The present invention is intended to be used in the formulation of a pharmaceutical composition for oral administration of N-pipéridino-5- ((4-chlorophenyl)-1- ((2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide with the formula:
its pharmaceutically acceptable salts and their solvates, hereinafter referred to as compounds of formula (I).
The compounds of formula (I) and their method of preparation are described in European patent application EP 656 354.
N-pipéridino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide also known by the code name SR 141716 and referred to as compound A in the description below, is particularly preferred for the pharmaceutical composition according to the present invention.
The pharmacological properties of formula (I) compounds, which are selective antagonists of the central cannabinoid receptor CBI, have been reported, inter alia, in the publication by Rinaldi-Carmona et al., FEBS Letters, 1994, 240-244.
For oral administration, such compounds must have good absorption, which implies both good solubility in aqueous media and good ability to cross the intestinal membrane (M. Rowland and T.N. Tozer in Clinical Pharmacokinetics, concepts and applications, Lea and Fehiger ed., 1989, 2nd edition, pp. 113-130).
The epithelial permeability of the compounds is assessed by using the Caco-2 cell line, which has the characteristic of differentiating in vitro to form an epithelial monolayer (Crit. Rev. Ther. Drug Carrier System, 1991, 8 (4), 105-330).
In addition, the hydrophobicity of compounds of formula (I) is very marked. For example, it has been observed that compound A is not water-insoluble and that this compound and its salts are practically insoluble in water regardless of pH. These compounds are soluble in alcohols and glycols, especially in polyethylene glycols (PEGs).
However, when solutions obtained with an alcohol or glycol are diluted in aqueous medium, the compound of formula (I) precipitates, due to its strong hydrophobic character.
The compounds of formula (I) and especially compound A are low in electrostatics. Micronization can be performed with good efficiency (about 85%) and yields particles of about 1 micron. Analytical controls performed after micronization show no change in crystal form.
In studying wettability, it was found that the rate of water penetration in a wet granulation powder bed is much higher than that measured in a dry powder bed. The study of the effects of incorporating wettable agents showed that a low concentration of sodium alkylsulfate significantly increases wettability.
In addition, the presence of a breakdown agent, such as cross-linked sodium carboxymethylcellulose, in the formulation has been found to improve the kinetics of dissolution.
Surprisingly, it was found that by combining sodium alkylsulfate and a breakdown agent in the same formula, the formula was quickly completely dissolved, with good reproducibility of results.
Thus, in one aspect, the present invention is concerned with a pharmaceutical composition for oral administration of a compound of formula (I) containing:
0,5% to 20% by weight of a compound of formula (I) in micronised form,0,05% to 0,5% by weight of a sodium alkyl sulphate,2,5% to 10% by weight of a disintegrating agent, and pharmaceutical excipients, the said composition being formulated by wet granulation.
Wet granulation is the pharmaceutical operation by which a mixture of powders containing the active substance constituting the internal phase of the formulation is densified by means of a granulation liquid, the wet mass thus obtained being dried and then calibrated before the ingredients constituting the external phase of the formulation are added.
According to the present invention, sodium alkylsulfate means a (C8-C12) sodium alkylsulfate such as sodium octyl sulfate or preferably sodium lauryl sulfate.
According to the present invention, the term "decomposer" means cellulose or cellulosic derivatives, such as sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, pregelatinised starch, sodium carboxymethylamidone; cross-linked sodium carboxymethylcellulose being a preferred decomposer.
The pharmaceutical compositions according to the present invention may be in the form of capsules, tablets, sachets or powders, preferably in the form of capsules.
The pharmaceutical excipients useful for the pharmaceutical composition according to the present invention include a diluent, a binder and a lubricant, and may also be added a dissolving agent, an anti-adhesive and possibly a colouring and/or flavouring agent.
The diluent used in the present invention may be one or more compounds which are capable of densifying the active substance to the desired mass. The preferred diluents are mineral phosphates, such as calcium phosphates; sugars, such as lactose hydrated or anhydrous, mannitol; and cellulose or cellulosic derivatives, such as microcrystalline cellulose, starch, corn starch or pre-glazed starch. In particular, lactose monohydrate, mannitol, microcrystalline cellulose and corn starch are preferred, used alone or in such a mixture as a mixture of lactose monohydrate and corn starch.
The binder used in the composition of the present invention may be one or more compounds which are capable of densifying a compound of formula (I) by transforming it into larger, denser particles with better flow rate. The preferred binder is alginic acid, sodium alginate; cellulose and cellulosic derivatives, such as sodium carboxymethylcellulose, ethylcellulose, hydroxyetylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose; polymers of acrylic acid povidone, for example povidone K-30; povidone K-30; being a particularly preferred example. The liqueur is present in a proportion of 10% of the pharmaceutical composition depending on the weight.
The lubricant used in the present invention may be one or more compounds which are capable of preventing problems in the preparation of dry forms, such as adhesion and/or grip problems which occur at the machinery level during compression or filling. The preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monosterate, glyceryl palmitosterate, magnesium stearate, sodium laurylphate, sodium stearate, zinc stearate, or stearic acid; the preferred lubricants are vegetable hydrogens, e.g. hydrogen sulphate; the preferred composition of the polymer is 0,2%; the preferred composition of the polymer is 0,5%; the most important component of the invention is magnesium stearate.
The anti-adhesive which may be used in the composition of the present invention may be one or more compounds which are capable of reducing the adhesive character of the formulation, e.g. preventing adhesion to metal surfaces. The preferred anti-adhesive is a compound containing silicon, e.g. silica or talc. The anti-adhesive may be present in a weight ratio of 0 to 5% in the pharmaceutical composition according to the invention.
The flow agent, if any, used in the composition of the present invention may be one or more compounds which are capable of facilitating the flow of the prepared formulation. The preferred flow agents are compounds containing silicon, e.g. anhydrous colloidal silica or precipitated silica. The flow agent may be present in a weight ratio of 0 to 15% in the pharmaceutical composition according to the invention.
The present invention describes the preparation of pharmaceutical formulations by a wet granulation process. For the internal phase, the active substance, diluent, binder, disintegrant, sodium alkyl sulfate, and possibly dye are mixed at room temperature and then moistened with the granulation liquid. The wet mass obtained is dried and then calibrated. The calibrated dry grains are then added to the external phase ingredient (s) namely the lubricant, and possibly the anti-adherent, the drainage agent and, if necessary, the dye and/or flavoring.
The purified water is used as granulation fluid.
In a preferred method, sodium alkylsulfate is added to purified water to make wet granulation.
In particular, the present invention relates to an oral pharmaceutical composition comprising:
0,5% to 20% by weight of compound A in micronised form,0,05% to 0,5% by weight of sodium lauryl sulphate,2,5% to 10% by weight of cross-linked sodium carboxymethyl cellulose, and pharmaceutical excipients, the latter being formulated by wet granulation.
Preferably, the present invention is intended as an oral pharmaceutical formulation, 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 sulphate,5% by weight of cross-linked sodium carboxymethyl cellulose,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 formulations in the form of capsules, prepared by wet granulation, having any of the following formulations expressed as a percentage by weight:
- What?
| i) Phase interne |
| composé A micronisé | 0,59 % |
| amidon de maïs | 30 % |
| lactose monohydrate 200 mesh | 60,78 % |
| povidone K 30 | 2,53 % |
| carboxyméthylcellulose sodique réticulée | 5 % |
| Granulation |
| laurylsulfate de sodium | 0,1 % |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1% |
| ii) Phase interne |
| composé A micronisé | 5,88 % |
| amidon de maïs | 30 % |
| lactose monohydrate 200 mesh | 55,49 % |
| povidone K 30 | 2,53 % |
| carboxyméthylcellulose sodique réticulée | 5 % |
| Granulation |
| laurylsulfate de sodium | 0,1% |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1 % |
| iii) Phase interne |
| composé A micronisé | 17,64 % |
| amidon de maïs | 30 % |
| lactose monohydrate 200 mesh | 43,73 % |
| povidone K 30 | 2,53 % |
| carboxyméthylcellulose sodique réticulée | 5 % |
| Granulation |
| laurylsulfate de sodium | 0,1 % |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1 % |
The characteristics and advantages of the compositions of the invention will be shown in the light of the following description, from the compositions given as examples.
The test
- What?
1.Study of the solubility of compounds of formula (I).
The solubilities of the compounds of formula (I) are measured in different aqueous media. The instantaneous solubility is estimated at room temperature by dosage. The results, expressed in μg per ml, are summarized in Table 1 below.
- What?
TABLEAU 1 | Composé de formule (I) | Milieu de mise en solution |
| | Eau | Eau + 10 % éthanol | Tampon acétique pH 7.5 | Tampon phosphate pH 7.5 |
| Composé A (base) | 1 | 1.2 | 1,9 | 1.6 |
| Chlorhydrate (solvaté) | 37 | 10 | 54 | 0,5 |
| Méthanesulfonate (solvaté) | 39 | 48 | 54 | 0.9 |
| Hydrogénosulfate | 13 | 38 | 30 | 0.9 |
| Paratoluènesulfonate | 3,9 | 7,3 | 2,4 | 0,2 |
| Phosphate | 1,3 | 7,5 | 0,9 | 0.7 |
| Composé A solvaté | 0,7 | 0,9 | 1,2 | 0,9 |
- What?
- What?
The solubility of compound A in various solvents (Table 2) and after dilution in water of the solutions formed (Table 3) was also measured.
- What?
TABLEAU 2 | Solvant | Solubilité du composé A |
| Ethanol | 35 mg/ml |
| Polyéthylèneglycol 400 | 50 mg/ml |
| Polyéthylèneglycol 1500 à 60°C | 80 mg/g |
TABLEAU 3 | Solvant | Solubilité du composé A | Dilution dans l'eau | Quantité de composé A dissous |
| | | | théorique | mesuré |
| Ethanol | 35 mg/ml | 10% | 3,5 mg/ml | |
| Polyéthylèneglycol 400 | 50 mg/ml | 30 % | 15 mg/ml | |
| Polyéthylèneglycol 1500 à 60°C | 80 mg/g | non diluable | | |
- What?
- What?
The moisture-absorbing properties of compound A have been 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 was compared with a formulation (formulation 2) obtained by wet granulation.
- What?
| Formulation 1 |
| composé A | 30 mg |
| amidon de maïs modifié | 48 mg |
| lactose monohydrate cristaux extra fins | 70,1 mg |
| silice colloïdale anhydre | 0,4 mg |
| stéarate de magnésium | 1,5 mg |
| |
| Gélule | |
| Formulation 2 |
| composé A | 30 mg |
| amidon de maïs modifié | 51 mg |
| lactose monohydrate 200 mesh | 83 mg |
| povidone K 30 | 4,3 mg |
| stéarate de magnésium | 1,7 mg |
| |
| Gélule | |
- What?
- What?
The wettability measured by the H. Mohamad method is 22 mg2/s for formulation 1 and 110 mg2/s for formulation 2.
- What?
Thus the wet granulation process improves the wettability by a factor of 5.
- What?
2.2. Influence of the active substance content.
For comparison, wet granulation formulations were prepared in which the active substance content is 10 mg (formulation 3) and 1 mg (formulation 4) respectively.
- What?
TABLEAU 4 | | Formulation 3 | Formulation 4 |
| composé A | 10 mg | 1 mg |
| amidon de maïs | 51 mg | 51 mg |
| lactose monohydrate 200 mesh | 103 mg | 112 mg |
| povidone K 30 | 4,3 mg | 4,3 mg |
| stéarate de magnésium | 1,7 mg | 1,7 mg |
| Gélule | 170 mg | 170 mg |
- What?
- What?
For formulation 3 the wettability is 500 mg2/s.
- What?
For formula 4 the wettability is 1000 mg2/s.
- What?
Thus, the wettability is inversely proportional to the amount of active substance contained in the formula.
- What?
2.3. Influence of excipients
Several formulations were prepared by wet granulation and compared with a reference formulation also obtained by wet granulation.
TABLEAU 5 | | Formulations |
| | | 4 | 5 | 6 | 7 |
| composé A | 30 | 30 | 30 | 30 | 30 |
| amidon de maïs | 51 | 51 | 51 | 51 | 51 |
| lactose monohydrate 200 mesh | 83 | 83 | 83 | 83 | 83 |
| povidone K 30 | 4,3 | 4,3 | 4,3 | 4,3 | 4,3 |
| laurylsulfate de sodium | | 0,17 | 0,85 | | |
| polyéthylèneglycol 6000 | | | | 1,7 | 8,5 |
| stéarate de magnésium | | 1,7 | 1,7 | 1,7 | 1,7 |
| mouillabilité | 600 | 1200 | 2300 | 1100 | 1100 |
| | ±150 | ±300 | ±300 | ±200 | ±200 |
- What?
- What?
Only 0.5% sodium lauryl sulphate significantly improves wettability.
- What?
Wetness measurements are not suitable for studying the effect of a disintegrating agent such as cross-linked sodium carboxymethylcellulose.
- What?
3. study of dissolution in the gastric environment.
The kinetics of dissolution of different formulations in a gastric medium were studied: at 37°C, in a phosphate citrate buffer at pH 3, for 30 minutes.
- What?
When 40 mg of compound A is placed alone in one litre of the solvent, no amount is observed to be dissolved.
- What?
To allow the dissolution of the test formulations, 0.2% sodium lauryl sulphate was added to the medium.as a surfactant.
- What?
For each formulation, 6 tests were carried out and the amount of compound A dissolved in the medium was measured every 5 minutes.
- What?
Table 7 shows the average percentage of dissolved compound A and the average deviation from this value for the different formulations described in Table 6.
- What?
For formulations C and D containing 1% and 5% of polyethylene glycol 6000 respectively, maximum dissolution is not achieved until 30 minutes have passed.
- What?
For formulations A and B containing 0,1% and 0,5% sodium lauryl sulphate respectively,the maximum value is reached after 20 minutes and 30 minutes respectively.
- What?
In addition, the measured results are dispersed for each of the formulations A, B, C or D.
- What?
The results obtained with formulations E, F, G show the interest of the presence of cross-linked sodium carboxymethylcellulose to promote dissolution.
- What?
For formulations E and G containing 5% and 2,5% of cross-linked sodium carboxymethylcellulose, 100% of compound A is dissolved after 20 minutes or 15 minutes respectively and results are relatively dispersed within the first 15 minutes.
- What?
Formulation F containing both 0,The best results are obtained by using 1% sodium lauryl sulphate and 5% cross-linked sodium carboxymethyl cellulose, since after 15 minutes all the A compound is dissolved and the difference between the results of the various tests is very small (between 2.3 and 1.5 between 15 and 30 minutes).
- What?
5. Assessment of the intestinal trans-epithelial passage of compound A.
On polycarbonate microporous filters covered with collagen, Caco-2 cells are seeded. The monolayer of cells formed on the filter then allows the apical compartment (mimicking the intestinal light) to be separated from the basal compartment (mimicking the blood circulation).
- What?
The composition containing the compound to be studied is placed on the apical side and the passage of this compound is assessed.The aqueous medium, pH = 6,5, has the following composition: NaCl = 8,0 g/l; KCl = 0,4 g/l; CaCl2 = 0,19 g/l; MgCl2 = 0,1 g/l; MgSO4 = 0,1 g/l; Na2HPO4 = 0,09 g/l; KH2PO4 = 0,06 g/l; NaHCO3 = 0,35 g/l; glucose = 1 g/l; red phenol = 0,01 g/l.
- What?
The permeability coefficient P is then determined in cm/s.
in which:
da/dt = change in the amount of test compound passing through the cell monolayer with time (moles/s)A = monolayer surface (cm2)Co = initial concentration of test compound (moles/l)
- What?
3.1. Permeability coefficient of the compound A introduced into the medium of Hank in solution 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.
- What?
3.2 Relative rate of trans-epithelial intestinal passage of compound A.
The rate of passage of compound A in the X formula was measured and compared with that of compound A in suspension.
- What?
| Formulation X |
| composé A | 30 mg |
| amidon de maïs modifié | 51 mg |
| lactose monohydrate 200 mesh | 83 mg |
| povidone K 30 | 4,3 mg |
| laurylsulfate de sodium | 0,17 mg |
| carboxyméthylcellulose sodique réticulée | 8,5 mg |
| stéarate de magnésium | 1,7 mg |
| |
| Gélule | |
| Formulation du composé A | vitesse de passage relative |
| Composé A en suspension dans le milieu de Hank | 1 |
| Composé A formulé dans X | 7 |
A capsule prepared by wet granulation and having the following composition:
- What?
| Phase interne |
| composé A micronisé | 1 mg |
| amidon de maïs | 51 mg |
| lactose monohydrate 200 mesh | 103,33 mg |
| povidone K 30 | 4,3 mg |
| carboxyméthylcellulose sodique réticulée | 8,5 mg |
| Granulation |
| laurylsulfate de sodium | 0,17 mg |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1,7 mg |
| Pour une gélule blanc opaque de taille 3 terminée à | 170 mg |
A capsule prepared by wet granulation and having the following composition:
- What?
| Phase interne |
| composé A micronisé | 10 mg |
| amidon de maïs | 51 mg |
| lactose monohydrate 200 mesh | 94,33 mg |
| povidone K 30 | 4,3 mg |
| carboxyméthylcellulose sodique réticulée | 8,5 mg |
| Granulation |
| laurylsulfate de sodium | 0,17 mg |
| eau purifiée | Q.S. |
| Phase externe | |
| stéarate de magnésium | 1,7 mg |
| Pour une gélule blanc opaque de taille 3 terminée à | 170 mg |
A capsule prepared by wet granulation and having the following composition:
- What?
| Phase interne |
| composé A micronisé | 30 mg |
| amidon de maïs | 51 mg |
| lactose monohydrate 200 mesh | 74,33 mg |
| povidone K 30 | 4,3 mg |
| carboxyméthylcellulose sodique réticulée | 8,5 mg |
| Granulation |
| laurylsulfate de sodium | 0.17 mg |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1,7 mg |
| Pour une gélule blanc opaque de taille 3 terminée à | 170 mg |
A capsule prepared by wet granulation with the following composition
- What?
| Phase interne |
| composé A micronisé | 30 mg |
| amidon de maïs | 51 mg |
| lactose monohydrate 200 mesh | 73,65 mg |
| povidone K 30 | 4,3 mg |
| carboxyméthylcellulose sodique réticulée | 8,5 mg |
| Granulation |
| laurylsulfate de sodium | 0,85 mg |
| eau purifiée | Q.S. |
| Phase externe |
| stéarate de magnésium | 1,7 mg |
| Pour une gélule blanc opaque de taille 3 terminée à | 170 mg |
| Phase interne |
| composé A micronisé |
1 mg |
| amidon de maïs |
50 mg |
| lactose monohydrate 200 mesh |
130 mg |
| hydroxypropylméthylcellulose 6 cP |
6 mg |
| carboxyméthylcellulose sodique réticulée |
10 mg |
| Granulation |
| laurylsulfate de sodium |
1 mg |
| eau purifiée |
Q.S. |
| Phase externe |
| stéarate de magnésium |
2 mg |
| Pour un comprimé terminé à |
200 mg |
| |
EXAMPLE 6: 10 mg tablet is not intended for use in children
| Phase interne |
| composé A micronisé |
10 mg |
| amidon de maïs |
50 mg |
| lactose monohydrate 200 mesh |
211,5 mg |
| hydroxypropylméthylcellulose 6 cP |
9 mg |
| carboxyméthylamidon sodique |
15 mg |
| laurylsulfate de sodium |
1,5 mg |
| Granulation |
| eau purifiée |
Q.S. |
| Phase externe |
| stéarate de magnésium |
3 mg |
| Pour un comprimé terminé à |
300 mg |
EXAMPLE 7: 30 mg tablet is not intended for use in the treatment of patients with severe liver disease.
| Phase interne |
| composé A micronisé |
30 mg |
| amidon de maïs |
80 mg |
| lactose monohydrate 200 mesh |
252mg |
| povidone K 30 |
12 mg |
| carboxyméthylcellulose sodique réticulée |
20 mg |
| laurylsulfate de sodium |
2 mg |
| Granulation |
| eau purifiée |
Q.S. |
| Phase externe |
| stéarate de magnésium |
4 mg |
| Pour un comprimé terminé à |
400 mg |