CA2281560A1 - Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium - Google Patents
Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium Download PDFInfo
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- CA2281560A1 CA2281560A1 CA002281560A CA2281560A CA2281560A1 CA 2281560 A1 CA2281560 A1 CA 2281560A1 CA 002281560 A CA002281560 A CA 002281560A CA 2281560 A CA2281560 A CA 2281560A CA 2281560 A1 CA2281560 A1 CA 2281560A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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Abstract
The invention concerns a pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium, containing: active principle: 0.1 to 15 wt.%; hydrophilic solvent: 0 to 60 wt.%; anionic surfactant 0 to 5 wt.%; polysorbate 80: 0 to. 5 wt.%; macrogoglyceride in sufficient amount. for 100 wt.%, provided that at least one selected constituent between the hydrophilic solvent and the anionic surfactant is present.
Description
' CA 02281560 1999-08-16 Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium The present invention relates to novel pharmaceutical compositions in which a heterocyclic compound in quaternary ammonium form is present as the S active principle.
In particular, the invention relates to pharmaceutical compositions for oral administration which contain, as the active principle, a compound of the formula Q
A~. ArrY(CH2)2-~-CH2-N-T-A-Z (I) Ar in which:
- A~ is a pharmaceutically acceptable anion;
- Am~ is:
i - either a group Am,~ of the formula /W~
Arl-(CH2)x NO
in which:
- Arl is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C,-C4)alkoxy, a (Cl-C4)-alkyl and a trifluoromethyl, said substituents being identical or different;
- x is zero or one; and - W1 is a (C,-C6)alkyl or a benzyl group, the substituent Wl being either in the axial position or in the equatorial position;
ii - or a group Amz of the formula /Wt Are-(CH2)X NO
Ri in which:
- Arl, x and W, are as defined above; and - R~ is a hydroxyl, a (Ci-C.~)alkoxy, a formyloxy, a (C1-C3)alkylcarbonyloxy, a carboxyl, a (C1-C4)alkoxycarbonyl, a cyano, a (C,-C3)alkylcarbonylamino, a mercapto or a (C1-C4)alkylthio;
iii - or a group Am3~ of the formula /Wi Arl-N N-+~
in which:
S - Ar, and W 1 are as defined above; and - R2 is hydrogen, a (C~-C3)alkyl or a (C,-C3)alkylcarbonyl;
iv - or a group Am4~ of the formula (CH2)P
Arl-(CH2)X N-0+
in which:
- Arl and x are as defined above; and - p is one or two;
v - or a group Ams~ of the formula N-Arl-(CH2)X O+
in which:
- Are and x are as defined above;
- Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C3)alkoxy, a (C,-C3)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl;
an indolyl;
- Q and Y have one of the following groups of meanings:
a) Q ~ and Y a b) Q2 and Y2 when Am~ is a group Ami~, Am2 , Am4~ or Ams~;
c) Q3 and Y3 when Am~ is a group Am~~ or Am2 or a group Am4~ in which Are is a phenyl and p is two; or d) Q4 and Y4 when Am~ is a group Am,~, Am3~, Aln4~ or Am5~;
- Q1 is hydrogen;
- Y1 is hydrogen ; a (C,-C4)alkyl ; an ~-(C1-C4)alkoxy-(C2-C4)alkylene ; an w-(C,-C4)alkylcarbonyloxy-(C2-C4)alkylene ; an w-benzoyloxy-(C2-C4)alkylene, an w-hydroxy-(C2-C4)alkylene ; an w-(C,-C4)alkylthio-(C2-C4)alkylene ; an w-(C,-C4)-alkylcarbonyl-(C2-C4)alkylene ; an w-carboxy-(C2-C4)alkylene ; an w-(Cl-C4)-alkoxycarbonyl-(C2-C4)alkylene ; an w-benzyloxy-(C2-C4)alkylene ; an w-formyl-oxy-(Cz-C4)alkylene; an w-R3NHC00-(C2-C4)alkylene; an w-R4RSNC0-(C2-C4)-alkylene; an w-R6CONR~-(C2-C4)alkylene; an w-RgOCONR~-(C2-C4)alkylene; an w-R4RSNCONR~-(C2-C4)alkylene ; an w-R9S02NR~-(C2-C4)alkylene ; an w-cyano-(C,-C3)alkylene;
- Q2 and YZ together form an ethylene, trimethylene or tetramethylene group;
- Q3 and Y3 together form a group O
-(CH2)n-C- in which n is one, two or three ;
- Q4 and Y4 together form a radical selected from:
A 1 ) -O-CH2_ A2) -O-CO-A3) -CH2-O-CO-Aq,) -O-CH2-CO-AS) -O-CH2-CH2_ A6) _N(R10)_CO_ A~) -N(R10)-CO-CO-Ag) -N(R10)-CH2-CH2_ - T is either a group -CO- when Q and Y are the groups Q1 and Y~, the groups QZ
and Y2 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A1), AS) or Ag); or a group -CH2- when Q and Y are the groups Q3 and Y3 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A2), A3), A4), A6) or A~);
- A is either a direct bond or a methylene group when T is -CO-, or a direct bond when T is -CH2-;
- Z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or polysubstituted by a (C,-C4)alkyl; a benzylamino; a carboxyl; a (Ci-Clo)alkyl;
a (C3-C~)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C,-C,o)alkoxy; a (C3-C~)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C,o)alkylthio; a (Ci-C6)alkylcarbonyloxy; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C~)cycloalkylcarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C,-C4)alkyl or a (C3-C~)cycloalkyl; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C,-C4)alkyl, a hydroxyl or a (Ci-C4)alkoxy;
- a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl;
- R3 is a (Ci-C~)alkyl or a phenyl;
- R4 and RS are each independently a hydrogen or a (C1-C~)alkyl; RS can also be a (C3-C~)cycloalkyl, a (C3-C~)cycloalkylmethyl, a phenyl or a benzyl; or R4 and R5, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C~-C4)alkyl;
- R6 is a hydrogen, a (Ci-C~)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C~)cycloalkyl which is unsubstituted or substituted by one or more methyls;
- R~ is a hydrogen or a (Ci-C~)alkyl;
- R8 is a (C~-C~)alkyl or a phenyl;
- R9 is a (C,-C~)alkyl; an amino which is unsubstituted or substituted by one or two (C~-C~)alkyls; a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (C,-C~)alkyl, a trifluoromethyl, a hydroxyl, a (C~-C~)alkoxy, a carboxyl, a (C1-C~)alkoxycarbonyl, a (C~-C~)alkylcarbonyloxy, a cyano, a nitro and an amino which is unsubstituted or substituted by one or two (C~-C~)alkyls, said substituents being identical or different;
- Rlo is hydrogen or a (C1-C4)alkyl, and its optional salts with mineral or organic acids, and their optional solvates.
The compounds of formula (I) which are useful for the invention include both the racemates and the optically pure isomers, as well as the axial and equatorial isomers when Am~ in the compound of formula (I) is a group Ami~, a group Am2~ or a group Am3~.
The compounds of formula (I) are described in patent applications EP-A-0 512 901, EP-A-0 515 240, EP-A-0 559 538, EP-A-0 591 040, WO 95/26 339, EP-A-0 700 382, EP-A-0 723 959 and WO 96/23 787.
Among the compounds of formula (I), those of the formula (CH2)P~
A . Arl-(CHz)x N-O(CH2)2 N-CO-CHZ-Z (I ) Ar' in which:
- Are, x, p and AD are as defined for a compound of formula (I);
- Ar' is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z' is a phenyl substituted in the 3-position by a halogen or a (C1-Cio)alkoxy, are preferred for the invention.
More particularly, the invention relates to pharmaceutical compositions for the oral administration of (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl-acetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, or SR
140333, of the formula N-(CH2)2 (S) N-CO-CH2 O CH, -O\ , s CH
Cl CH3 Cl in which A~ is a pharmaceutically acceptable anion.
The benzenesulfonate of SR 140333, hereafter called compound A, is very particularly preferred. The international non-proprietary name of compound A
is nolpitantium besilate.
The compounds of formula (I) have been described as antagonists of substance P, which is the natural agonist of the NK1 receptors. For oral administration, such compounds must have a good absorption, which entails both a good solubility in aqueous media and a good capacity to pass through the intestinal membrane (M. Rowland and T.N. Tozer in Clinical pharmacokinetics, concepts and applications, published by Lea and Fehiger, 1989, 2nd edition, pp. 113 -130).
The solubility of the compounds of formula (I) has been studied in different media: their solubility in water is generally below 5 mg/ml, but they are soluble in hydrophilic solvents such as alcohols or glycols.
Being quaternary ammonium compounds, the compounds of formula (I) remain in ionized form irrespective of the pH of the medium in which they are present, especially at neutral pH, which is the pH of the intestinal medium.
It is known that ionic compounds, especially quaternary ammonium compounds, cannot easily pass through the epithelial membranes (J.P. Labaune in Pharmacocinetique, Principes fondamentaux, published by Masson, 1988, 2nd edition, pp. 7 - 33).
The cell line Caco-2 has the particular characteristic of exhibiting differentiation in vitro to form an epithelial monolayer. This line is conventionally used for evaluating the ability of compounds to permeate the epithelium (Crit.
Rev.
Ther. Drug Carrier System, 1991, 8 (4), 105 - 330).
1 S In this model, the permeability to compound A is 3.4.10'' cm/s.
Furthermore, correlations made between the in vitro results and the in vivo results have shown that a coefficient of permeability of this order corresponds to an absorption of less than 5% for totally solubilized molecules. In the present case, studies performed on the rat with a 0.6% aqueous solution of compound A in methyl cellulose have shown that its estimated absorption is less than 1 %.
Thus, to develop an oral galenic formulation for the compounds of formula (I), it is necessary to overcome both their very low solubility in aqueous media and their poor passage through the intestinal epithelium.
To modify the particular cationic character due to the quaternary ammonium form of the compounds according to the invention, it is possible to transform them by adding a stoichiometric amount of an anionic surfactant to give an ion pair of overall neutral charge. However, the ion pair formed between the cationic part of the compound of formula (I) and the anionic part of the surfactant has a higher molecular weight than the compound (I), so its hydrophobic character increases and this ion pair is practically insoluble in water.
It has been found that the intestinal absorption of the ion pair formed by a compound of formula (I) and an anionic surfactant decreases relative to that of a compound of formula (I) in ammonium form.
Non-ionic surfactants and absorption promoters have also been tested in order to find out their effect on the ability of a compound of formula (I) to permeate membranes. These products have not shown any positive effects.
Derivatives are known which are in semi-solid form at ordinary temperature and which, by possessing both lipidic character and amphiphilic character, can be used to solubilize lipophilic active principles and facilitate their intestinal absorption (Bull. Techn. Gattefosse, 1994, 87 49 - 54). Such compounds are selected from saturated polyglycosylated glycerides consisting of a mixture of glycerol monoesters, diesters and triesters of fatty acids with Cg-C1g hydrocarbon chains, and polyethylene glycol monoesters and diesters of fatty acids with Cg-C,8 hydrocarbon chains. The most valuable of these are:
- lauroyl macrogoglyceride with a melting point of 44°C and a hydrophilic/
lipophilic balance (HLB) of 14;
- stearoyl macrogoglyceride with a melting point of 50°C and a hydrophilic/
lipophilic balance of 13; and - caprylocaproyl macrogoglyceride, an oily liquid with a hydrophilic/
lipophilic balance of 14.
These compounds are marketed by Gattefosse under the trade marks Gelucire° 44-14, Gelucire~ 50-13 and Labrasol°
respectively.
The compounds (I) of hydrophilic character are not soluble in such derivatives; in particular, they are not soluble in the products Gelucire~ 44-14, Gelucire° 50-13 and Labrasol~.
According to the present invention, it has now been found that a compound of formula (I) can be solubilized in a saturated polyglycosylated glyceride provided that at least one of the following constituents:
- a hydrophilic solvent - an anionic surfactant is added.
The resulting formulation makes it possible to improve the bioavailability of the active principle.
It is also advantageous to solubilize a compound of formula (I) in a saturated polyglycosylated glyceride by adding both a hydrophilic solvent and an anionic surfactant.
Surprisingly, it has been found that the addition of one particular polysorbate, namely polysorbate 80, to a solution of compound A in the cell culture medium improves the transepithelial passage in the Caco-2 model.
It can thus be advantageous to add a small proportion of polysorbate 80 to the formulation determined above.
Thus, according to one of its aspects, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1% to 15% by weight - hydrophilic solvent 0% to 60% by weight - anionic surfactant 0 to S% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride in sufficient amount (QS) for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present. Preferably, in the absence of anionic surfactant, the concentration of active principle is less than or equal to 30%
by weight of the concentration of hydrophilic solvent.
According to the present invention, macrogoglyceride is understood as meaning the products Gelucire° 44-14, Gelucire° 50-13 and Labrasol° as described above, the product Gelucire ° 44-14 being preferred.
The hydrophilic solvent used can be an alcohol such as ethanol or a glycol derivative such as propylene glycol or the product Transcutol°, which is a monoethyl ether of diethylene glycol. Propylene glycol is the preferred hydrophilic solvent.
The anionic surfactant used can be a bile salt such as sodium taurocholate or a sodium alkylsulfate such as sodium octylsulfate or, preferably, sodium lauryl-sulfate, the latter being a preferred anionic surfactant according to the invention.
The pharmaceutical compositions according to the invention can be presented in different forms intended for oral administration, examples being gelatin capsules, sachets, drops, vials to be taken orally, or bottles.
Advantageously the present invention relates to a pharmaceutical com-position which contains:
- active principle 0.1% to 15% by weight - hydrophilic solvent 1% to 60% by weight - anionic surfactant 0.03% to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
In particular, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1 to 15% by weight - hydrophilic solvent 5 to 60% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent.
In particular also, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1 to 15% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0.03 to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
According to the invention, the anionic surfactant is preferably in a stoichiometric amount relative to the active principle. As the anionic surfactant is introduced in concentrated aqueous solution, the above pharmaceutical composition contains from 0.1 to 12% of water.
When preparing gelatin capsules of the soft or hard type, the proportion of hydrophilic solvent in the pharmaceutical composition must be compatible with gelatin. Thus the present invention relates more particularly to pharmaceutical compositions for the preparation of gelatin capsules which contain:
- active principle 0.1 to 9% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0 to 3% by weight - polysorbate 80 0 to 5% by weight macrogoglyceride QS for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.
Pharmaceutical compositions for the preparation of gelatin capsules which contain:
- active principle 0.1 to 7% by weight - hydrophilic solvent 5 to 20% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to about 30% by weight of the concentration of hydrophilic solvent, are very particularly preferred.
Pharmaceutical compositions for the preparation of gelatin capsules which 5 contain:
- active principle 0.1 to 7% by weight - hydrophilic solvent 0 to 15% by weight - anionic surfactant 0.03 to 2% by weight - polysorbate 80 0 to 5% by weight 10 - macrogoglyceride QS for 100% by weight are also preferred.
The anionic surfactant is preferably in a stoichiometric amount relative to the active principle.
The pharmaceutical composition according to the invention preferably contains an amount greater than or equal to 1 % by weight of hydrophilic solvent and particularly preferably contains an amount greater than or equal to 1 % by weight of propylene glycol.
It is also possible to prepare enteric formulations for pharmaceutical compositions in the form of gelatin capsules.
Such formulations are used to protect the active principle from the strong acidity in the stomach. They are prepared by coating the gelatin capsule with a polymer film which is insoluble in an acid environment and soluble in a basic environment. Examples of coating films which may be mentioned are cellulose acetophthalate, polyvinyl acetophthalate, hydroxypropyl methyl cellulose phthalate or methacrylic acid copolymers.
Examples of methacrylic acid copolymers which may be mentioned are the type C methacrylic acid copolymer marketed under the trade mark EUDRAGIT°
L30 D-SS by ROHM, or the ethyl acrylate/methacrylic acid copolymer marketed under the trade mark KOLLICOAT~ MAE 30D by BASF.
The elasticity of the coating film can be increased by adding plasticizers such as a polyethylene glycol, 1,2-propylene glycol, dibutyl phthalate or a citrate.
In certain cases, in particular when preparing enteric formulations with gelatin capsules, it may be preferable to cover the gelatin capsule with a film coating consisting of a precoating before the enteric coating. The precoating can be made, for example, of hydroxypropyl cellulose, povidone or a methacrylic acid copolymer in association with appropriate excipients.
In one particular embodiment, the present invention relates to a pharma-ceutical composition for the oral administration of compound A which contains:
compound A 0.1 to 9% by weight propylene glycol 1 to 30% by weight sodium laurylsulfate 0 to 3% by weight Gelucire° 44-14 QS for 100% by weight.
More particularly, the present invention relates to a pharmaceutical composition of the following formulation:
compound A 0.1 to 7% by weight propylene glycol 5 to 20% by weight Gelucire~ 44-14 QS for 100% by weight, with the proviso that the concentration of compound A is less than or equal to about 30% by weight of the concentration of propylene glycol.
The present invention further relates to a pharmaceutical composition of the following formulation:
compound A 0.1 to 7% by weight propylene glycol 1 to 15% by weight sodium laurylsulfate 0.03 to 2% by weight Gelucire~ 44-14 QS for 100% by weight, the sodium laurylsulfate preferably being in a stoichiometric amount relative to the compound A.
In one particular embodiment, the present invention relates to a pharma-ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.6% by weight propylene glycol 15.9% by weight Gelucire~ 44-14 80.5% by weight.
In another particular embodiment, the present invention relates to a pharma-ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.4% by weight propylene glycol 15.3% by weight sodium laurylsulfate 1.5% by weight water 2.7% by weight Gelucire ° 44-14 77.1 % by weight.
A pharmaceutical composition as described above can be prepared by the following procedure when there is no anionic surfactant in the composition:
the active principle is suspended in the hydrophilic solvent and the suspension is heated, with stirnng, to a temperature of between 60°C and 80°C, depending on the concentration of active principle introduced into the hydrophilic solvent. 90%
of the macrogoglyceride, molten at 60°C, is added, optionally followed by the polysorbate 80. Finally the appropriate amount of macrogoglyceride is added to make up to 100%.
When the pharmaceutical composition contains an anionic surfactant, it can be prepared by the following procedure: the active principle is mixed with 90%
of the macrogoglyceride heated to 60°C. The anionic surfactant, dissolved hot in the minimum amount of water, is added to the suspension formed, followed, if appropriate, by the hydrophilic solvent and the polysorbate 80. Finally the appropriate amount of macrogoglyceride is added to make up to 100%.
Very particularly, when preparing enteric formulations, the film coating of a gelatin capsule according to the invention can contain a precoating film and a coating film of the following compositions:
Precoating:
type C methacrylic acid copolymer 46.6% by weight glycerol 4.6% by weight polysorbate 80 in 33% aqueous solution 4.6% by weight water 44.2% by weight.
Coating:
type C methacrylic acid copolymer 54.8% by weight glycerol 3.3% by weight polysorbate 80 in 33% solution 0.7% by weight water 41.2% by weight.
The characteristics and advantages of the compositions according to the invention will become apparent from the following description based on the compositions given as Examples. In these Examples, the percentages are expressed by weight.
TESTS
1. Testing of the solubility of compound A
1.1. Solubility in water The solubility was measured at the saturation point, after 24 hours, at room temperature; the measurements were made by UV spectrometry at ~, = 275 nm after calibration in an ethanolic solution.
Concentration of compound0.31 0.31 0.31 0.29 0.31 A
m /ml 1.2. Solubility in different solvents The instantaneous solubility is evaluated, at room temperature, by successive additions of the studied solvent to compound A in a hemolysis tube until limpidity is observed.
Taking the density differences into account, the solubilities are determined by weight/weight.
water 0.33 mg/g ethanol 36.5 mg/g methanol 365.0 mg/g benzyl alcohol > 450.0 mg/g Transcutol~ 5.0 mg/g polyethylene glycol 400 0.45 mg/g propylene glycol 12 mg/g glycerol oleate 0.64 mg/g groundnut oil < 0.2 mg/g Gelucire 44-14 < 0.2 mg/g Compound A is also soluble ide (DMSO) in an in dimethyl sulfox amount of 168 mg/ml.
1.3. Variation in the solubilityin propyleneglycol as a function of temperature Solubility of compound A in propylene glycol Concentration of 12 155 350 com ound A in m /
1.4. Study of the solubility in glycerides Solubility of compound A in Gelucire~ 44-14 Concentration < 0.2 0.4 of com ound A in m /
1.5. Solubility of compound A in water in the presence of a stoichiometric amount of sodium laurylsulfate: below 0.1 ~g/ml.
2. Evaluation of the intestinal transepithelial passage of compound A
Caco-2 cells are inoculated onto microporous polycarbonate filters covered with collagen. The cellular monolayer formed on the filter then makes it possible to separate an apical compartment (imitating the intestinal lumen) from a basal compartment (imitating the blood circulation).
The composition containing the compound to be studied is then placed on the apical side and the passage of this compound, dispersed or solubilized in Hank's medium, through this cellular barner is evaluated by measuring the kinetics of its appearance on the basal side. This aqueous medium, of pH 6.5, has the following composition: NaCI = 8.0 g/1; KCl = 0.4 g/1; CaCl2 = 0.19 g/1; MgCl2 =
0.1 g/l; MgS04 = 0.1 g/1; Na2HP04 = 0.09 g/l; KH2P04 = 0.06 g/l; NaHC03 = 0.35 g/1; glucose = 1 g/l; phenol red = 0.01 g/1.
The coefficient of permeability P, in cm/s, which characterizes the rate of passage of the molecule through the membrane, is then determined, namely:
P = (da/dt).(1/A.Co) where:
da/dt = variation of the amount of test compound passing through the cellular monolayer as a function of time (molls) A = surface area of the monolayer (cm2) Co = initial concentration of the tested compound (mol/1) 2.1. Coefficient of permeability to compound A, introduced in Hank's medium, in solution in DMSO
P = 3.4.10-~ cm/s The permeability to compound A measured in this way in solution (in DMSO) indicates an intrinsic characteristic of this compound. This result confirms the very poor ability of compound A to pass through the epithelium.
2.2. Relative rate of intestinal transepithelial passage of compound A
Different formulations were prepared with compound A so as to measure their rate of passage and compare it with that of compound A in solution in DMSO
Formulation 1:
- compound A 4.4%
- propylene glycol 15.9%
5 - Gelucire~ 44-14 79.7%
Formulation 2:
- compound A 4.2%
- Gelucire 44-14 76.3%
- propylene glycol 15.3%
10 - sodium laurylsulfate 1.4%
- H20 2.8%
Formulation 3:
- compound A 4.3%
- Gelucire 44-14 91.23%
15 - sodium laurylsulfate 1.52%
- H20 2.95%
Formulation 4:
- compound A 4.31 - Gelucire~ 44-14 91.19%
- sodium octylsulfate 1.53%
- H20 2.97%
Formulation 5:
- compound A 7.4%
- propylene glycol 28.7%
- Gelucire~ 44-14 63.9%
Formulation 6:
- compound A 8%
- propylene glycol 46%
- Gelucire 44-14 46%
Formulation 7:
- compound A 6%
- propylene glycol 34%
- Labrasol~ 60%
FormulationSolution1 2 3 4 5 6 7 DMSO
Relative 1 12 15 7 7 10 8 10 rate Each of these formulations causes a notable improvement in the transepithelial passage of compound A and none of these formulations caused a deterioration of the epithelial monolayer.
All these formulations were observed under the optical microscope. Total solubilization of compound A was found, except in the case of formulations 3 and 4, where compound A is partially in crystalline form.
The best result is obtained with formulation 2, which combines the formation of the ion pair with sodium laurylsulfate and the use of a mixture of Gelucire~ 44-14 and propylene glycol.
EXAMPLE 1: Gelatin capsule compound A 4.4%
propylene glycol 15.9%
Gelucire° 44-14 79,7%
for a size 1 white-opaque gelatin capsule.
The active principle is solubilized in the propylene glycol at 70°C, the solution obtained is then incorporated into the Gelucire° 44-14 at 60°C, with mechanical stirring, and finally the gelatin capsule is filled at 40°C.
EXAMPLE 2: Gelatin capsule compound A 4.2%
propylene glycol 15.3%
sodium laurylsulfate in 34%
aqueous solution 1.4%
water 2.8%
Gelucire~ 44-14 76.3%
for a size 1 white-opaque gelatin capsule.
The active principle is mixed with 90% of the Gelucire~ 44-14 heated to 60°C. The aqueous sodium laurylsulfate solution is added and the remaining Gelucire° 44-14 is then added to make up to 100%. The mixture is incorporated into the gelatin capsule after cooling to 40°C.
EXAMPLE 3: Liquid form for bottles compound A 6.0%
propylene glycol 34.0%
Labrasol~ 60.0%
EXAMPLE 4: Vial to be taken orally compound A g,0%
propylene glycol 46.0%
Gelucire 44-14 46.0%
EXAMPLE 5: Gelatin capsule compound A 4.5%
propylene glycol 15.0%
Gelucire~ 44-14 80.5%
EXAMPLE 6: Gelatin capsule compound A 4.4%
propylene glycol 13.0%
sodium laurylsulfate 1.5%
water 3.0%
Gelucire 44-14 78.1%
EXAMPLE 7: Liquid for bottles compound A g,0%
propylene glycol 27.5%
polysorbate 80 2.0%
Labrasol 62.5%
EXAMPLE 8: Liquid for bottles compound A 7.5%
propylene glycol 20.5%
polysorbate 80 2.0%
sodium laurylsulfate 2.6%
water 4.9%
Labrasol 62.5%
EXAMPLE 9: Enteric gelatin capsule A gelatin capsule is prepared according to Example l and a film coating is applied in 2 layers, one a precoating layer and the other a coating layer.
Precoating:
Eudragit~ L30 D-55 46.6%
glycerol 4.6%
polysorbate 80 in 33% aqueous solution4.6%
water 44.2%
Coating:
Eudragit~ L30 D-55 54.8%
glycerol 3.3%
polysorbate 80 in 33% aqueous solution0.7%
water 41.2%
In particular, the invention relates to pharmaceutical compositions for oral administration which contain, as the active principle, a compound of the formula Q
A~. ArrY(CH2)2-~-CH2-N-T-A-Z (I) Ar in which:
- A~ is a pharmaceutically acceptable anion;
- Am~ is:
i - either a group Am,~ of the formula /W~
Arl-(CH2)x NO
in which:
- Arl is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C,-C4)alkoxy, a (Cl-C4)-alkyl and a trifluoromethyl, said substituents being identical or different;
- x is zero or one; and - W1 is a (C,-C6)alkyl or a benzyl group, the substituent Wl being either in the axial position or in the equatorial position;
ii - or a group Amz of the formula /Wt Are-(CH2)X NO
Ri in which:
- Arl, x and W, are as defined above; and - R~ is a hydroxyl, a (Ci-C.~)alkoxy, a formyloxy, a (C1-C3)alkylcarbonyloxy, a carboxyl, a (C1-C4)alkoxycarbonyl, a cyano, a (C,-C3)alkylcarbonylamino, a mercapto or a (C1-C4)alkylthio;
iii - or a group Am3~ of the formula /Wi Arl-N N-+~
in which:
S - Ar, and W 1 are as defined above; and - R2 is hydrogen, a (C~-C3)alkyl or a (C,-C3)alkylcarbonyl;
iv - or a group Am4~ of the formula (CH2)P
Arl-(CH2)X N-0+
in which:
- Arl and x are as defined above; and - p is one or two;
v - or a group Ams~ of the formula N-Arl-(CH2)X O+
in which:
- Are and x are as defined above;
- Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C3)alkoxy, a (C,-C3)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl;
an indolyl;
- Q and Y have one of the following groups of meanings:
a) Q ~ and Y a b) Q2 and Y2 when Am~ is a group Ami~, Am2 , Am4~ or Ams~;
c) Q3 and Y3 when Am~ is a group Am~~ or Am2 or a group Am4~ in which Are is a phenyl and p is two; or d) Q4 and Y4 when Am~ is a group Am,~, Am3~, Aln4~ or Am5~;
- Q1 is hydrogen;
- Y1 is hydrogen ; a (C,-C4)alkyl ; an ~-(C1-C4)alkoxy-(C2-C4)alkylene ; an w-(C,-C4)alkylcarbonyloxy-(C2-C4)alkylene ; an w-benzoyloxy-(C2-C4)alkylene, an w-hydroxy-(C2-C4)alkylene ; an w-(C,-C4)alkylthio-(C2-C4)alkylene ; an w-(C,-C4)-alkylcarbonyl-(C2-C4)alkylene ; an w-carboxy-(C2-C4)alkylene ; an w-(Cl-C4)-alkoxycarbonyl-(C2-C4)alkylene ; an w-benzyloxy-(C2-C4)alkylene ; an w-formyl-oxy-(Cz-C4)alkylene; an w-R3NHC00-(C2-C4)alkylene; an w-R4RSNC0-(C2-C4)-alkylene; an w-R6CONR~-(C2-C4)alkylene; an w-RgOCONR~-(C2-C4)alkylene; an w-R4RSNCONR~-(C2-C4)alkylene ; an w-R9S02NR~-(C2-C4)alkylene ; an w-cyano-(C,-C3)alkylene;
- Q2 and YZ together form an ethylene, trimethylene or tetramethylene group;
- Q3 and Y3 together form a group O
-(CH2)n-C- in which n is one, two or three ;
- Q4 and Y4 together form a radical selected from:
A 1 ) -O-CH2_ A2) -O-CO-A3) -CH2-O-CO-Aq,) -O-CH2-CO-AS) -O-CH2-CH2_ A6) _N(R10)_CO_ A~) -N(R10)-CO-CO-Ag) -N(R10)-CH2-CH2_ - T is either a group -CO- when Q and Y are the groups Q1 and Y~, the groups QZ
and Y2 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A1), AS) or Ag); or a group -CH2- when Q and Y are the groups Q3 and Y3 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A2), A3), A4), A6) or A~);
- A is either a direct bond or a methylene group when T is -CO-, or a direct bond when T is -CH2-;
- Z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or polysubstituted by a (C,-C4)alkyl; a benzylamino; a carboxyl; a (Ci-Clo)alkyl;
a (C3-C~)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C,-C,o)alkoxy; a (C3-C~)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C,o)alkylthio; a (Ci-C6)alkylcarbonyloxy; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C~)cycloalkylcarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C,-C4)alkyl or a (C3-C~)cycloalkyl; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C,-C4)alkyl, a hydroxyl or a (Ci-C4)alkoxy;
- a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl;
- R3 is a (Ci-C~)alkyl or a phenyl;
- R4 and RS are each independently a hydrogen or a (C1-C~)alkyl; RS can also be a (C3-C~)cycloalkyl, a (C3-C~)cycloalkylmethyl, a phenyl or a benzyl; or R4 and R5, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C~-C4)alkyl;
- R6 is a hydrogen, a (Ci-C~)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C~)cycloalkyl which is unsubstituted or substituted by one or more methyls;
- R~ is a hydrogen or a (Ci-C~)alkyl;
- R8 is a (C~-C~)alkyl or a phenyl;
- R9 is a (C,-C~)alkyl; an amino which is unsubstituted or substituted by one or two (C~-C~)alkyls; a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (C,-C~)alkyl, a trifluoromethyl, a hydroxyl, a (C~-C~)alkoxy, a carboxyl, a (C1-C~)alkoxycarbonyl, a (C~-C~)alkylcarbonyloxy, a cyano, a nitro and an amino which is unsubstituted or substituted by one or two (C~-C~)alkyls, said substituents being identical or different;
- Rlo is hydrogen or a (C1-C4)alkyl, and its optional salts with mineral or organic acids, and their optional solvates.
The compounds of formula (I) which are useful for the invention include both the racemates and the optically pure isomers, as well as the axial and equatorial isomers when Am~ in the compound of formula (I) is a group Ami~, a group Am2~ or a group Am3~.
The compounds of formula (I) are described in patent applications EP-A-0 512 901, EP-A-0 515 240, EP-A-0 559 538, EP-A-0 591 040, WO 95/26 339, EP-A-0 700 382, EP-A-0 723 959 and WO 96/23 787.
Among the compounds of formula (I), those of the formula (CH2)P~
A . Arl-(CHz)x N-O(CH2)2 N-CO-CHZ-Z (I ) Ar' in which:
- Are, x, p and AD are as defined for a compound of formula (I);
- Ar' is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z' is a phenyl substituted in the 3-position by a halogen or a (C1-Cio)alkoxy, are preferred for the invention.
More particularly, the invention relates to pharmaceutical compositions for the oral administration of (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl-acetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, or SR
140333, of the formula N-(CH2)2 (S) N-CO-CH2 O CH, -O\ , s CH
Cl CH3 Cl in which A~ is a pharmaceutically acceptable anion.
The benzenesulfonate of SR 140333, hereafter called compound A, is very particularly preferred. The international non-proprietary name of compound A
is nolpitantium besilate.
The compounds of formula (I) have been described as antagonists of substance P, which is the natural agonist of the NK1 receptors. For oral administration, such compounds must have a good absorption, which entails both a good solubility in aqueous media and a good capacity to pass through the intestinal membrane (M. Rowland and T.N. Tozer in Clinical pharmacokinetics, concepts and applications, published by Lea and Fehiger, 1989, 2nd edition, pp. 113 -130).
The solubility of the compounds of formula (I) has been studied in different media: their solubility in water is generally below 5 mg/ml, but they are soluble in hydrophilic solvents such as alcohols or glycols.
Being quaternary ammonium compounds, the compounds of formula (I) remain in ionized form irrespective of the pH of the medium in which they are present, especially at neutral pH, which is the pH of the intestinal medium.
It is known that ionic compounds, especially quaternary ammonium compounds, cannot easily pass through the epithelial membranes (J.P. Labaune in Pharmacocinetique, Principes fondamentaux, published by Masson, 1988, 2nd edition, pp. 7 - 33).
The cell line Caco-2 has the particular characteristic of exhibiting differentiation in vitro to form an epithelial monolayer. This line is conventionally used for evaluating the ability of compounds to permeate the epithelium (Crit.
Rev.
Ther. Drug Carrier System, 1991, 8 (4), 105 - 330).
1 S In this model, the permeability to compound A is 3.4.10'' cm/s.
Furthermore, correlations made between the in vitro results and the in vivo results have shown that a coefficient of permeability of this order corresponds to an absorption of less than 5% for totally solubilized molecules. In the present case, studies performed on the rat with a 0.6% aqueous solution of compound A in methyl cellulose have shown that its estimated absorption is less than 1 %.
Thus, to develop an oral galenic formulation for the compounds of formula (I), it is necessary to overcome both their very low solubility in aqueous media and their poor passage through the intestinal epithelium.
To modify the particular cationic character due to the quaternary ammonium form of the compounds according to the invention, it is possible to transform them by adding a stoichiometric amount of an anionic surfactant to give an ion pair of overall neutral charge. However, the ion pair formed between the cationic part of the compound of formula (I) and the anionic part of the surfactant has a higher molecular weight than the compound (I), so its hydrophobic character increases and this ion pair is practically insoluble in water.
It has been found that the intestinal absorption of the ion pair formed by a compound of formula (I) and an anionic surfactant decreases relative to that of a compound of formula (I) in ammonium form.
Non-ionic surfactants and absorption promoters have also been tested in order to find out their effect on the ability of a compound of formula (I) to permeate membranes. These products have not shown any positive effects.
Derivatives are known which are in semi-solid form at ordinary temperature and which, by possessing both lipidic character and amphiphilic character, can be used to solubilize lipophilic active principles and facilitate their intestinal absorption (Bull. Techn. Gattefosse, 1994, 87 49 - 54). Such compounds are selected from saturated polyglycosylated glycerides consisting of a mixture of glycerol monoesters, diesters and triesters of fatty acids with Cg-C1g hydrocarbon chains, and polyethylene glycol monoesters and diesters of fatty acids with Cg-C,8 hydrocarbon chains. The most valuable of these are:
- lauroyl macrogoglyceride with a melting point of 44°C and a hydrophilic/
lipophilic balance (HLB) of 14;
- stearoyl macrogoglyceride with a melting point of 50°C and a hydrophilic/
lipophilic balance of 13; and - caprylocaproyl macrogoglyceride, an oily liquid with a hydrophilic/
lipophilic balance of 14.
These compounds are marketed by Gattefosse under the trade marks Gelucire° 44-14, Gelucire~ 50-13 and Labrasol°
respectively.
The compounds (I) of hydrophilic character are not soluble in such derivatives; in particular, they are not soluble in the products Gelucire~ 44-14, Gelucire° 50-13 and Labrasol~.
According to the present invention, it has now been found that a compound of formula (I) can be solubilized in a saturated polyglycosylated glyceride provided that at least one of the following constituents:
- a hydrophilic solvent - an anionic surfactant is added.
The resulting formulation makes it possible to improve the bioavailability of the active principle.
It is also advantageous to solubilize a compound of formula (I) in a saturated polyglycosylated glyceride by adding both a hydrophilic solvent and an anionic surfactant.
Surprisingly, it has been found that the addition of one particular polysorbate, namely polysorbate 80, to a solution of compound A in the cell culture medium improves the transepithelial passage in the Caco-2 model.
It can thus be advantageous to add a small proportion of polysorbate 80 to the formulation determined above.
Thus, according to one of its aspects, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1% to 15% by weight - hydrophilic solvent 0% to 60% by weight - anionic surfactant 0 to S% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride in sufficient amount (QS) for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present. Preferably, in the absence of anionic surfactant, the concentration of active principle is less than or equal to 30%
by weight of the concentration of hydrophilic solvent.
According to the present invention, macrogoglyceride is understood as meaning the products Gelucire° 44-14, Gelucire° 50-13 and Labrasol° as described above, the product Gelucire ° 44-14 being preferred.
The hydrophilic solvent used can be an alcohol such as ethanol or a glycol derivative such as propylene glycol or the product Transcutol°, which is a monoethyl ether of diethylene glycol. Propylene glycol is the preferred hydrophilic solvent.
The anionic surfactant used can be a bile salt such as sodium taurocholate or a sodium alkylsulfate such as sodium octylsulfate or, preferably, sodium lauryl-sulfate, the latter being a preferred anionic surfactant according to the invention.
The pharmaceutical compositions according to the invention can be presented in different forms intended for oral administration, examples being gelatin capsules, sachets, drops, vials to be taken orally, or bottles.
Advantageously the present invention relates to a pharmaceutical com-position which contains:
- active principle 0.1% to 15% by weight - hydrophilic solvent 1% to 60% by weight - anionic surfactant 0.03% to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
In particular, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1 to 15% by weight - hydrophilic solvent 5 to 60% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent.
In particular also, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) which contains:
- active principle 0.1 to 15% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0.03 to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
According to the invention, the anionic surfactant is preferably in a stoichiometric amount relative to the active principle. As the anionic surfactant is introduced in concentrated aqueous solution, the above pharmaceutical composition contains from 0.1 to 12% of water.
When preparing gelatin capsules of the soft or hard type, the proportion of hydrophilic solvent in the pharmaceutical composition must be compatible with gelatin. Thus the present invention relates more particularly to pharmaceutical compositions for the preparation of gelatin capsules which contain:
- active principle 0.1 to 9% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0 to 3% by weight - polysorbate 80 0 to 5% by weight macrogoglyceride QS for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.
Pharmaceutical compositions for the preparation of gelatin capsules which contain:
- active principle 0.1 to 7% by weight - hydrophilic solvent 5 to 20% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to about 30% by weight of the concentration of hydrophilic solvent, are very particularly preferred.
Pharmaceutical compositions for the preparation of gelatin capsules which 5 contain:
- active principle 0.1 to 7% by weight - hydrophilic solvent 0 to 15% by weight - anionic surfactant 0.03 to 2% by weight - polysorbate 80 0 to 5% by weight 10 - macrogoglyceride QS for 100% by weight are also preferred.
The anionic surfactant is preferably in a stoichiometric amount relative to the active principle.
The pharmaceutical composition according to the invention preferably contains an amount greater than or equal to 1 % by weight of hydrophilic solvent and particularly preferably contains an amount greater than or equal to 1 % by weight of propylene glycol.
It is also possible to prepare enteric formulations for pharmaceutical compositions in the form of gelatin capsules.
Such formulations are used to protect the active principle from the strong acidity in the stomach. They are prepared by coating the gelatin capsule with a polymer film which is insoluble in an acid environment and soluble in a basic environment. Examples of coating films which may be mentioned are cellulose acetophthalate, polyvinyl acetophthalate, hydroxypropyl methyl cellulose phthalate or methacrylic acid copolymers.
Examples of methacrylic acid copolymers which may be mentioned are the type C methacrylic acid copolymer marketed under the trade mark EUDRAGIT°
L30 D-SS by ROHM, or the ethyl acrylate/methacrylic acid copolymer marketed under the trade mark KOLLICOAT~ MAE 30D by BASF.
The elasticity of the coating film can be increased by adding plasticizers such as a polyethylene glycol, 1,2-propylene glycol, dibutyl phthalate or a citrate.
In certain cases, in particular when preparing enteric formulations with gelatin capsules, it may be preferable to cover the gelatin capsule with a film coating consisting of a precoating before the enteric coating. The precoating can be made, for example, of hydroxypropyl cellulose, povidone or a methacrylic acid copolymer in association with appropriate excipients.
In one particular embodiment, the present invention relates to a pharma-ceutical composition for the oral administration of compound A which contains:
compound A 0.1 to 9% by weight propylene glycol 1 to 30% by weight sodium laurylsulfate 0 to 3% by weight Gelucire° 44-14 QS for 100% by weight.
More particularly, the present invention relates to a pharmaceutical composition of the following formulation:
compound A 0.1 to 7% by weight propylene glycol 5 to 20% by weight Gelucire~ 44-14 QS for 100% by weight, with the proviso that the concentration of compound A is less than or equal to about 30% by weight of the concentration of propylene glycol.
The present invention further relates to a pharmaceutical composition of the following formulation:
compound A 0.1 to 7% by weight propylene glycol 1 to 15% by weight sodium laurylsulfate 0.03 to 2% by weight Gelucire~ 44-14 QS for 100% by weight, the sodium laurylsulfate preferably being in a stoichiometric amount relative to the compound A.
In one particular embodiment, the present invention relates to a pharma-ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.6% by weight propylene glycol 15.9% by weight Gelucire~ 44-14 80.5% by weight.
In another particular embodiment, the present invention relates to a pharma-ceutical composition for the preparation of gelatin capsules which contains:
compound A 3.4% by weight propylene glycol 15.3% by weight sodium laurylsulfate 1.5% by weight water 2.7% by weight Gelucire ° 44-14 77.1 % by weight.
A pharmaceutical composition as described above can be prepared by the following procedure when there is no anionic surfactant in the composition:
the active principle is suspended in the hydrophilic solvent and the suspension is heated, with stirnng, to a temperature of between 60°C and 80°C, depending on the concentration of active principle introduced into the hydrophilic solvent. 90%
of the macrogoglyceride, molten at 60°C, is added, optionally followed by the polysorbate 80. Finally the appropriate amount of macrogoglyceride is added to make up to 100%.
When the pharmaceutical composition contains an anionic surfactant, it can be prepared by the following procedure: the active principle is mixed with 90%
of the macrogoglyceride heated to 60°C. The anionic surfactant, dissolved hot in the minimum amount of water, is added to the suspension formed, followed, if appropriate, by the hydrophilic solvent and the polysorbate 80. Finally the appropriate amount of macrogoglyceride is added to make up to 100%.
Very particularly, when preparing enteric formulations, the film coating of a gelatin capsule according to the invention can contain a precoating film and a coating film of the following compositions:
Precoating:
type C methacrylic acid copolymer 46.6% by weight glycerol 4.6% by weight polysorbate 80 in 33% aqueous solution 4.6% by weight water 44.2% by weight.
Coating:
type C methacrylic acid copolymer 54.8% by weight glycerol 3.3% by weight polysorbate 80 in 33% solution 0.7% by weight water 41.2% by weight.
The characteristics and advantages of the compositions according to the invention will become apparent from the following description based on the compositions given as Examples. In these Examples, the percentages are expressed by weight.
TESTS
1. Testing of the solubility of compound A
1.1. Solubility in water The solubility was measured at the saturation point, after 24 hours, at room temperature; the measurements were made by UV spectrometry at ~, = 275 nm after calibration in an ethanolic solution.
Concentration of compound0.31 0.31 0.31 0.29 0.31 A
m /ml 1.2. Solubility in different solvents The instantaneous solubility is evaluated, at room temperature, by successive additions of the studied solvent to compound A in a hemolysis tube until limpidity is observed.
Taking the density differences into account, the solubilities are determined by weight/weight.
water 0.33 mg/g ethanol 36.5 mg/g methanol 365.0 mg/g benzyl alcohol > 450.0 mg/g Transcutol~ 5.0 mg/g polyethylene glycol 400 0.45 mg/g propylene glycol 12 mg/g glycerol oleate 0.64 mg/g groundnut oil < 0.2 mg/g Gelucire 44-14 < 0.2 mg/g Compound A is also soluble ide (DMSO) in an in dimethyl sulfox amount of 168 mg/ml.
1.3. Variation in the solubilityin propyleneglycol as a function of temperature Solubility of compound A in propylene glycol Concentration of 12 155 350 com ound A in m /
1.4. Study of the solubility in glycerides Solubility of compound A in Gelucire~ 44-14 Concentration < 0.2 0.4 of com ound A in m /
1.5. Solubility of compound A in water in the presence of a stoichiometric amount of sodium laurylsulfate: below 0.1 ~g/ml.
2. Evaluation of the intestinal transepithelial passage of compound A
Caco-2 cells are inoculated onto microporous polycarbonate filters covered with collagen. The cellular monolayer formed on the filter then makes it possible to separate an apical compartment (imitating the intestinal lumen) from a basal compartment (imitating the blood circulation).
The composition containing the compound to be studied is then placed on the apical side and the passage of this compound, dispersed or solubilized in Hank's medium, through this cellular barner is evaluated by measuring the kinetics of its appearance on the basal side. This aqueous medium, of pH 6.5, has the following composition: NaCI = 8.0 g/1; KCl = 0.4 g/1; CaCl2 = 0.19 g/1; MgCl2 =
0.1 g/l; MgS04 = 0.1 g/1; Na2HP04 = 0.09 g/l; KH2P04 = 0.06 g/l; NaHC03 = 0.35 g/1; glucose = 1 g/l; phenol red = 0.01 g/1.
The coefficient of permeability P, in cm/s, which characterizes the rate of passage of the molecule through the membrane, is then determined, namely:
P = (da/dt).(1/A.Co) where:
da/dt = variation of the amount of test compound passing through the cellular monolayer as a function of time (molls) A = surface area of the monolayer (cm2) Co = initial concentration of the tested compound (mol/1) 2.1. Coefficient of permeability to compound A, introduced in Hank's medium, in solution in DMSO
P = 3.4.10-~ cm/s The permeability to compound A measured in this way in solution (in DMSO) indicates an intrinsic characteristic of this compound. This result confirms the very poor ability of compound A to pass through the epithelium.
2.2. Relative rate of intestinal transepithelial passage of compound A
Different formulations were prepared with compound A so as to measure their rate of passage and compare it with that of compound A in solution in DMSO
Formulation 1:
- compound A 4.4%
- propylene glycol 15.9%
5 - Gelucire~ 44-14 79.7%
Formulation 2:
- compound A 4.2%
- Gelucire 44-14 76.3%
- propylene glycol 15.3%
10 - sodium laurylsulfate 1.4%
- H20 2.8%
Formulation 3:
- compound A 4.3%
- Gelucire 44-14 91.23%
15 - sodium laurylsulfate 1.52%
- H20 2.95%
Formulation 4:
- compound A 4.31 - Gelucire~ 44-14 91.19%
- sodium octylsulfate 1.53%
- H20 2.97%
Formulation 5:
- compound A 7.4%
- propylene glycol 28.7%
- Gelucire~ 44-14 63.9%
Formulation 6:
- compound A 8%
- propylene glycol 46%
- Gelucire 44-14 46%
Formulation 7:
- compound A 6%
- propylene glycol 34%
- Labrasol~ 60%
FormulationSolution1 2 3 4 5 6 7 DMSO
Relative 1 12 15 7 7 10 8 10 rate Each of these formulations causes a notable improvement in the transepithelial passage of compound A and none of these formulations caused a deterioration of the epithelial monolayer.
All these formulations were observed under the optical microscope. Total solubilization of compound A was found, except in the case of formulations 3 and 4, where compound A is partially in crystalline form.
The best result is obtained with formulation 2, which combines the formation of the ion pair with sodium laurylsulfate and the use of a mixture of Gelucire~ 44-14 and propylene glycol.
EXAMPLE 1: Gelatin capsule compound A 4.4%
propylene glycol 15.9%
Gelucire° 44-14 79,7%
for a size 1 white-opaque gelatin capsule.
The active principle is solubilized in the propylene glycol at 70°C, the solution obtained is then incorporated into the Gelucire° 44-14 at 60°C, with mechanical stirring, and finally the gelatin capsule is filled at 40°C.
EXAMPLE 2: Gelatin capsule compound A 4.2%
propylene glycol 15.3%
sodium laurylsulfate in 34%
aqueous solution 1.4%
water 2.8%
Gelucire~ 44-14 76.3%
for a size 1 white-opaque gelatin capsule.
The active principle is mixed with 90% of the Gelucire~ 44-14 heated to 60°C. The aqueous sodium laurylsulfate solution is added and the remaining Gelucire° 44-14 is then added to make up to 100%. The mixture is incorporated into the gelatin capsule after cooling to 40°C.
EXAMPLE 3: Liquid form for bottles compound A 6.0%
propylene glycol 34.0%
Labrasol~ 60.0%
EXAMPLE 4: Vial to be taken orally compound A g,0%
propylene glycol 46.0%
Gelucire 44-14 46.0%
EXAMPLE 5: Gelatin capsule compound A 4.5%
propylene glycol 15.0%
Gelucire~ 44-14 80.5%
EXAMPLE 6: Gelatin capsule compound A 4.4%
propylene glycol 13.0%
sodium laurylsulfate 1.5%
water 3.0%
Gelucire 44-14 78.1%
EXAMPLE 7: Liquid for bottles compound A g,0%
propylene glycol 27.5%
polysorbate 80 2.0%
Labrasol 62.5%
EXAMPLE 8: Liquid for bottles compound A 7.5%
propylene glycol 20.5%
polysorbate 80 2.0%
sodium laurylsulfate 2.6%
water 4.9%
Labrasol 62.5%
EXAMPLE 9: Enteric gelatin capsule A gelatin capsule is prepared according to Example l and a film coating is applied in 2 layers, one a precoating layer and the other a coating layer.
Precoating:
Eudragit~ L30 D-55 46.6%
glycerol 4.6%
polysorbate 80 in 33% aqueous solution4.6%
water 44.2%
Coating:
Eudragit~ L30 D-55 54.8%
glycerol 3.3%
polysorbate 80 in 33% aqueous solution0.7%
water 41.2%
Claims (26)
1. A pharmaceutical composition for the oral administration of an active principle of the formula in which:
- A ~ is a pharmaceutically acceptable anion;
- Am ~ is:
i - either a group Am 1 ~ of the formula in which:
- Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)-alkyl and a trifluoromethyl, said substituents being identical or different;
- x is zero or one; and - W1 is a (C1-C6)alkyl or a benzyl group, the substituent W1 being either in the axial position or in the equatorial position;
ii - or a group Am2~ of the formula in which:
- Ar i, x and Wi are as defined above; and - R1 is a hydroxyl, a (C1-C4)alkoxy, a formyloxy, a (C1-C3)alkylcarbonyloxy, a carboxyl, a (C1-C4)alkoxycarbonyl, a cyano, a (C1-C3)alkylcarbonylamino, a mercapto or a (C1-C4)alkylthio;
iii - or a group Am3~ of the formula in which:
- Ar1 and W1 are as defined above; and - R2 is hydrogen, a (C1-C3)alkyl or a (C1-C3)alkylcarbonyl;
iv - or a group Am4~ of the formula in which:
- Ar1 and x are as defined above; and - p is one or two;
v - or a group Am5~ of the formula in which:
- Ar1 and x are as defined above;
- Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C3)alkoxy, a (C1-C3)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl;
an indolyl;
- Q and Y have one of the following groups of meanings:
a) Q1 and Y1;
b) Q2 and Y2 when Am~ is a group Am1~, Am2~, Am4~ or Am5~;
c) Q3 and Y3 when Am~ is a group Am1~ or Am2~ or a group Am4~ in which Ar1 is a phenyl and p is two; or d) Q4 and Y4 when Am~ is a group Am1~, Am3~, Am4~ or Am5~;
- Q1 is hydrogen;
- Y1 is hydrogen ; a (C1-C4)alkyl ; an .omega.-(C1-C4)alkoxy-(C2-C4)alkylene ;
an .omega.-(C1-C1) alkylcarbonyloxy-(C2-C4)alkylene ; an .omega.-benzoyloxy-(C2-C4)alkylene ; an .omega.-hydroxy-(C2-C4)alkylene ; an .omega.-(C1-C4)alkylthio-(C2-C4)alkylene ; an .omega.-(C1-C4)-alkylcarbonyl-(C2-C4)alkylene ; an .omega.-carboxy-(C2-C4)alkylene ; an .omega.-(C1-C4)-alkoxycarbonyl-(C2-C4)alkylene ; an .omega.-benzyloxy-(C2-C4)alkylene ; an .omega.-formyl-oxy-(C2-C4)alkylene; an .omega.-R3NHCOO-(C2-C4)alkylene; an .omega.-R4R5NCO-(C2-C4)-alkylene ; an .omega.-R6CONR7-(C2-C4)alkylene ; an .omega.-R8OCONR7-(C2-C4)alkylene ;
an .omega.-R4R5NCONR7-(C2-C4)alkylene ; an .omega.-R9SO2NR7-(C2-C4)alkylene or an .omega.-cyano-(C1-C3)alkylene;
-~Q2 and Y2 together form an ethylene, trimethylene or tetramethylene group;
- Q3 and Y3 together form a group in which n is one, two or three ;
- Q4 and Y4 together form a radical selected from:
A1) -O-CH2-A2) -O-CO-A3) -CH2-O-CO-A4) -O-CH2-CO-A5) -O-CH2-CH2-A6) -N(R10)-CO-A7) -N(R10)-CO-CO-A8) -N(R10)-CH2-CH2-- T is either a group -CO- when Q and Y are the groups Q1 and Y1, the groups and Y2 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A1), A5) or A8); or a group -CH2- when Q and Y are the groups Q3 and Y3 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A2), A3), A4), A6) or A7);
- A is either a direct bond or a methylene group when T is -CO-, or a direct bond when T is -CH2-;
- Z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or polysubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl;
a (C3-C7)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C7)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a (C1-C6)alkylcarbonyloxy; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkylcarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; and a (pyrrolidin-1-yl) carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy;
- a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl;
- R3 is a (C1-C7)alkyl or a phenyl;
- R4 and R5 are each independently a hydrogen or a (C1-C7)alkyl; R5 can also be a (C3-C7)cycloalkyl, a (C3-C7)cycloalkylmethyl, a phenyl or a benzyl; or R4 and R5, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R6 is a hydrogen, a (C1-C7)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls;
- R7 is a hydrogen or a (C1-C7)alkyl;
- R8 is a (C1-C7)alkyl or a phenyl;
- R9 is a (C1-C7)alkyl; an amino which is unsubstituted or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7) alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is unsubstituted or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
- R10 is hydrogen or a (C1-C4)alkyl, or one of its optional salts with mineral or organic acids, or one of their optional solvates, said composition containing:
- active principle 0.1% to 15% by weight - hydrophilic solvent 0% to 60% by weight - anionic surfactant 0 to 5% by weight - polysorbate 0 to 5% by weight - macrogoglyceride in sufficient amount (QS) for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.
- A ~ is a pharmaceutically acceptable anion;
- Am ~ is:
i - either a group Am 1 ~ of the formula in which:
- Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)-alkyl and a trifluoromethyl, said substituents being identical or different;
- x is zero or one; and - W1 is a (C1-C6)alkyl or a benzyl group, the substituent W1 being either in the axial position or in the equatorial position;
ii - or a group Am2~ of the formula in which:
- Ar i, x and Wi are as defined above; and - R1 is a hydroxyl, a (C1-C4)alkoxy, a formyloxy, a (C1-C3)alkylcarbonyloxy, a carboxyl, a (C1-C4)alkoxycarbonyl, a cyano, a (C1-C3)alkylcarbonylamino, a mercapto or a (C1-C4)alkylthio;
iii - or a group Am3~ of the formula in which:
- Ar1 and W1 are as defined above; and - R2 is hydrogen, a (C1-C3)alkyl or a (C1-C3)alkylcarbonyl;
iv - or a group Am4~ of the formula in which:
- Ar1 and x are as defined above; and - p is one or two;
v - or a group Am5~ of the formula in which:
- Ar1 and x are as defined above;
- Ar is a phenyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C3)alkoxy, a (C1-C3)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl;
an indolyl;
- Q and Y have one of the following groups of meanings:
a) Q1 and Y1;
b) Q2 and Y2 when Am~ is a group Am1~, Am2~, Am4~ or Am5~;
c) Q3 and Y3 when Am~ is a group Am1~ or Am2~ or a group Am4~ in which Ar1 is a phenyl and p is two; or d) Q4 and Y4 when Am~ is a group Am1~, Am3~, Am4~ or Am5~;
- Q1 is hydrogen;
- Y1 is hydrogen ; a (C1-C4)alkyl ; an .omega.-(C1-C4)alkoxy-(C2-C4)alkylene ;
an .omega.-(C1-C1) alkylcarbonyloxy-(C2-C4)alkylene ; an .omega.-benzoyloxy-(C2-C4)alkylene ; an .omega.-hydroxy-(C2-C4)alkylene ; an .omega.-(C1-C4)alkylthio-(C2-C4)alkylene ; an .omega.-(C1-C4)-alkylcarbonyl-(C2-C4)alkylene ; an .omega.-carboxy-(C2-C4)alkylene ; an .omega.-(C1-C4)-alkoxycarbonyl-(C2-C4)alkylene ; an .omega.-benzyloxy-(C2-C4)alkylene ; an .omega.-formyl-oxy-(C2-C4)alkylene; an .omega.-R3NHCOO-(C2-C4)alkylene; an .omega.-R4R5NCO-(C2-C4)-alkylene ; an .omega.-R6CONR7-(C2-C4)alkylene ; an .omega.-R8OCONR7-(C2-C4)alkylene ;
an .omega.-R4R5NCONR7-(C2-C4)alkylene ; an .omega.-R9SO2NR7-(C2-C4)alkylene or an .omega.-cyano-(C1-C3)alkylene;
-~Q2 and Y2 together form an ethylene, trimethylene or tetramethylene group;
- Q3 and Y3 together form a group in which n is one, two or three ;
- Q4 and Y4 together form a radical selected from:
A1) -O-CH2-A2) -O-CO-A3) -CH2-O-CO-A4) -O-CH2-CO-A5) -O-CH2-CH2-A6) -N(R10)-CO-A7) -N(R10)-CO-CO-A8) -N(R10)-CH2-CH2-- T is either a group -CO- when Q and Y are the groups Q1 and Y1, the groups and Y2 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A1), A5) or A8); or a group -CH2- when Q and Y are the groups Q3 and Y3 or the groups Q4 and Y4 in which Q4 and Y4 together form a radical A2), A3), A4), A6) or A7);
- A is either a direct bond or a methylene group when T is -CO-, or a direct bond when T is -CH2-;
- Z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or polysubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl;
a (C3-C7)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C7)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a (C1-C6)alkylcarbonyloxy; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkylcarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; and a (pyrrolidin-1-yl) carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy;
- a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl;
- R3 is a (C1-C7)alkyl or a phenyl;
- R4 and R5 are each independently a hydrogen or a (C1-C7)alkyl; R5 can also be a (C3-C7)cycloalkyl, a (C3-C7)cycloalkylmethyl, a phenyl or a benzyl; or R4 and R5, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R6 is a hydrogen, a (C1-C7)alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls;
- R7 is a hydrogen or a (C1-C7)alkyl;
- R8 is a (C1-C7)alkyl or a phenyl;
- R9 is a (C1-C7)alkyl; an amino which is unsubstituted or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7) alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is unsubstituted or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
- R10 is hydrogen or a (C1-C4)alkyl, or one of its optional salts with mineral or organic acids, or one of their optional solvates, said composition containing:
- active principle 0.1% to 15% by weight - hydrophilic solvent 0% to 60% by weight - anionic surfactant 0 to 5% by weight - polysorbate 0 to 5% by weight - macrogoglyceride in sufficient amount (QS) for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.
2. A pharmaceutical composition according to claim 1, characterized in that the active principle is a compound of the formula in which:
- Ar1, x, p and A- are as defined for a compound of formula (I) in claim 1;
- Ar' is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z' is a phenyl substituted in the 3-position by a halogen or a (C1-C10)alkoxy.
- Ar1, x, p and A- are as defined for a compound of formula (I) in claim 1;
- Ar' is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z' is a phenyl substituted in the 3-position by a halogen or a (C1-C10)alkoxy.
3. A pharmaceutical composition according to claim 1 or 2, characterized in that the active principle is (S)-1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane of the formula in which A- is a pharmaceutically acceptable anion
4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that the active principle is nolpitantium besilate.
5. A pharmaceutical composition according to any one of claims 1 to 4, characterized in that it contains:
- active principle 0.1% to 15% by weight - hydrophilic solvent 1 % to 60% by weight - anionic surfactant 0.03% to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
- active principle 0.1% to 15% by weight - hydrophilic solvent 1 % to 60% by weight - anionic surfactant 0.03% to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
6. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that it is presented in the form of gelatin capsules, sachets, drops, vials to be taken orally, or bottles.
7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the macrogoglyceride is selected from Gélucire R 44-14, Gélucire R 50-13 and Labrasol R.
8. A pharmaceutical composition according to claim 7, characterized in that the macrogoglyceride is Gelucire R 44-14.
9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that the hydrophilic solvent is selected from ethanol, propylene glycol and Transcutol R.
10. A pharmaceutical composition according to claim 9, characterized in that the hydrophilic solvent is propylene glycol.
11. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that the anionic surfactant is selected from a bile salt and a sodium alkylsulfate.
12. A pharmaceutical composition according to claim 11, characterized in that the anionic surfactant is sodium laurylsulfate.
13. A pharmaceutical composition according to any one of claims 1 to 12, containing an amount greater than or equal to 1% by weight of hydrophilic solvent.
14. A pharmaceutical composition according to any one of claims 1 to 13, characterized in that the anionic surfactant is in a stoichiometric amount relative to the active principle.
15. A pharmaceutical composition according to any one of claims 1 to 14, characterized in that the anionic surfactant is incorporated into the formulation in concentrated aqueous solution.
16. A pharmaceutical composition according to any one of claims 1 to 9, containing:
- active principle 0.1 to 15% by weight - hydrophilic solvent 5 to 60% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent.
- active principle 0.1 to 15% by weight - hydrophilic solvent 5 to 60% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent.
17. A pharmaceutical composition according to any one of claims 1 to 15, containing - active principle 0.1 to 15% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0.03 to 5% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
18. A pharmaceutical composition according to any one of claims 1 to 15, containing:
- active principle 0.1 to 9% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0 to 3% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that at least one selected from the hydrophilic solvent and the anionic surfactant is present.
- active principle 0.1 to 9% by weight - hydrophilic solvent 0 to 30% by weight - anionic surfactant 0 to 3% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that at least one selected from the hydrophilic solvent and the anionic surfactant is present.
19. A pharmaceutical composition according to claim 18, containing:
- active principle 0.1 to 7% by weight - hydrophilic solvent 5 to 20% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to about 30% by weight of the concentration of hydrophilic solvent.
- active principle 0.1 to 7% by weight - hydrophilic solvent 5 to 20% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight, with the proviso that the concentration of active principle is less than or equal to about 30% by weight of the concentration of hydrophilic solvent.
20. A pharmaceutical composition according to claim 18, containing:
- active principle 0.1 to 7% by weight - hydrophilic solvent 0 to 15% by weight - anionic surfactant 0.03 to 2% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
- active principle 0.1 to 7% by weight - hydrophilic solvent 0 to 15% by weight - anionic surfactant 0.03 to 2% by weight - polysorbate 80 0 to 5% by weight - macrogoglyceride QS for 100% by weight.
21. A pharmaceutical composition according to any one of claims 1 to 15, containing:
- nolpitantium besilate 0.1 to 9% by weight - propylene glycol 1 to 30% by weight - sodium laurylsulfate 0 to 3% by weight - Gélucire ~ 44-14 QS for 100% by weight.
- nolpitantium besilate 0.1 to 9% by weight - propylene glycol 1 to 30% by weight - sodium laurylsulfate 0 to 3% by weight - Gélucire ~ 44-14 QS for 100% by weight.
22. A pharmaceutical composition according to claim 21, containing:
- nolpitantium besilate 0.1 to 7% by weight - propylene glycol 5 to 20% by weight - Gélucire R 44-14 QS for 100% by weight, with the proviso that the concentration of nolpitantium besilate is less than or equal to about 30% by weight of the concentration of propylene glycol.
- nolpitantium besilate 0.1 to 7% by weight - propylene glycol 5 to 20% by weight - Gélucire R 44-14 QS for 100% by weight, with the proviso that the concentration of nolpitantium besilate is less than or equal to about 30% by weight of the concentration of propylene glycol.
23. A pharmaceutical composition according to claim 21, containing:
- nolpitantium besilate 0.1 to 7% by weight - propylene glycol 1 to 15% by weight - sodium laurylsulfate 0.03 to 2% by weight - Gélucire R 44-14 QS for 100% by weight.
- nolpitantium besilate 0.1 to 7% by weight - propylene glycol 1 to 15% by weight - sodium laurylsulfate 0.03 to 2% by weight - Gélucire R 44-14 QS for 100% by weight.
24. A pharmaceutical composition according to claim 21, containing:
- nolpitantium besilate 3.6% by weight - propylene glycol 15.9% by weight - Gélucire R 44-14 80.5% by weight.
- nolpitantium besilate 3.6% by weight - propylene glycol 15.9% by weight - Gélucire R 44-14 80.5% by weight.
25. A pharmaceutical composition containing - nolpitantium besilate 3.4% by weight - propylene glycol 15.3% by weight - sodium laurylsulfate 1.5% by weight - water 2.7% by weight - Gélucire R 44-14 77.1% by weight.
26. A pharmaceutical composition according to any one of claims 1 to 25, characterized in that it is presented in the form of an enteric gelatin capsule.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9701825A FR2759584B1 (en) | 1997-02-17 | 1997-02-17 | PHARMACEUTICAL COMPOSITION FOR THE ORAL ADMINISTRATION OF HETEROCYCLIC COMPOUNDS IN QUATERNARY AMMONIUM FORM |
| FR97/01825 | 1997-02-17 | ||
| PCT/FR1998/000298 WO1998035662A1 (en) | 1997-02-17 | 1998-02-17 | Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2281560A1 true CA2281560A1 (en) | 1998-08-20 |
Family
ID=9503804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002281560A Abandoned CA2281560A1 (en) | 1997-02-17 | 1998-02-17 | Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0969825A1 (en) |
| JP (1) | JP2001511795A (en) |
| AR (1) | AR011805A1 (en) |
| AU (1) | AU6404998A (en) |
| BR (1) | BR9807694A (en) |
| CA (1) | CA2281560A1 (en) |
| FR (1) | FR2759584B1 (en) |
| HR (1) | HRP980075A2 (en) |
| NO (1) | NO993928D0 (en) |
| WO (1) | WO1998035662A1 (en) |
| ZA (1) | ZA981289B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188424A (en) * | 2011-03-23 | 2011-09-21 | 浙江理工大学 | Anti-leukemia effects of SR140333 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2676054B1 (en) * | 1991-05-03 | 1993-09-03 | Sanofi Elf | NOVEL N-ALKYLENEPIPERIDINO COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2676055B1 (en) * | 1991-05-03 | 1993-09-03 | Sanofi Elf | AMINO POLYCYCLIC COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2688219B1 (en) * | 1992-03-03 | 1994-07-08 | Sanofi Elf | AMATONIUM QUATERNARY SALTS OF AMINO AROMATIC COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR2696178B1 (en) * | 1992-09-30 | 1994-12-30 | Sanofi Elf | Quaternary basic amides, process for their preparation and pharmaceutical compositions containing them. |
| FR2717804B1 (en) * | 1994-03-25 | 1996-06-21 | Sanofi Sa | Salts of substituted nitrogen heteroaromatic compounds, process for their preparation and pharmaceutical compositions containing them. |
| ATE177095T1 (en) * | 1994-08-25 | 1999-03-15 | Merrell Pharma Inc | SUBSTITUTED PIPERIDINE FOR THE TREATMENT OF ALLERGIC DISEASES |
| FR2725986B1 (en) * | 1994-10-21 | 1996-11-29 | Adir | NOVEL PIPERIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2725900B1 (en) * | 1994-10-21 | 1997-07-18 | Sanofi Sa | USE OF NK1 RECEPTOR ANTAGONISTS FOR THE PREPARATION OF DRUGS WITH CARDIOREGULATORY ACTION |
| FR2729954B1 (en) * | 1995-01-30 | 1997-08-01 | Sanofi Sa | SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2729951B1 (en) * | 1995-01-30 | 1997-04-18 | Sanofi Sa | NOVEL HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
-
1997
- 1997-02-17 FR FR9701825A patent/FR2759584B1/en not_active Expired - Fee Related
-
1998
- 1998-02-16 HR HR9701825A patent/HRP980075A2/en not_active Application Discontinuation
- 1998-02-16 AR ARP980100675A patent/AR011805A1/en unknown
- 1998-02-17 BR BR9807694A patent/BR9807694A/en not_active Application Discontinuation
- 1998-02-17 AU AU64049/98A patent/AU6404998A/en not_active Abandoned
- 1998-02-17 CA CA002281560A patent/CA2281560A1/en not_active Abandoned
- 1998-02-17 ZA ZA981289A patent/ZA981289B/en unknown
- 1998-02-17 EP EP98909549A patent/EP0969825A1/en not_active Withdrawn
- 1998-02-17 JP JP53543298A patent/JP2001511795A/en active Pending
- 1998-02-17 WO PCT/FR1998/000298 patent/WO1998035662A1/en not_active Application Discontinuation
-
1999
- 1999-08-16 NO NO993928A patent/NO993928D0/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188424A (en) * | 2011-03-23 | 2011-09-21 | 浙江理工大学 | Anti-leukemia effects of SR140333 |
Also Published As
| Publication number | Publication date |
|---|---|
| HRP980075A2 (en) | 1998-10-31 |
| WO1998035662A1 (en) | 1998-08-20 |
| JP2001511795A (en) | 2001-08-14 |
| NO993928L (en) | 1999-08-16 |
| AU6404998A (en) | 1998-09-08 |
| EP0969825A1 (en) | 2000-01-12 |
| NO993928D0 (en) | 1999-08-16 |
| ZA981289B (en) | 1998-08-26 |
| BR9807694A (en) | 2000-03-21 |
| FR2759584A1 (en) | 1998-08-21 |
| AR011805A1 (en) | 2000-09-13 |
| FR2759584B1 (en) | 1999-06-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |