Classifications

• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• compositions containing N-Su ⁇ fonyl indoline derivatives ".
• the present invention relates, in general, to new pharmaceutical compositions containing as active principles derivatives of N-sulfonyl indoline.
• the invention relates to pharmaceutical compositions either for parenteral administration or for oral administration containing, as active principles, one or more isomers of N- [5-chloro-3- (2-chlorophenyl) -1- (3,4 - dimethoxyphenylsulfonyl) -3-hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] -pyrrolidine- 2-carboxamide of formula:
• the isomer çjs is called the compounds of formula I in which the 2-chlorophenyl and 2-carbamoyl-pyrrolidinocarbonyl groups are on the same side of the ring.
• trans isomer is called the compounds of formula I in which these 2-chlorophenyl and 2-carbamoyl-pyrrolidinocarbonyl groups are each on one side of the ring.
• these compounds of formula I are in the form of optical isomers due to the asymmetric carbon represented by the asterisk.
• N-sulfonyl indoline derivatives in question are known compounds which have been described in patent application EP 0526348. These compounds have revealed an affinity for the receptors for vasopressin and for oxytocin and consequently are useful in particular in the treatment of the central nervous system, of the cardiovascular system and of the gastric sphere.
• liquid pharmaceutical compositions when introduced into pharmaceutical envelopes such as soft capsules, liquid pharmaceutical compositions require an absence of water, the gelatin-based tunic being incompatible with an aqueous formulation.
• volume of pharmaceutical composition to be administered should be minimized so that such a presentation, in the form of a capsule or soft capsule is possible.
• lipophilic matrices such as vegetable or animal oils have been proposed which, if necessary, can be combined with lubricating agents such as fats, waxes or even mineral oils.
• lubricating agents such as fats, waxes or even mineral oils.
• anhydrous, emulsifiable or microemulsifiable pharmaceutical composition containing the active principles of formula I this composition making it possible to achieve a presentation in particular in tablet form.
• a first object of the invention relates to an anhydrous solubilizing / stabilizing system, emulsifiable or microemulsifiable in water, for the solubilization of the N-sulfonyl indoline derivatives of formula I, comprising one or more constituents chosen from amphiphilic compounds , nonionic hydrophilic surfactants and nonionic hydrophilic compounds having both amphiphilic and surfactant properties, it being understood that said system comprises either at least a mixture of an amphiphilic compound and a hydrophilic nonionic surfactant, or at least one nonionic hydrophilic compound endowed with both surfactant and amphiphilic properties.
• the invention relates to a solubilizing / stabilizing system as above comprising:
• glycolic type namely propylene glycol, polyethylene glycols and glycolic ethers (preferably polyethylene glycols and glycolic ethers), the system further comprising one or more hydrophilic nonionic surfactants ,
• nonionic hydrophilic compounds which are both amphiphilic and surfactants chosen from saturated polyglycolysed glycerides, the system optionally comprising one or more nonionic hydrophilic surfactants, and optionally one or more amphiphilic glycolic type compounds, namely polyethylene glycols.
• the solubilizing / stabilizing system of the invention refers in particular to a system comprising at least two different compounds, one acting as amphiphilic solvent or solubilizer, the other as a nonionic hydrophilic surfactant.
• this system can combine more than two compounds, for example several compounds acting as amphiphilic co-solvents or even several nonionic hydrophilic surfactant compounds.
• one or the other is capable of playing both the role of amphiphilic solvent and that of non-ionic hydrophilic surfactant.
• this solubilizing / stabilizing system can be limited to a single non-ionic hydrophilic compound acting both as a solvent or amphiphilic solubilizer and as a surfactant.
• amphiphilic solvents mentioned above are generally selected from glycolic-type compounds.
• PEG polyethylene glycols
• a polyethylene glycol of a given molecular weight can be used alone or alternatively as a mixture with one or more polyethylene glycols of various molecular weight.
• the polyethylene glycols used in the context of the invention are present at room temperature either in liquid form or in semi-solid form depending on their molecular weight. Consequently, these polymers will be appropriately selected according to whether the desired solubilizing / stabilizing system must be in liquid form or, on the contrary, semi-solid.
• polyethylene glycol 400 or "PEG 400" liquid at ordinary temperature polyethylene glycol 1000 or "PEG 1000", polyethylene glycol 1500 or “PEG 1500", polyethylene glycol 2000 or “PEG 2000”, polyethylene glycol 6000 or “PEG 6000", as well as a 50/50 mixture by weight of polyethylene glycol 600 or "PEG 600” and of polyethylene glycol 1500 or "PEG 1500", all these polyethylene glycols being semi-solid to room temperature, with the exception of PEG-400 as indicated above.
• Such compounds are chosen from saturated polyglycolysed glycerides also designated macrogolglycerides, that is to say compounds consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids, and polyethylene glycol mono and diesters and fatty acids.
• macrogolglycerides that is to say compounds consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids, and polyethylene glycol mono and diesters and fatty acids.
• HLB hydrophilic / lipophilic balance
• glycolic derivatives can be used as solvent or cosolvent in the context of the invention, that is to say amphiphilic compounds endowed with a solubilizing power.
• Such glycol derivatives are chosen from glycol ethers, in general from diethylene glycol ethers such as a mono (C, -
• the methyl and ethyl ethers which are marketed are preferred, in particular diethylene glycol monoethyl ether.
• glycolic ethers can be used alone as an amphiphilic solvent in the solubilizing / stabilizing system of the invention or preferably combined in all proportions with one or more polyethylene glycols of low molecular weight, that is to say between 400 and 600 such as described above where this glycolic ether then plays the role of co-solvent and even of co-surfactant.
• the surfactant it is generally chosen from non-ionic hydrophilic compounds whose HLB value is between 12 and 22, preferably between 12 and 18.
• Surfactants of this type may for example be an ethylene oxide / propylene oxide such as those sold under the trademarks PLURONIC ® P94 (HLB: 13.5) and PLURONIC ® F127 (HLB: 22), an oil polyethoxylated castor such as that marketed under the brand CREMOPHOR ® EL (HLB: 13), a non-ethoxylated polysorbate, an ethoxylated polysorbate such as polysorbate 80 (HLB: 15) marketed under the brand TWEEN ® 80 or MONTANOX ® 80 DF or polysorbate 20 sold under the trademark TWEEN ® 20 (HLB: 16.5), or a polyethylene hydroxystearate such as polyethylene hydroxystearate - 660 (HLB: 13) marketed under the trademark Solutol ® HS15.
• surfactant used in the context of the present invention may alternatively be constituted, by a mixture, of such nonionic hydrophilic surfactant compounds, a mixture whose HLB value would also be between 12 and 22, preferably between 12 and 18.
• a surfactant mixture there may be mentioned a mixture of ethoxylated polysorbate and non-ethoxylated polysorbate such that the final HLB value would be between 12 and 22, preferably between 12 and 18, for example a mixture of polysorbate 80 (HLB: 15 ) and non ethoxylated polysorbate sold under the trade mark SPAN ® 20 (HLB: 8.6).
• solubilizing / stabilizing systems of the invention those generally consisting of: a) either of an amphiphilic compound chosen from polyethylene glycols of molecular weight between 400 and 600, the system further comprising a nonionic hydrophilic surfactant and optionally a diethylene glycol ether b) or of an amphiphilic compound chosen from polyethylene glycols of molecular weight between 600 and 10,000, for example between 600 and 2000 or even between 2000 and 10,000, the system further comprising a nonionic hydrophilic surfactant c) either of a solubilizing / surfactant compound chosen from saturated polyglycolysed glycerides , the system optionally comprising a nonionic hydrophilic surfactant.
• the systems formed can be envisaged:
• the invention relates to an anhydrous solubilizing / stabilizing system emulsifiable or microemulsifiable in water for the solubilization of the N-sulfonyl indoline derivatives of formula I comprising:
• amphiphilic glycolic type compounds chosen from propylene glycol, polyethylene glycols of average molecular weight between 400 and 600 and ethers of diethylene glycol such as a mono (C r C 4 ) alkyl ether of diethylene glycol, preferably said polyethylene glycols and said diethylene glycol ethers, the system further comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22, preferably between 12 and 18, such that the solubilizing / stabilizing system thus formed is in liquid form.
• amphiphilic glycolic type compounds chosen from polyethylene glycols of average molecular weight between 2000 and 10000, the system further comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18, such that the solubilizing / stabilizing system thus formed is in semi-solid form.
• non-ionic hydrophilic compounds both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and fatty acids, and polyethylene glycol mono and diesters of acids fatty, the system optionally comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18 and optionally one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 600 and 10,000, for example between 600 and 2000 or alternatively between 2000 and 10,000, so that the solubilizing / stabilizing system thus formed is in semi-solid form.
• solubilizing / stabilizing systems of the invention can advantageously serve to solubilize the compounds of formula I so as to form compositions which are dilutable or dispersible in an aqueous medium.
• These high-stability solutions are capable, in the presence of water, of providing stable microemulsions in the temperature ranges generally used for pharmaceutical compositions.
• the amount of Compound ⁇ may reach 20 mg / ml when the amphiphilic solubilizing agent is a mixture PEG 400 / TRANSCUTOL ® product and the stabilizer is polysorbate 80.
• Solutions concentrated in Compound ⁇ whose dilution line intersects the heterogeneous zone "B '" are no longer completely dilutable but dispersible in aqueous medium, that is to say as concentrated solutions spontaneously forming an emulsion more or less fine when dispersed in water.
• the concentration of this active principle can be up to 60 mg / ml, a concentration 3 times higher than that of the solution dilutable in water.
• solubilizing / stabilizing system of the invention capable of solubilizing the hydrophobic active principles of formula I can be validly used with a view to introducing these active principles into pharmaceutical compositions.
• composition a pharmaceutical composition, microemulsifiable or emulsifiable in an aqueous medium comprising:
• an injectable pharmaceutical composition comprising:
• a solubilizing / stabilizing system in liquid form consisting of one or more glycolic-type amphiphilic compounds chosen from propylene glycol, polyethylene glycols of average molecular weight included 13 between 400 and 600, and further comprising one or more nonionic hydrophilic surfactants of HLB between 12 and 22, preferably between 12 and 18 such as for example polysorbate 80, and optionally a diethylene glycol ether such as the product TRANSCUTOL® “an appropriate pharmaceutical vehicle.
• suitable pharmaceutical vehicle is essentially meant water or a physiologically acceptable ketone derivative, the active principles of formula I, in particular Compound ⁇ having been shown to be particularly soluble in these organic compounds.
• a polyvinylpyrrolidone PVP
• PVP polyvinylpyrrolidone
• a keto derivative of choice to further promote the solubility of the active ingredient of the formula I injectable compositions.
• pharmaceutical compositions for administration by injection can be prepared, these compositions not exceeding 10 mg / ml, ie 1% by weight of compound of formula I.
• compositions can contain from 2 to 6 mg / ml of Compound ⁇ . They will also comprise a nonionic hydrophilic surfactant such as polysorbate 80 at a concentration not exceeding 4% by weight of the final composition.
• a nonionic hydrophilic surfactant such as polysorbate 80 at a concentration not exceeding 4% by weight of the final composition.
• compositions have been found to be physically stable and dilutable in physiological saline or in glucose serum.
• the invention relates to a liquid pharmaceutical composition for oral administration comprising:
• a solubilizing / stabilizing system in liquid form consisting of one or more amphiphilic compounds, of glycolic type chosen from propylene glycol, polyethylene glycols of average molecular weight between 400 and 600 and ethers of diethylene glycol, (preferably said polyethylene glycols and said diethylene glycol ethers), the system further comprising one or more non-hydrophilic surfactants ionic HLB between 12 and 22, preferably between 12 and 18 such as for example polysorbate 80 or the product brand PLURONIC® P 94.
• one or more polyethylene glycols of low molecular weight that is to say between 5 approximately 400 and approximately 600.
• the polyethylene glycol preferably used is PEG 400.
• one or more diethylene glycol ethers are generally combined, such as methyl or ethyl ethers.
• the monoethyl ether of diethylene glycol is recommended as the preferred diethylene glycol ether or o, the TRANSCUTOL® brand product.
• diethylene glycol ethers will however be used at concentrations not exceeding, preferably 50% by weight or better still not exceeding 20% by weight of the final composition.
• nonionic hydrophilic surfactant it is preferably chosen
• polysorbate 80 constitutes a surfactant of choice for the purposes of the invention.
• a particularly preferred solubilizing / stabilizing system consists of a mixture of PEG 400 / TRANSCUTOL® product / polysorbate 80.
• compositions of the invention are in the form of homogeneous and transparent liquids. They may contain high concentrations of active principle of formula I due to their anhydrous nature, these 5 concentrations being able to reach up to 150 mg / ml or 15% by weight, more particularly 60mg / ml or 6% by weight of Compound ⁇ .
• compositions spontaneously dispersible in an aqueous medium, while being able to accept water without phase shift, become compatible, consequently with a soft capsule type capsule setting.
• liquid pharmaceutical compositions for oral administration have been shown to increase the speed of transepithelial transport as well as the bioavailability of the active principles of formula I.
• the invention relates to a semi-solid pharmaceutical composition for oral administration comprising:
• a hydrophobic active principle of formula I generally at a concentration not exceeding 15% by weight of the composition
• a semi-solid solubilizing / stabilizing system comprising: either one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 600 and
• system further comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22, preferably between 12 and 18,
• hydrophilic nonionic compounds which are both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and 0 of fatty acids, and polyethylene glycol mono and diesters of acids fatty, the system optionally comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and
• glycolic-type amphiphilic compounds chosen from polyethylene glycols of average molecular weight between 600 and
• one or more polyethylene glycols of molecular weight between 600 and 2000 are used.
• PEG 1000, PEG 2000, PEG 6000 or a 50/50 mixture by weight of PEG 600 / PEG 1500 constitute preferred amphiphilic solvents according to the invention.
• polyethylene glycols will be selected in such a way that the resulting oral composition is compatible in particular in terms of viscosity with filling equipment, for example for the constitution of soft capsules.
• nonionic hydrophilic surfactant it is preferably chosen from compounds having an HLB close to 15.
• polysorbate 80 constitutes a surfactant of choice for the purposes of the invention. This surfactant will however be incorporated into the semi-solid compositions in question at a concentration not exceeding 20%, preferably not exceeding 12% by weight thereof.
• a solubilizing / stabilizing system preferably used consists of PEG 1000 and polysorbate 80 or a 50/50 mixture by weight of PEG 600/1500 as well as polysorbate 80 or PEG 2000 and polysorbate 80.
• the polyglycolysed glycerides, of solid and waxy consistency at room temperature will be selected in such a way that their liquefaction temperature is close to body temperature.
• the products marked GELUCIRE ® 44-14 and GELUCIRE ® 50-13 constitute mixtures of polyglycolysed glycerides of choice because of their liquefaction temperature of 44 ° C and 50 ° C respectively, of their amphiphilic nature conferred by fatty acid chains and the polyethylene glycol motif and by their favorable hydrophilic surfactant nature (HLB: 14 and 13 respectively).
• the semi-solid pharmaceutical compositions may be administered in a reduced volume given the high solubility of the active principles of formula I in this type of mixture of polyglycolysed glycerides.
• the product has been observed in experimental tests that the product
• GELUCIRE ® 44-14 improves the membrane permeability and allows a transepithelial transport speed of the Compound ⁇ approximately twice as high as that obtained with the liquid compositions of the invention introduced in soft capsule. Similarly, a very marked improvement in bioavailability was observed, this improvement being analogous to that recorded with the liquid compositions of the invention which can be used in soft capsules.
• another subject of the invention relates to a pharmaceutical soft capsule containing a liquid pharmaceutical composition for oral administration as described above, that is to say containing a hydrophobic active principle of formula I and a solubilizing system / stabilizing.
• compositions of the invention containing, as solubilizer / stabilizer, saturated polyglycolysed glycerides as described above are hot formed in the liquid state and then solidify by cooling.
• Another subject of the invention therefore relates to a pharmaceutical capsule containing a semi-solid pharmaceutical composition for oral administration as described above.
• compositions of the invention can be prepared in a conventional manner by dissolving the active principle of formula I in the chosen solvent (s) or solubilizer (s) to which the non-ionic hydrophilic surfactant has been added, these various constituents being in liquid form.
• solubilizing / stabilizing system will therefore be heated until a liquid mixture is obtained.
• This heating operation is particularly indicated when polyethylene glycols of molecular weight> 600 or mixtures of monoesters, diesters and triesters of glycerol and fatty acid, and of polyethylene glycol mono and diesters of fatty acids, in particular the products, are used.
• compositions of the invention can also be presented in solid form such as powder, granule or tablet. Consequently, another subject of the invention relates to a solid pharmaceutical composition for oral administration comprising:
• a solubilizing / stabilizing system comprising: - either one or more amphiphilic compounds, of glycolic type chosen from polyethylene glycol of average molecular weight between
• the system comprising or in addition to one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18,
• non-ionic hydrophilic compounds which are both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and fatty acids, and of mono and diester of polyethylene glycol and of fatty acids, the system optionally comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22 "preferably between 12 and 18, and optionally one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight included between 600 and 10,000 • • an appropriate excipient or pharmaceutical vehicle
• the solid pharmaceutical compositions of the invention will comprise a surfactant preferably chosen from compounds having an HLB close to 15.
• the polysorbates 20 or 80 constitute surfactants which are particularly advantageous for the purposes of the invention.
• This surfactant will however be introduced into the solid compositions in question at a concentration not exceeding 20% by weight thereof, preferably not exceeding 12%.
• excipients will be incorporated into the active principle and into the solubilizing / stabilizing system chosen.
• excipients can be selected from compounds such as for example lactose, starches, polyvinylpyrrolidone, carboxymethylcellulose.
• the invention also relates to a solid pharmaceutical composition for oral administration, this composition being in the form of a powder, a granule or a tablet.
• the solid compositions of the invention can be prepared in various ways, for example by applying one of the methods below from the various ingredients selected: a) mixing all the ingredients in powder form, including the active principle, melting the saturated polyglycolysed glyceride, that is to say the macrogolglyceride or the polyethylene glycol / surfactant mixture, then granulating the powder mixture with the molten phase, and the granules obtained are screened either b) the macrogolglyceride or the polyethylene glycol / surfactant mixture is melted, the active principle is granulated, the granules formed are screened and mixed with the remaining excipients or c) the macrogolglyceride or the polyethylene glycol / surfactant mixture is melted, the active principle is dissolved in this molten phase, the remaining excipients are mixed, this mixture of excipients is granulated with the molten phase and then the granules formed are sieved.
• the granules in question or the mixture of granules and excipients in question can be used directly by introducing them into hard capsules.
• these granules or this mixture of granules and excipients can be ground and then the powder obtained is distributed in unitary sachets.
• compositions according to the invention will appear in the light of the description below from compositions given by way of examples.
• an immortalized human cell line of colonic origin was used.
• Caco-2 cells are seeded on microporous polycarbonate filters coated with collagen.
• the cell monolayer formed on the filter then makes it possible to separate an apical compartment (mimicking the intestinal lumen) from a basal compartment (mimicking the blood circulation).
• the coefficient of permeability P is then determined, in cm / sec, which characterizes the speed of passage of the molecule through the membrane, namely:
• da - variation of the quantity of test compound crossing the cell monolayer dt as a function of time (mole / s)
• A surface of the monolayer (cm 2 )
• Co initial concentration of the test compound (mole / 1)
• composition A of formulation:
• compositions have been tested for oral administration in which the compound to be studied is Compound ⁇ .
• the compositions below were used so that the compound ⁇ is incubated at 50 ⁇ mol in Hank's solution.
• compositions C to G were diluted (Compositions C to E) or dispersed (Compositions F and G) in Hank's medium.
• composition IV dimethylsulfoxide
• composition IV the formulation devoid of surfactant
• composition II the solution in dimethylsulfoxide
• composition III an improvement is observed compared to the suspension control (Composition III). This improvement is particularly marked when the formulations with the surfactant are compared with the suspension formulation (Composition
• composition IV the presence of the surfactant favorably influences the passage since the permeability coefficient is at least 2 times higher than in the case of the composition without surfactant (Composition IV). This favorable influence of the surfactant is linked to its stabilizing and / or promoter effect.
• composition H of the invention which can be used in a soft capsule, namely:
• Composition V Compound ⁇ suspended in Hank's culture medium
• Composition VI Compound ⁇ dissolved in dimethyl sulfoxide and then introduced into Hank's culture medium
• Composition VII (usable in capsule): Compound ⁇ 20.00 mg
• Composition V (suspension) reduced to 1.
• compositions VI, VII and H improve the passage of Compound ⁇ compared to the suspension of this compound (Composition V).
• the improvement provided by Composition VII which can be used as a capsule is much less than the improvement recorded with Composition VI soluble using dimethyl sulfoxide.
• Composition H which can be used in a soft capsule, allows a very strong improvement in the passage, an improvement which even turns out to be greater than that observed with the solution of Compound ⁇ in dimethyl sulfoxide (Composition VI). They further confirm that the solubilization step has a decisive impact on the transepithelial passage of Compound ⁇ and that the surfactant has an absorption promoting effect while maintaining the solubilized state.
• compositions below were used on Caco-2 cells in quantities such that Compound ⁇ is incubated at 100 ⁇ mol in a Hank solution added with taurocholic acid and phospholipid at 37 ° C.
• composition L does not modify the measured permeability coefficient 27 on Caco-2 cells, when the surfactant, in this case polysorbate 80, remains present in the composition.
• compositions M and N based on GELUCIRE® product are observed that compositions M and N based on GELUCIRE® product.
• compositions of the invention allow an improvement in the transmambranar passage compared to the reference compositions without causing a destructuring effect on this membrane.
• Plasma assays were carried out in dogs after oral administration of 20 mg of Compound ⁇ either in the form of Composition H introduced in soft capsule or in the form of Composition VII introduced in hard capsule. Compared to the hard capsule, the administration of the soft capsule containing the
• Composition H results in:
• Composition H microdispersible liquid was compared with two other formulations of the same concentration of Compound ⁇ introduced in hard capsule, one with micronized active ingredient, the other with non-micronized active ingredient.
• composition H namely:
• Second the solvent for the solubilization of Compound ⁇ is prepared by mixing 50 parts of PVP KOLLIDON ® 12 PF containing 25% water with 50 parts of PEG 400 5 so as to constitute a solvent formed of 12.5% of PVP KOLLIDON ® 12PF,
• Soft capsules are obtained containing a composition of the following formulation: % by weight Compound ⁇ 6
• the solubilizing / stabilizing system is prepared from:
• the composition formed is introduced into soft capsules.
• the composition formed is introduced into capsules and cooled.
• Hard capsules are obtained containing a composition of the following formulation:
• the mixture is stirred at 55 ° C. until homogenized and then the Compound ⁇ is introduced directly at 55 ° C. into the solubilizing / stabilizing system thus formed.
• soft capsules or capsules were prepared containing compositions of the following formulations.
• the percentages are expressed by weight relative to the weight of the final composition.
• the GELUCIRE® 44-14 product is melted at around 60 ° C. and then the compound ⁇ is dissolved therein. The remaining excipients are then mixed and the mixture obtained is granulated with the solution of compound ⁇ . The granules obtained are sieved and compressed.
• Capsules with the same formulation as in Example 27 are obtained by melting the product GELUCIRE® 44-14 at 60 ° C and then dissolving the compound ⁇ therein. The remaining excipients are then mixed and the mixture obtained is granulated with the solution of compound ⁇ . The sieves are screened and the granules formed are introduced into capsules.
• the PEG 2000 / TWEEN®20 mixture is melted at approximately 60 ° C. and then the compound ⁇ is dissolved therein. 36 The remaining excipients are then mixed and the mixture formed is granulated with the solution of compound ⁇ . The granules obtained are sieved and compressed.
• Capsules with the same formulation as in Example 29 are obtained by melting the PEG 2000 / TWEN®20 mixture, at around 60 ° C and dissolving the compound ⁇ therein. The remaining excipients are mixed and the mixture formed is then granulated with the solution of compound ⁇ . The sieves are introduced and the granules obtained are introduced into capsules.

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• 1996
  • 1996-12-05 FR FR9614957A patent/FR2756736B1/fr not_active Expired - Fee Related
• 1997
  • 1997-12-03 DZ DZ970212A patent/DZ2362A1/xx active
  • 1997-12-04 AR ARP970105696A patent/AR009651A1/es unknown
  • 1997-12-04 AU AU53262/98A patent/AU716575B2/en not_active Ceased
  • 1997-12-04 JP JP10525294A patent/JP2000507618A/ja active Pending
  • 1997-12-04 CN CN97180304A patent/CN1239887A/zh active Pending
  • 1997-12-04 ZA ZA9710919A patent/ZA9710919B/xx unknown
  • 1997-12-04 CO CO97071118A patent/CO4910129A1/es unknown
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  • 1997-12-04 KR KR1019997004983A patent/KR20000069308A/ko not_active Ceased
  • 1997-12-04 EP EP97950228A patent/EP0941090A1/de not_active Withdrawn
  • 1997-12-04 HU HU0001386A patent/HUP0001386A3/hu unknown
  • 1997-12-04 EE EEP199900206A patent/EE9900206A/xx unknown
  • 1997-12-04 RU RU99114019/14A patent/RU2174394C2/ru active
  • 1997-12-04 SK SK755-99A patent/SK75599A3/sk unknown
  • 1997-12-04 BR BR9712406-0A patent/BR9712406A/pt unknown
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