4 -met i lpi razol o-3-carboxamide in micronized form, -0.05% to 0.5% by weight of sodium lauryl sulfate, - 2.5% to 10% by weight of crosslinked sodium carboxymethylcellulose.

3. The pharmaceutical composition according to claim 1, characterized in that it contains: 0.5% to 20% by weight of N-piperidino-5- (4-chlorophenyl) -1- (2, -dichlorophenyl) -4-methylpyrazolo-3 -carboxamide in micronized form, -0.1% by weight of lauryl sodium sulfate, -5% by weight of cross-linked sodium carboxymethylcellulose, -1% to 10% by weight of binder, -0.2% to 5% in weight of lubricant, and a diluent in sufficient quantity for 100%.

4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that the sodium alkyl sulfate is added to the purified water for wet granulation.

5. The pharmaceutical composition according to any of claims 1 to 4, characterized in that it is in the form of lozenges, tablets, sachets or powders.

6. The pharmaceutical composition according to claim 1 in the form of a tablet, characterized in that it has the following formulation, expressed in weight percentage: Internal phase N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -methylpyrazolo-3-carboxamide in micronized form 0.59% corn starch 30% lactose monohydrate 200 mesh 60.78% povidone K 30 2.53% cross-linked sodium carboxymethylcellulose 5% Granulation sodium lauryl sulfate 0.1% water CS External phase magnesium stearate 1%

7. The pharmaceutical composition according to claim 1 in the form of a tablet, characterized in that it has the following formulation, expressed in weight percentage: Internal phase N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazolo-3-carboxamide in micronized form 5.88% corn starch 30% lactose monohydrate 200 mesh 55.49 % Povidone K 30 2.53% cross-linked sodium carboxymethylcellulose 5% Granulation laur ilsul f a to sodium 0, 1! water C. S External phase magnesium stearate 1%

8. The pharmaceutical composition according to claim 1 in the form of a tablet, characterized in that it has the following formulation, expressed in weight percentage: Internal phase N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazolo-3-carboxamide in micronized form 17.64% corn starch 30% lactose monohydrate 200 mesh 43,73 % Povidone K 30 2.53% cross-linked sodium carboxymethylcellulose 5% Granulation laur ilsul fa t o sodium 0, 1% water C.S. External phase magnesium stearate 1 9-

9. The process for the preparation of a pharmaceutical composition according to any of claims 1 to 5, characterized in that: a) the active principle, the disaggregation agent and the active ingredient are mixed at room temperature. sodium alkyl sulphate with a diluent, a binder and optionally a dye; b) the mixture is wetted with purified water; c) dry and calibrate the wet mass thus obtained; d) to the calibrated dry grains thus obtained, a lubricant is added, and optionally a nonstick, a draining agent, a colorant and / or a flavoring.

10. The process according to claim 9, for the preparation of a pharmaceutical composition according to one of claims 6 to 8, characterized in that the sodium alkyl sulfate is incorporated in step b).