[go: up one dir, main page]

EP0927026A1 - Pharmaceutical compositions containing amisulpride and their therapeutic applications - Google Patents

Pharmaceutical compositions containing amisulpride and their therapeutic applications

Info

Publication number
EP0927026A1
EP0927026A1 EP97919108A EP97919108A EP0927026A1 EP 0927026 A1 EP0927026 A1 EP 0927026A1 EP 97919108 A EP97919108 A EP 97919108A EP 97919108 A EP97919108 A EP 97919108A EP 0927026 A1 EP0927026 A1 EP 0927026A1
Authority
EP
European Patent Office
Prior art keywords
amisulpride
isomers
levorotatory
composition according
dextrorotatory
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97919108A
Other languages
German (de)
French (fr)
Inventor
Véronique Andrieu
Alain Cuine
Jean Montel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Synthelabo SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthelabo SA filed Critical Synthelabo SA
Publication of EP0927026A1 publication Critical patent/EP0927026A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to new pharmaceutical compositions, mainly intended for oral administration, comprising 4 -am ⁇ no-N- [(1-ethylpyrrol ⁇ dm- 2-yl) methyl] -5- (ethylsulfonyl) -2- methoxybenzam ⁇ de or amisulpnde, its isomers and some of their derivatives, these compositions having improved bioavailability.
  • Amisulpnde its isomers and some of their derivatives are described in French patent 78,01632, the teaching of which is fully incorporated in the present description.
  • Amisulpride is an antipsychotic used in the treatment of psychoses, particularly in the treatment of paranoid and productive schizophrenia, psychoses acute delusions as well as in the treatment of deficiency states of schizophrenia, residual psychotic changes and states of 1 inhibition with slowdown. Amisulpnde is also useful in the treatment of dysthymia.
  • Amisulpnde can be administered orally, generally in the form of tablets, dosed at 50 or 200 mg each (see Vidal, section Solian, pages 1463 and 1464, ed. Du Vidal, 1996).
  • the daily doses of amisulpride thus administered are often very high and can exceed 1 g / day.
  • patients treated with amisulpnde should take several of these tablets daily.
  • some of these patients by reason of their condition, may find it difficult to regularly absorb, without forgetting, a high number of tablets and therefore to follow their treatment correctly.
  • the plaintiff sought to develop a new form of amisulpnde, intended mainly for oral administration, requiring only a limited number of daily doses (or number of doses / day), or even a single daily dose.
  • Tablets comprising a higher dose of amisulpnde, for example doses greater than 600 mg, were first considered. However, such tablets have been found to be too large to be easily swallowed by patients.
  • the Applicant has been able to observe that the limited biodispombility (of the order of 35 to 45%) of 1 amisulpnde administered orally could be attributed to a partial and irregular passage of this compound at the gastrointestinal level and, thus, its passage to the cerebral level could sometimes be insufficient.
  • the main object of the invention is therefore new forms of amisulpnde with improved bioavailability, in particular when they are administered orally.
  • the invention consists of new pharmaceutical compositions, mainly intended for oral administration, characterized in that they comprise a lipophilic phase and at least one active principle consisting of 1 amisulpnde, one of its levorotatory isomers and dextrorotatory or a derivative of 1 amisulpnde or one of its levorotatory and dextrorotatory isomers, this derivative being chosen from an addition salt with a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide, 1 amisulpride or one of its levorotatory and dextrorotatory isomers.
  • active principle consisting of 1 amisulpnde, one of its levorotatory isomers and dextrorotatory or a derivative of 1 amisulpnde or one of its levorotatory and dextrorotatory isomers, this derivative being chosen from an addition salt with a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide, 1 amisulpride or
  • FIG. 1 represents the plasma concentrations of amisulpride measured in the rat after absorption of various formulations comprising the same dose of amisulprid.
  • FIG. 2 represents the plasma concentrations of amisulpride measured in the rat after absorption of formulations comprising variable doses of amisulpride.
  • said active ingredient is dissolved, partially or completely, in the lipophilic phase.
  • a composition according to the invention is very particularly suitable for 1 amisulpride per se, ie 4 -amino-N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) - 2-methoxybenzamide , its levogyre isomers
  • a preferred tartrate consists of the compound described in Example IV of patent FR 78 01632, that is to say the (D) -tartrate of (S) - (, -) - amisulpride, in other words the [S- (R *, R *)] -2,3-dihydroxybutaned ⁇ oate du (S) - (-) -4-amino- N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) -2-methoxybenzamide.
  • a composition according to the invention may also be suitable for the other derivatives mentioned above. These derivatives and their process of obtaining, are described in more detail in the French patent 78,01632, already cited.
  • acids suitable for forming salts of 1 • amisulpride per se and of its isomers mention may more particularly be made of hydrochloric, bromhydric, sulfunic, phosphoric, oxalic, acetic, tart ⁇ que, citric, methane-sulphonic acids.
  • amisulpride will be understood to mean both amisulpride per se and its isomers and derivatives mentioned above.
  • compositions according to the invention make it possible to significantly increase the bioavailability of 1 amisulpnde compared to the oral forms known hitherto.
  • bioavailability means the fraction of the active principle which is absorbed from its pharmaceutical form and which reaches the site of action.
  • a pharmaceutical composition according to the invention can comprise from 25 to 300 mg, more generally from 100 to 250 mg of amisulp ⁇ de / unit dose. Such a content authorizes the administration of one to three unit doses per day only, preferably one to two unit doses per day.
  • the concentration of amisulpride in a composition pharmaceutical of the invention can be between 1 mg / ml and 350 mg / ml, preferably between 10 mg / ml and 310 mg / ml.
  • the lipophilic phase can be solid or, preferably, liquid at room temperature.
  • the lipophilic phase may consist of (i) one or more fatty acids, (ii) one or more monoglycerides or acetylated or polyethoxylated derivatives of monoglycerides, (iii) one or more diglycerides or acetylated or polyethoxylated derivatives of diglycerides, (iv) one or more several oils, such as mineral, animal, vegetable, transesterified and / or polyethoxylated or synthetic oils or (v) a mixture comprising two or more of the compounds mentioned under points (i), (ii), (iii) and (iv ), in particular, a mixture comprising a fatty acid and an oil.
  • fatty acids of those comprising from 12 to 22 carbon atoms, in particular oleic, arachidonic, linolenic, linoleic or ricinoleic acids.
  • monoglycerides diglycerides or acetylated or polyethoxylated derivatives of these compounds, mention may in particular be made of those comprising, respectively) one or two fatty chains comprising from 12 to 24 carbon atoms, and more particularly, those marketed by the companies Abitec and Eastman under the brands Capmul ® and Myvacet ® , in particular mono glycerol caprylate, mono glycerol stearate, monoacetylated monoglycerides and diacetylated monoglycerides.
  • mineral oils suitable in the context of the invention there may be mentioned paraffin oils and petrolatum oil.
  • vegetable oils mention may be made of olive, peanut, soybean, rapeseed, palm, sesame, grape seed, corn, walnut or sunflower oils.
  • vegetable oils transesterified and / or polyethoxylated include polyethoxylated olive oils, sunflower polyethoxylated, palm polyethoxylated or polyethoxylated castor, including those sold under the trademark Labrafil ® by Gattefossé.
  • liver oils in particular cod or halibut liver oils.
  • synthetic oils mention may be made of silicone oils.
  • Oleic acid constitutes a particularly preferred lipophilic phase.
  • the lipophilic phase can be in the form of either an emulsion or a self-emulsifiable mixture.
  • Such an emulsion in addition to the lipophilic phase, comprises a hydrophilic phase and, generally, at least one surfactant.
  • the emulsion can be of the water in oil (W / O) type or, preferably, oil in water (O / W).
  • the emulsion can be of the submicron emulsion type.
  • Such an emulsion has a discontinuous phase in the form of particles with an average diameter of less than 1 ⁇ m, generally between 0.3 and 0.7 ⁇ m.
  • the emulsion can also be of the microemulsion type, for which the discontinuous phase is generally in the form of particles with an average diameter of between 0.05 and 0.250 ⁇ m.
  • the hydrophilic phase can consist of one or more compounds chosen from alcohols such as glycerol, propylene glycol, polyethylene glycols whose weight molecular is between 100 and 3000, or water. This is preferred in the context of the present invention.
  • the dispersed phase of an emulsion according to the invention can represent from 5 to 30% by weight, generally from 10 to 20% by weight of the total weight of the emulsion.
  • the surfactant is chosen according to the nature of the emulsion. Those skilled in the art know, in particular according to their HLB (Hydrophilic-Lipophilic Balance), which surfactant to choose to obtain a W / O, O / W emulsion or a micro-emulsion.
  • HLB Hydrophilic-Lipophilic Balance
  • surfactant which may be suitable in the context of the present invention include sorbitan esters and polyoxyethylene sorbitan esters such as those sold under the T een ® and Span ®, the lécithmes of animal or vegetable origin, castor oil polyoxyethylene, such as those sold under the Cremophor ® brand, sucrose fatty acid esters (sugar esters or), esters of fatty alcohols and polyethylene glycol, esters fatty acids and polyethylene glycol, bile acids, these surfactants can be used alone or as a mixture.
  • An emulsion according to the invention can comprise from 0.01 to 5% by weight of surfactants relative to the dispersed phase.
  • self-emulsifying mixture means a mixture consisting of a lipophilic phase, consisting of at least one oil and / or at least one fatty acid such as those described above, with at least one surfactant, this mixture being able to form an emulsion by simple mechanical stirring with an aqueous phase.
  • a self-emulsifying mixture according to the invention can, after oral administration, form emulsions with the hydrophilic phases of the organism.
  • the constituent surfactants of such a self-emulsifiable mixture may be selected from sorbitan esters and polyoxyethylene sorbitan esters such as those sold under the T een ® and Span ®, in particular polysorbate 80.
  • the content of surfactants in the self-emulsifying mixture can be between 0.5 and 10% by weight relative to the lipophilic phase.
  • the pharmaceutical composition according to the invention is in the form of a lipid solution.
  • a lipid solution essentially comprises a lipophilic phase, generally consisting of at least one fatty acid and / or at least one oil, such as those mentioned above, the amisulpride being dissolved in this lipophilic phase.
  • a lipid solution is substantially free of hydrophilic phase and of surfactant.
  • the lipophilic phase of the lipid solution consists of a fatty acid, more preferably oleic acid.
  • a pharmaceutical composition according to the invention may also comprise pharmaceutically acceptable excipients, such as diluents, preserving agents, osmotic agents, antioxidants, thickening agents, stabilizing agents, viscosity-reducing agents such as ethanol. , gelling agents and pH buffers.
  • pharmaceutically acceptable excipients such as diluents, preserving agents, osmotic agents, antioxidants, thickening agents, stabilizing agents, viscosity-reducing agents such as ethanol. , gelling agents and pH buffers.
  • compositions of the invention can be prepared in a conventional manner for a person skilled in the art.
  • a lipid solution according to the invention can be prepared by dissolving, with stirring, the amisulpnde in the lipophilic phase. If necessary, other excipients can then be added, such as those mentioned above.
  • the lipophilic phase containing 1 amisulpride can be introduced, with stirring, into the hydrophilic phase in which the surfactant (s) and (s) have been previously added and, where appropriate , hydrophilic excipients. Agitation may be achieved by means of a device of the Ultra-Turrax ® kind.
  • a high pressure die for example of the type APV-Gaulm ®
  • a self-emulsifying mixture according to the invention can be prepared conventionally, by introducing, with stirring, the required surfactant (s) into a lipophilic phase containing 1 amisulpride, this lipophilic phase being itself prepared as indicated above.
  • a composition according to the invention can be presented in liquid form, divided or not, accompanied or not with a dosing device such as a spoon, in gelled form, in the form of soft capsules, of globules or, preferably, in the form of capsules.
  • a dosing device such as a spoon
  • gelled form in the form of soft capsules, of globules or, preferably, in the form of capsules.
  • These capsules can consist of gelatin or starch and are usually sealed in a conventional manner.
  • compositions according to the invention are mainly and preferably intended for oral administration. They can however be administered by other routes, for example by the rectal route.
  • the invention relates to the use of 1 amisulpnde to prepare pharmaceutical compositions described above, for the treatment of dysthymia, the treatment of psychoses, more particularly for the treatment of paranoid and productive schizophrenia, acute delusional psychosis, as well as for the treatment of deficit states of schizophrenia, residual psychotic changes and inhibition states with slowing down.
  • Said pharmaceutical compositions can also be used in the therapeutic treatment of delusional flushes, 1 hebephreno-catatonia, migraines, with or without photophobia or nausea.
  • they can be used in the treatment of autism. They are still useful in withdrawal linked to the consumption of alcohol and / or narcotics and / or tobacco; more particularly, they reduce the risk of relapse during the post-weaning deficit period.
  • the invention relates to new pharmaceutical compositions comprising 1 amisulpride and at least one pharmaceutically acceptable excipient, said compositions allowing the prolongation and / or the intensification of the gastrointestinal absorption of 1 amisulpride from so that the biodispombility of 1 amisulpride is greater than 50%, more generally between 60 and 75%.
  • These pharmaceutical compositions are mainly intended for oral administration.
  • Example 1 Self-emulsifying mixture suitable for rats
  • a self-emulsifying mixture according to the invention is prepared by introducing 100 mg of amisulpride per se, as well as 4 mg of polysorbate 80, in oleic acid (qs 100 ml). Then, it is stirred slowly until complete dissolution.
  • Example 2 Submicron O / W emulsion suitable for rats
  • O / W submicronic emulsion according to the invention is prepared in the following manner:
  • a hydrophilic phase is prepared by mixing 3.3 g of soya lecithin, 5.6 g of glycerin, 2 g of solidified polyoxyethylene castor oil (Cremophor ® RH 40) and 0.1 g of sodium hydrogen sulfite. This mixture is dissolved or dispersed in 82 g of water and heated to 70-80 ° C.
  • the lipophilic phase is added to the hydrophilic phase and stirred with an Ultra-Turrax ® stirrer at 5000 revolutions / min. for ten minutes.
  • a coarse emulsion which is refined by means of a homogenizer type high pressure APV Gaulm ®, in order to obtain a liquid emulsion in which the average diameter of lipophilic particle is less than 1 .mu.m.
  • Example 3 O / W hydrophilic emulsion suitable for rats
  • a hydrophilic O / W emulsion according to the invention is prepared in the following manner:
  • a 2.25 mg / ml solution of polysorbate 80 in double-distilled glycerol is mixed with a lipid solution of amisulpnde per se in oleic acid. This mixture is then stirred with an Ultra-Turrax ® agitator, at 5000 rpm. for ten minutes.
  • Example 4 O / W aqueous emulsion suitable for rats
  • O / W aqueous emulsion according to the invention is prepared in the following manner:
  • a hydrophilic phase is prepared by mixing lécithme of n a, polyoxyethylenated castor oil solidified (Cremophor ® RH 40) and one sodium hvdrogénosulfite. This mixture is dissolved or dispersed in water (qs 100 ml) and heated to 70-80 ° C.
  • a lipophilic phase is prepared consisting of a solution of amisulpride per se in oleic acid.
  • the lipophilic phase is added to the hydrophilic phase and stirred with an Ultra-Turrax ® stirrer at 5000 revolutions / min. for ten minutes.
  • Amisulpide per se in oleic acid was introduced with slow stirring so as to obtain a lipid solution of amisulpride per se at 10 mg / ml in accordance with the invention.
  • Amisulpride per se was introduced with oleic acid under slow stirring so as to obtain a 25 mg / ml solution of amisulpride lipid.
  • This solution was divided into size 1 capsules at a rate of 0.4 g per capsule. Each capsule contained 100 mg of amisulpride per se.
  • Example 6 was reproduced by replacing 1 amisulpride per se with (D) -tartrate from (S) - (-) - amisulpride, that is to say the compound of Example IV of patent FR 78 01632. There were thus obtained capsules containing 100 mg of active principle.
  • compositions in accordance with the invention were tested in rats, according to the following protocol:
  • the rats were Spragues Da ley OFA, males from 200 to
  • T 0 After administration of the pharmaceutical composition (T 0 ), whether or not in accordance with the invention, the animals were replaced in their cage. They were kept on hold for a maximum of four hours after treatment. Samples were taken from the vena cava below time 0; 0.08; 0.25; 1; 2; 4; 6; 8; 16 and 24 hours. The tubes containing the collected blood were centrifuged and the recovered plasma was stored in the freezer.
  • the concentration of amisulpnde per se in the plasma was measured by HPLC with fluorimetric detection.
  • compositions according to the invention were tested, each comprising 10 mg / ml of amisulpride per se.
  • compositions tested were those of Examples 1, 3, 4 and 5.
  • compositions were compared with a reference solution, not in accordance with the invention, consisting of an aqueous 0.9% sodium chloride solution comprising 10 mg / ml of amisulpnde per se, the pH of which was adjusted to 3.5-6.5 using 1M hydrochloric acid.
  • Form T max (hours) C max (ng / ml) AUC (ng / ml / h) pharmaceutical (Tl T2) solution of 1 82 287 reference (0.08-16) solution 0.08 108 410 lipid (0.08 -16) emulsion 0.08 110 213 aqueous (0.08-8) emulsion 0.08 107 310 hydrophilic (0.08-16) self-mixing 4 63 324 emulsifiable (0.08-24)
  • Lipid solutions comprising increasing concentrations of amisulpnde per se were tested according to the protocol described in Example 8.
  • the lipid solutions were prepared by stirring until the required dose of amisulpride per se was dissolved in 10 ml of oleic acid.
  • the lipid solutions were compared with a reference solution consisting of an aqueous solution of sodium chloride comprising 50 mg / ml of amisulpride per se, the pH of which was adjusted to 3.5-6.5 using acid. hydrochloric 1M.
  • the results obtained are shown in FIG. 2.
  • the plasma concentrations of amisulpride per are expressed in ng / ml.
  • T max , C max and the areas under the curve (AUC) obtained for each composition tested are grouped in Table II below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention concerns a pharmaceutical composition, particularly to be orally administered, containing a lipophilic phase and at least one active principle consisting of amisulpride, one of its laevo-rotary and dextro-rotary isomers or an amisulpride derivative selected among its additive salts with phamaceutically acceptable acids, its quaternary ammonium salts, its oxides and their leavo-rotary and dextro-rotary isomers. The invention has useful therapeutic applications.

Description

COMPOSITIONS PHARMACEUTIQUES COMPRENANT DE L'AMISULPRIDE ET LEURS APPLICATIONS THERAPEUTIQUES PHARMACEUTICAL COMPOSITIONS COMPRISING AMISULPRIDE AND THERAPEUTIC APPLICATIONS THEREOF
La présente invention a pour objet de nouvelles compositions pharmaceutiques, principalement destinées à l'administration par voie orale, comprenant du 4 -amιno-N- [ (1-éthylpyrrolιdm- 2-yl)méthyl] -5- (éthylsulfonyl) -2-méthoxybenzamιde ou amisulpnde, ses isomères et certains de leurs dérivés, ces compositions présentant une biodisponibilité améliorée.The present invention relates to new pharmaceutical compositions, mainly intended for oral administration, comprising 4 -amιno-N- [(1-ethylpyrrolιdm- 2-yl) methyl] -5- (ethylsulfonyl) -2- methoxybenzamιde or amisulpnde, its isomers and some of their derivatives, these compositions having improved bioavailability.
L ' amisulpnde , ses isomères et certains de leurs dérivés sont décrits dans le brevet français 78 01632, dont l'enseignement est intégralement incorporé dans la présente description. L ' amisulpnde est un neuroleptique utilisé dans le traitement des psychoses, plus particulièrement dans le traitement des schizophrénies paranoides et productives, des psychoses délirantes aiguës, ainsi que dans le traitement des états déficitaires des schizophrénies, des évolutions psychotiques résiduelles et des états d1 inhibition avec ralentissement. L' amisulpnde est également utile dans le traitement de la dysthymie .Amisulpnde, its isomers and some of their derivatives are described in French patent 78,01632, the teaching of which is fully incorporated in the present description. Amisulpride is an antipsychotic used in the treatment of psychoses, particularly in the treatment of paranoid and productive schizophrenia, psychoses acute delusions as well as in the treatment of deficiency states of schizophrenia, residual psychotic changes and states of 1 inhibition with slowdown. Amisulpnde is also useful in the treatment of dysthymia.
L' amisulpnde peut être administré par voie orale, généralement sous forme de comprimés, dosés à 50 ou 200 mg chacun (voir Vidal, rubrique Solian, page 1463 et 1464, éd. du Vidal, 1996) . Les doses quotidiennes en amisulpride ainsi administré, sont souvent très élevées et peuvent dépasser 1 g/iour. Dans ce cas, les patients traités par 1 ' amisulpnde doivent absorber plusieurs de ces comprimés quotidiennement . Or certains de ces patients, en raison même de leur état, peuvent rencontrer des difficultés à absorber régulièrement, sans en oublier, un nombre élevé de comprimés et donc à suivre correctement leur traitement. La demanderesse a alors cherché à mettre au point une nouvelle forme d ' amisulpnde, destinée principalement à l'administration par voie orale, ne nécessitant qu'un nombre de prises quotidiennes (ou nombre de doses/jour) limitées, voire une seule prise quotidienne.Amisulpnde can be administered orally, generally in the form of tablets, dosed at 50 or 200 mg each (see Vidal, section Solian, pages 1463 and 1464, ed. Du Vidal, 1996). The daily doses of amisulpride thus administered are often very high and can exceed 1 g / day. In this case, patients treated with amisulpnde should take several of these tablets daily. However, some of these patients, by reason of their condition, may find it difficult to regularly absorb, without forgetting, a high number of tablets and therefore to follow their treatment correctly. The plaintiff then sought to develop a new form of amisulpnde, intended mainly for oral administration, requiring only a limited number of daily doses (or number of doses / day), or even a single daily dose.
II a tout d'abord été envisagé des comprimés comprenant une dose plus forte d ' amisulpnde, par exemple des doses supérieures à 600 mg . Toutefois de tels comprimés se sont avérés présenter une taille trop importante pour être facilement avalés par les patients.Tablets comprising a higher dose of amisulpnde, for example doses greater than 600 mg, were first considered. However, such tablets have been found to be too large to be easily swallowed by patients.
Par ailleurs, et sans être tenue par la théorie, la demanderesse a pu constater que la biodispombilité limitée (de l'ordre de 35 à 45 %) de 1 ' amisulpnde administré par voie orale pouvait être attribuée à un passage partiel et irrégulier de ce composé au niveau gastro-intestinal et, qu'ainsi, son passage au niveau cérébral pouvait parfois être insuffisant .Furthermore, and without being bound by theory, the Applicant has been able to observe that the limited biodispombility (of the order of 35 to 45%) of 1 amisulpnde administered orally could be attributed to a partial and irregular passage of this compound at the gastrointestinal level and, thus, its passage to the cerebral level could sometimes be insufficient.
Il a alors été envisagé de prolonger et/ou d'intensifier l'absorption gastro- intestinale de 1 ' amisulpnde pour en améliorer la biodispombilité, en vue notamment, de diminuer le nombre de prises quotidiennes d ' amisulpnde, tout en maintenant, voire en améliorant, l'efficacité thérapeutique de ce composé .It was then envisaged to prolong and / or intensify the gastrointestinal absorption of 1 amisulpnde in order to improve the biodispombility thereof, with a view in particular to reducing the number of daily doses of amisulpnde, while maintaining or even improving the therapeutic efficacy of this compound.
L'invention a alors pour principal objet de nouvelles formes d ' amisulpnde présentant une biodisponibilité améliorée, notamment quand elles sont administrées par voie orale.The main object of the invention is therefore new forms of amisulpnde with improved bioavailability, in particular when they are administered orally.
Plus spécifiquement, l'invention consiste en de nouvelles compositions pharmaceutiques, principalement destinées à l'administration par voie orale, caractérisées en ce qu'elles comprennent une phase lipophile et au moins un principe actif consistant en 1 ' amisulpnde, un de ses isomères levogyre et dextrogyre ou un dérivé de 1 ' amisulpnde ou de l'un de ses isomères levogyre et dextrogyre, ce dérivé étant choisi parmi un sel d'addition avec un acide pharmacologiquement acceptable, un sel d'ammonium quaternaire ou un oxyde, de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre .More specifically, the invention consists of new pharmaceutical compositions, mainly intended for oral administration, characterized in that they comprise a lipophilic phase and at least one active principle consisting of 1 amisulpnde, one of its levorotatory isomers and dextrorotatory or a derivative of 1 amisulpnde or one of its levorotatory and dextrorotatory isomers, this derivative being chosen from an addition salt with a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide, 1 amisulpride or one of its levorotatory and dextrorotatory isomers.
La figure 1 représente les concentrations plasmatiques en amisulpride mesurées chez le rat après absorption de diverses formulations comprenant une même dose d ' amisulprid .FIG. 1 represents the plasma concentrations of amisulpride measured in the rat after absorption of various formulations comprising the same dose of amisulprid.
La figure 2 représente les concentrations plasmatiques en amisulpride mesurées chez le rat après absorption de formulations comprenant des doses variables d ' amisulpride .FIG. 2 represents the plasma concentrations of amisulpride measured in the rat after absorption of formulations comprising variable doses of amisulpride.
Généralement, ledit principe actif est dissout, partiellement ou totatement, dans la phase lipophile.Generally, said active ingredient is dissolved, partially or completely, in the lipophilic phase.
Une composition selon l'invention convient tout particulièrement pour 1 ' amisulpride per se, c'est à dire le 4 -amino-N- [ (l-éthylpyrrolidin-2-yl) méthyl] -5- (éthylsulfonyl) - 2-méthoxybenzamide, ses isomères levogyreA composition according to the invention is very particularly suitable for 1 amisulpride per se, ie 4 -amino-N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) - 2-methoxybenzamide , its levogyre isomers
( (S) - { - ) - amisulpride) et dextrogyre ( (i.) - (+) - amisulpride), des mélanges de ces isomères, les tartrates de 1 ' amisulpride per se et de ses isomères, et plus particulièrement les tartrates desdits isomères, et des mélanges de ces tartrates. Un tartrate préféré consiste en le composé décrit dans l'exemple IV du brevet FR 78 01632, c'est à dire le (D) -tartrate du (S) - (, - ) - amisulpride, autrement dit le [S- (R*,R*) ] -2,3-dihydroxybutanedιoate du (S) - ( - ) -4-amino- N- [ (l-éthylpyrrolidin-2-yl) méthyl] -5- (éthylsulfonyl) -2- méthoxybenzamide .((S) - {-) - amisulpride) and dextrorotatory ((i.) - (+) - amisulpride), mixtures of these isomers, the tartrates of amisulpride per se and its isomers, and more particularly tartrates said isomers, and mixtures of these tartrates. A preferred tartrate consists of the compound described in Example IV of patent FR 78 01632, that is to say the (D) -tartrate of (S) - (, -) - amisulpride, in other words the [S- (R *, R *)] -2,3-dihydroxybutanedιoate du (S) - (-) -4-amino- N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) -2-methoxybenzamide.
Une composition selon l'invention peut aussi convenir pour les autres dérivés mentionnés plus haut. Ces dérivés et leur procédé d'obtention, sont décrits plus en détail dans le brevet français 78 01632, déjà cité. A titre d'acides convenant pour former des sels de 1 • amisulpride per se et de ses isomères, on peut plus particulièrement citer les acides chlorhydπque, bromhydnque, sulfunque, phosphorique, oxalique, acétique, tartπque, citrique, méthane- sul fonique .A composition according to the invention may also be suitable for the other derivatives mentioned above. These derivatives and their process of obtaining, are described in more detail in the French patent 78,01632, already cited. As acids suitable for forming salts of 1 • amisulpride per se and of its isomers, mention may more particularly be made of hydrochloric, bromhydric, sulfunic, phosphoric, oxalic, acetic, tartπque, citric, methane-sulphonic acids.
Par souci de simplicité, et sauf indication contraire, on entendra dans la description ci-après par "amisulpride", aussi bien 1 ' amisulpride per se que ses isomères et ses dérivés mentionnés ci -dessus.For the sake of simplicity, and unless otherwise indicated, in the description below, the term "amisulpride" will be understood to mean both amisulpride per se and its isomers and derivatives mentioned above.
Les compositions selon l'invention permettent d'augmenter notablement la biodisponibilité de 1 ' amisulpnde par rapport aux formes orales connues jusqu'alors.The compositions according to the invention make it possible to significantly increase the bioavailability of 1 amisulpnde compared to the oral forms known hitherto.
En raison de cette biodisponibilité améliorée, il est alors possible de résoudre le problème consistant à disposer de formes d ' amisulpride ne nécessitant qu'un nombre de prises quotidiennes limitées. En effet, l'amélioration de la biodisponibilité obtenue permet de réduire significativement les doses d ' amisulpride administrées.Because of this improved bioavailability, it is then possible to solve the problem of having forms of amisulpride requiring only a limited number of daily intakes. Indeed, the improvement in bioavailability obtained makes it possible to significantly reduce the doses of amisulpride administered.
Dans le cadre de la présente invention, on entend par le terme "biodisponibil té" , la fraction du principe actif qui est absorbé depuis sa forme pharmaceutique et qui parvient au site d'action.In the context of the present invention, the term "bioavailability" means the fraction of the active principle which is absorbed from its pharmaceutical form and which reaches the site of action.
Une composition pharmaceutique selon l'invention peut comprendre de 25 à 300 mg, plus généralement de 100 à 250 mg d ' amisulpπde/dose unitaire. Une telle teneur autorise l'administration d'une à trois doses unitaires par our seulement, de préférence une à deux doses unitaires par jour.A pharmaceutical composition according to the invention can comprise from 25 to 300 mg, more generally from 100 to 250 mg of amisulpπde / unit dose. Such a content authorizes the administration of one to three unit doses per day only, preferably one to two unit doses per day.
La concentration en amisulpride dans une composition pharmaceutique de l'invention, peut être comprise entre 1 mg/ml et 350 mg/ml, de préférence entre 10 mg/ml et 310 mg/ml.The concentration of amisulpride in a composition pharmaceutical of the invention, can be between 1 mg / ml and 350 mg / ml, preferably between 10 mg / ml and 310 mg / ml.
La phase lipophile peut être solide ou, de préférence, liquide à la température ambiante.The lipophilic phase can be solid or, preferably, liquid at room temperature.
La phase lipophile peut consister en (i) un ou plusieurs acides gras, (ii) un ou plusieurs monoglycérides ou dérivés acétylés ou polyéthoxylés de monoglycérides , (iii) un ou plusieurs diglycérides ou dérivés acétylés ou polyéthoxylés de diglycérides, (iv) une ou plusieurs huiles, telles des huiles minérales, animales, végétales, végétales transestérifiées et/ou polyéthoxylées ou synthétiques ou (v) un mélange comprenant deux ou plus des composés mentionnés sous les points (i) , (ii) , (iii) et (iv) , en particulier, un mélange comprenant un acide gras et une huile.The lipophilic phase may consist of (i) one or more fatty acids, (ii) one or more monoglycerides or acetylated or polyethoxylated derivatives of monoglycerides, (iii) one or more diglycerides or acetylated or polyethoxylated derivatives of diglycerides, (iv) one or more several oils, such as mineral, animal, vegetable, transesterified and / or polyethoxylated or synthetic oils or (v) a mixture comprising two or more of the compounds mentioned under points (i), (ii), (iii) and (iv ), in particular, a mixture comprising a fatty acid and an oil.
A titre d'acides gras on peut citer ceux comprenant de 12 à 22 atomes de carbone, en particulier les acides oléique, arachidonique, linolénique, linoléique ou ricinoléique .Mention may be made, as fatty acids, of those comprising from 12 to 22 carbon atoms, in particular oleic, arachidonic, linolenic, linoleic or ricinoleic acids.
A titre de monoglycérides, diglycérides ou dérivés acétylés ou polyéthoxylés de ces composés, on peut notamment citer ceux comprenant, respectivement) une ou deux chaines grasses comprenant de 12 à 24 atomes de carbone, et plus particulièrement, ceux commercialisés par les sociétés Abitec et Eastman sous les marques Capmul® et Myvacet®, en particulier le mono caprylate de glycérol, le mono stéarate de glycérol, les monoglycérides monoacétylés et les monoglycérides diacétylés.As monoglycerides, diglycerides or acetylated or polyethoxylated derivatives of these compounds, mention may in particular be made of those comprising, respectively) one or two fatty chains comprising from 12 to 24 carbon atoms, and more particularly, those marketed by the companies Abitec and Eastman under the brands Capmul ® and Myvacet ® , in particular mono glycerol caprylate, mono glycerol stearate, monoacetylated monoglycerides and diacetylated monoglycerides.
A titre d'huiles minérales convenant dans le cadre de l'invention, on peut citer les huiles de paraffine et l'huile de vaseline. A titre d'huiles végétales, on peut citer les huiles d'olive, d'arachide, de soja, de colza, de palme, de sésame, de pépin de raisins, de mais, de noix ou de tournesol. A titre d'huiles végétales transestérifiées et/ou polyéthoxylées , on peut citer les huiles d'olive polyéthoxylées, de tournesol polyéthoxylées, de palme polyéthoxylées ou de ricin polyéthoxylées, notamment celles commercialisées sous la marque Labrafil® par la société Gattefossé.As mineral oils suitable in the context of the invention, there may be mentioned paraffin oils and petrolatum oil. As vegetable oils, mention may be made of olive, peanut, soybean, rapeseed, palm, sesame, grape seed, corn, walnut or sunflower oils. For vegetable oils transesterified and / or polyethoxylated include polyethoxylated olive oils, sunflower polyethoxylated, palm polyethoxylated or polyethoxylated castor, including those sold under the trademark Labrafil ® by Gattefossé.
A titre d'huiles animales, on peut citer les huiles de foie, notamment les huiles de foie de morue ou de flétan. A titre d'huiles synthétiques, on peut citer les huiles de silicone .Mention may be made, as animal oils, of liver oils, in particular cod or halibut liver oils. As synthetic oils, mention may be made of silicone oils.
L'acide oléïque constitue une phase lipophile particulièrement préférée.Oleic acid constitutes a particularly preferred lipophilic phase.
La phase lipophile peut se présenter sous la forme, soit d'une émulsion, soit d'un mélange auto-émulsionnable .The lipophilic phase can be in the form of either an emulsion or a self-emulsifiable mixture.
Une telle émulsion, outre la phase lipophile, comprend une phase hydrophile et, généralement, au moins un agent tensio- actif. L'émulsion peut être du type eau dans huile (E/H) ou, de préférence, huile dans eau (H/E) . L'émulsion peut être du type émulsion submicronique. Une telle émulsion présente une phase discontinue sous forme de particules de diamètre moyen inférieur à 1 μm, généralement compris entre 0,3 et 0,7 μm. L'émulsion peut aussi être du type micro-émulsion, pour lesquelles la phase discontinue se présente généralement sous forme de particules de diamètre moyen compris entre 0,05 et 0,250 μm.Such an emulsion, in addition to the lipophilic phase, comprises a hydrophilic phase and, generally, at least one surfactant. The emulsion can be of the water in oil (W / O) type or, preferably, oil in water (O / W). The emulsion can be of the submicron emulsion type. Such an emulsion has a discontinuous phase in the form of particles with an average diameter of less than 1 μm, generally between 0.3 and 0.7 μm. The emulsion can also be of the microemulsion type, for which the discontinuous phase is generally in the form of particles with an average diameter of between 0.05 and 0.250 μm.
La phase hydrophile peut être constituée d'un ou plusieurs composés choisis parmi les alcools tels que le glycérol, le propylène glycol , les polyéthylène glycols dont le poids moléculaire est compris entre 100 et 3000, ou l'eau. Celle-ci est préférée dans le cadre de la présente invention.The hydrophilic phase can consist of one or more compounds chosen from alcohols such as glycerol, propylene glycol, polyethylene glycols whose weight molecular is between 100 and 3000, or water. This is preferred in the context of the present invention.
La phase dispersée d'une émulsion selon l'invention peut représenter de 5 à 30 % en poids, généralement de 10 à 20 % en poids du poids total de l'émulsion.The dispersed phase of an emulsion according to the invention can represent from 5 to 30% by weight, generally from 10 to 20% by weight of the total weight of the emulsion.
L'agent tensio-actif est choisi en fonction de la nature de l'émulsion. L'homme du métier sait, notamment en fonction de son HLB (Hydrophile-Lipophile Balance) , quel agent tensio- actif choisir pour obtenir une émulsion E/H, H/E ou une micro-émulsion.The surfactant is chosen according to the nature of the emulsion. Those skilled in the art know, in particular according to their HLB (Hydrophilic-Lipophilic Balance), which surfactant to choose to obtain a W / O, O / W emulsion or a micro-emulsion.
A titre d'agent tensio-actif pouvant convenir dans le cadre de la présente invention, on peut citer les esters de sorbitane et les esters de sorbitane polyoxyethylenes, tels que ceux commercialisés sous les marques T een® et Span®, les lécithmes d'origine animales ou végétales, les huiles de ricin polyoxyethylenees, telles celles commercialisées sous la marque Cremophor®, les esters de saccharose et d'acides gras (ou sucroesters) , les esters d'alcools gras et de polyéthylène glycol, les esters d'acides gras et de polyéthylène glycol, les acides biliaires, ces agents tensio- actifs pouvant être utilisés seuls ou en mélange. Une émulsion selon l'invention peut comprendre de 0,01 à 5 % en poids d'agents tensio-actifs par rapport à la phase dispersée .As a surfactant which may be suitable in the context of the present invention include sorbitan esters and polyoxyethylene sorbitan esters such as those sold under the T een ® and Span ®, the lécithmes of animal or vegetable origin, castor oil polyoxyethylene, such as those sold under the Cremophor ® brand, sucrose fatty acid esters (sugar esters or), esters of fatty alcohols and polyethylene glycol, esters fatty acids and polyethylene glycol, bile acids, these surfactants can be used alone or as a mixture. An emulsion according to the invention can comprise from 0.01 to 5% by weight of surfactants relative to the dispersed phase.
Au sens de la présente invention, on entend par le terme "mélange auto-émulsionnable", un mélange constitué d'une phase lipophile, consistant en au moins une huile et/ou au moins un acide gras tels ceux décrits ci -dessus, avec au moins un agent tensio-actif , ce mélange pouvant former une émulsion par simple agitation mécanique avec une phase aqueuse. Un mélange auto-émulsionnable selon l'invention peut, après administration par voie orale, former des émulsions avec les phases hydrophiles de l'organisme. Les agents tensio-actifs constitutifs d'un tel mélange auto- émulsionnable peuvent être choisis parmi les esters de sorbitane et les esters de sorbitane polyoxyethylenes, tels que ceux commercialisés sous les marques T een® et Span®, en particulier le polysorbate 80.For the purposes of the present invention, the term "self-emulsifying mixture" means a mixture consisting of a lipophilic phase, consisting of at least one oil and / or at least one fatty acid such as those described above, with at least one surfactant, this mixture being able to form an emulsion by simple mechanical stirring with an aqueous phase. A self-emulsifying mixture according to the invention can, after oral administration, form emulsions with the hydrophilic phases of the organism. The constituent surfactants of such a self-emulsifiable mixture may be selected from sorbitan esters and polyoxyethylene sorbitan esters such as those sold under the T een ® and Span ®, in particular polysorbate 80.
La teneur en agents tensio-actifs du mélange auto- émulsionnable peut être comprise entre 0,5 et 10 % en poids par rapport à la phase lipophile.The content of surfactants in the self-emulsifying mixture can be between 0.5 and 10% by weight relative to the lipophilic phase.
Avantageusement, la composition pharmaceutique selon l'invention se présente sous la forme d'une solution lipidique. Celle-ci comprend essentiellement une phase lipophile, consistant généralement en au moins un acide gras et/ou au moins une huile, tels ceux mentionnés plus haut, 1 ' amisulpride étant dissous dans cette phase lipophile. Une telle solution lipidique est substantiellement exempte de phase hydrophile et d'agent tensio-actif . Préférentiellement, la phase lipophile de la solution lipidique est constituée d'un acide gras, plus préférentiellement l'acide oléique.Advantageously, the pharmaceutical composition according to the invention is in the form of a lipid solution. This essentially comprises a lipophilic phase, generally consisting of at least one fatty acid and / or at least one oil, such as those mentioned above, the amisulpride being dissolved in this lipophilic phase. Such a lipid solution is substantially free of hydrophilic phase and of surfactant. Preferably, the lipophilic phase of the lipid solution consists of a fatty acid, more preferably oleic acid.
Une composition pharmaceutique selon l'invention peut en outre comprendre des excipients pharmaceutiquement acceptables, tels des diluants, des agents conservateurs, des agents osmotiques, des anti-oxydants , des agents épaississants, des agents stabilisants, des agents diminuant la viscosité tels 1 ' éthanol , des agents gélifiants et des tampons du pH.A pharmaceutical composition according to the invention may also comprise pharmaceutically acceptable excipients, such as diluents, preserving agents, osmotic agents, antioxidants, thickening agents, stabilizing agents, viscosity-reducing agents such as ethanol. , gelling agents and pH buffers.
Les compositions pharmaceutiques de l'invention peuvent être préparées de manière conventionnelle pour l'homme du métier.The pharmaceutical compositions of the invention can be prepared in a conventional manner for a person skilled in the art.
Ainsi, une solution lipidique selon l'invention, peut être préparée en dissolvant sous agitation 1 ' amisulpnde dans la phase lipophile. Le cas échéant, on peut alors ajouter d'autres excipients, tels ceux mentionnés plus haut.Thus, a lipid solution according to the invention can be prepared by dissolving, with stirring, the amisulpnde in the lipophilic phase. If necessary, other excipients can then be added, such as those mentioned above.
En vue de la préparation d'une émulsion, on peut introduire sous agitation, la phase lipophile contenant 1 ' amisulpride dans la phase hydrophile dans laquelle on a préalablement ajouté le ou (les) agents tensio-actif (s) et, le cas échéant, des excipients hydrophiles. L'agitation peut être réalisée au moyen d'un dispositif du type Ultra-Turrax® . En vue de la préparation d'une émulsion submicronique, on peut affiner l'émulsion ainsi obtenue au moyen d'une filière à très haute pression, par exemple du type APV-Gaulm® For the preparation of an emulsion, the lipophilic phase containing 1 amisulpride can be introduced, with stirring, into the hydrophilic phase in which the surfactant (s) and (s) have been previously added and, where appropriate , hydrophilic excipients. Agitation may be achieved by means of a device of the Ultra-Turrax ® kind. For the preparation of a submicron emulsion, one can refine the emulsion thus obtained by means of a high pressure die, for example of the type APV-Gaulm ®
Un mélange auto-émulsionnable selon l'invention peut être préparé classiquement, en introduisant , sous agitation, le (ou les) tensio-actif (s) requis dans une phase lipophile contenant 1 ' amisulpride , cette phase lipophile étant elle- même préparée comme indiqué ci -dessus.A self-emulsifying mixture according to the invention can be prepared conventionally, by introducing, with stirring, the required surfactant (s) into a lipophilic phase containing 1 amisulpride, this lipophilic phase being itself prepared as indicated above.
Une composition selon l'invention peut être présentée sous forme liquide, divisée ou non, accompagnée ou non d'un dispositif de dosage comme une cuillère, sous forme gélifiée, sous forme de capsules molles, de globules ou, de préférence, sous forme de gélules. Ces gélules peuvent être constituées de gélatine ou d'amidon et sont habituellement scellées de manière conventionnelle.A composition according to the invention can be presented in liquid form, divided or not, accompanied or not with a dosing device such as a spoon, in gelled form, in the form of soft capsules, of globules or, preferably, in the form of capsules. These capsules can consist of gelatin or starch and are usually sealed in a conventional manner.
Les compositions pharmaceutiques selon 1 ' invention sont principalement et préférentiellement destinées à l'administration par voie orale. Elles peuvent toutefois être administrée par d'autres voies, par exemple par la voie rectale .The pharmaceutical compositions according to the invention are mainly and preferably intended for oral administration. They can however be administered by other routes, for example by the rectal route.
Selon un autre aspect, l'invention concerne l'utilisation de 1 ' amisulpnde pour préparer les compositions pharmaceutiques décrites ci -dessus, pour le traitement de la dysthymie, le traitement des psychoses, plus particulièrement pour le traitement des schizophrénies paranoides et productives, des psychoses délirantes aiguës, ainsi que pour le traitement des états déficitaires des schizophrénies, des évolutions psychotiques résiduelles et des états d' inhibition avec ralentissement. Lesdites compositions pharmaceutiques peuvent encore être mises en oeuvre dans le traitement thérapeutique des bouffées délirantes, de 1 ' hébéphréno-catatonie, des migraines, avec ou sans photophobie ou nausée. Par ailleurs, en raison de l'effet inhibiteur de 1 ' amisulpride, elles peuvent être utilisée dans le traitement de l'autisme. Elles s'avèrent encore utiles dans le sevrage lié à la consommation d'alcool et/ou de stupéfiants et/ou de tabac; plus particulièrement, elles permettent de diminuer les risques de rechute pendant la période déficitaire post-sevrage .According to another aspect, the invention relates to the use of 1 amisulpnde to prepare pharmaceutical compositions described above, for the treatment of dysthymia, the treatment of psychoses, more particularly for the treatment of paranoid and productive schizophrenia, acute delusional psychosis, as well as for the treatment of deficit states of schizophrenia, residual psychotic changes and inhibition states with slowing down. Said pharmaceutical compositions can also be used in the therapeutic treatment of delusional flushes, 1 hebephreno-catatonia, migraines, with or without photophobia or nausea. Furthermore, because of the inhibitory effect of 1 amisulpride, they can be used in the treatment of autism. They are still useful in withdrawal linked to the consumption of alcohol and / or narcotics and / or tobacco; more particularly, they reduce the risk of relapse during the post-weaning deficit period.
Selon encore un autre aspect, l'invention concerne de nouvelles compositions pharmaceutiques comprenant de 1 ' amisulpride et au moins un excipient pharmaceutiquement acceptable, lesdites compositions autorisant la prolongation et/ou l'intensification de l'absorption gastro-intestinale de 1 ' amisulpride de sorte que la biodispombilité de 1 ' amisulpride soit supérieure à 50 %, plus généralement comprise entre 60 et 75 %. Ces compositions pharmaceutiques sont principalement destinées à une administration orale. Les compositions comprenant une phase lipophile et de 1 ' amisulpride qui sont décrites plus haut, permettent de conférer une telle biodisponibilité .According to yet another aspect, the invention relates to new pharmaceutical compositions comprising 1 amisulpride and at least one pharmaceutically acceptable excipient, said compositions allowing the prolongation and / or the intensification of the gastrointestinal absorption of 1 amisulpride from so that the biodispombility of 1 amisulpride is greater than 50%, more generally between 60 and 75%. These pharmaceutical compositions are mainly intended for oral administration. The compositions comprising a lipophilic phase and 1 amisulpride which are described above, make it possible to confer such a bioavailability.
Les exemples qui suivent ont pour but d'illustrer la présente invention.The following examples are intended to illustrate the present invention.
Exemple 1 : mélange auto-émulsionnable adapté au rat On prépare un mélange auto-émulsionnable selon l'invention en introduisant 100 mg d ' amisulpride per se, ainsi que 4 mg de polysorbate 80, dans de l'acide oléïque (qsp 100 ml) . Puis, on agite lentement jusqu'à dissolution complète.Example 1: Self-emulsifying mixture suitable for rats A self-emulsifying mixture according to the invention is prepared by introducing 100 mg of amisulpride per se, as well as 4 mg of polysorbate 80, in oleic acid (qs 100 ml). Then, it is stirred slowly until complete dissolution.
Exemple 2 : émulsion submicronique H/E adaptée au ratExample 2: Submicron O / W emulsion suitable for rats
On prépare une émulsion submicronique H/E selon l'invention de la manière suivante:An O / W submicronic emulsion according to the invention is prepared in the following manner:
On prépare une phase hydrophile en mélangeant 3,3 g de lécithine de soja, 5,6 g de glycérine, 2 g d'huile de ricin polyoxyéthylénée solidifiée (Cremophor® RH 40) et 0,1 g d'hydrogénosulfite de sodium. On dissout ou disperse ce mélange dans 82 g d'eau et on chauffe à 70-80°C.A hydrophilic phase is prepared by mixing 3.3 g of soya lecithin, 5.6 g of glycerin, 2 g of solidified polyoxyethylene castor oil (Cremophor ® RH 40) and 0.1 g of sodium hydrogen sulfite. This mixture is dissolved or dispersed in 82 g of water and heated to 70-80 ° C.
Par ailleurs, on prépare une phase lipophile en chauffant à 70-80°C une solution de 6,25 g d ' amisulpride per se et de 1,3 g d'un sucroester de HLB=15, 22,25 g d'acide oléïque. On ajoute la phase lipophile à la phase hydrophile et on agite avec un agitateur Ultra-Turrax®, à 5000 tours/mm. pendant dix minutes.In addition, a lipophilic phase is prepared by heating to 70-80 ° C a solution of 6.25 g of amisulpride per se and 1.3 g of a sucroester of HLB = 15, 22.25 g of oleic acid . The lipophilic phase is added to the hydrophilic phase and stirred with an Ultra-Turrax ® stirrer at 5000 revolutions / min. for ten minutes.
On obtient ainsi une émulsion grossière que l'on affine au moyen d'un homogénéisateur a très haute pression du type APV- Gaulm®, afin d'obtenir une émulsion liquide dont le diamètre moyen des particules lipophiles est inférieur à 1 μm.Thus, a coarse emulsion which is refined by means of a homogenizer type high pressure APV Gaulm ®, in order to obtain a liquid emulsion in which the average diameter of lipophilic particle is less than 1 .mu.m.
Exemple 3 : émulsion hydrophile H/E adaptée au ratExample 3: O / W hydrophilic emulsion suitable for rats
On prépare une émulsion hydrophile H/E selon l'invention, de la manière suivante:A hydrophilic O / W emulsion according to the invention is prepared in the following manner:
On mélange une solution à 2,25 mg/ml de polysorbate 80 dans du glycérol bidistillé avec une solution lipidique d ' amisulpnde per se dans l'acide oléïque. On agite ensuite ce mélange avec un agitateur Ultra-Turrax®, à 5000 tours/mm. pendant dix minutes.A 2.25 mg / ml solution of polysorbate 80 in double-distilled glycerol is mixed with a lipid solution of amisulpnde per se in oleic acid. This mixture is then stirred with an Ultra-Turrax ® agitator, at 5000 rpm. for ten minutes.
On obtient ainsi une émulsion comprenant:An emulsion is thus obtained comprising:
% masse/vol ..% mass / vol.
amisulpride per se 1 acide oléïque 9,1 polysorbate 80 2,25 glycérol qsp 100amisulpride per se 1 oleic acid 9.1 polysorbate 80 2.25 glycerol qs 100
Exemple 4 : émulsion aqueuse H/E adaptée au ratExample 4: O / W aqueous emulsion suitable for rats
On prépare une émulsion aqueuse H/E selon 1 ' invention de la manière suivante:An O / W aqueous emulsion according to the invention is prepared in the following manner:
On prépare une phase hydrophile en mélangeant de la lécithme de so a, de l'huile de ricin polyoxyéthylénée solidifiée (Cremophor RH 40®) et de 1 ' hvdrogénosulfite de sodium. On dissout ou disperse ce mélange dans de l'eau (qsp 100 ml) et on chauffe à 70-80°C.A hydrophilic phase is prepared by mixing lécithme of n a, polyoxyethylenated castor oil solidified (Cremophor ® RH 40) and one sodium hvdrogénosulfite. This mixture is dissolved or dispersed in water (qs 100 ml) and heated to 70-80 ° C.
Par ailleurs, on prépare une phase lipophile consistant en une solution d' amisulpride per se dans l'acide oléïque. On ajoute la phase lipophile à la phase hydrophile et on agite avec un agitateur Ultra-Turrax®, à 5000 tours/mm. pendant dix minutes.Furthermore, a lipophilic phase is prepared consisting of a solution of amisulpride per se in oleic acid. The lipophilic phase is added to the hydrophilic phase and stirred with an Ultra-Turrax ® stirrer at 5000 revolutions / min. for ten minutes.
On obtient ainsi une émulsion comprenant:An emulsion is thus obtained comprising:
% masse/vol.% mass / vol.
amisulpride per se 1 acide oléïque 9,1 lécithme de so a 1,34 huile de ricin polyoxyéthylénée 0,8 hydrogénosulfite de sodium 0,04 eau purifiée qsp 100amisulpride per se 1 oleic acid 9.1 lecithm of so a 1.34 polyoxyethylene castor oil 0.8 sodium hydrogen sulfite 0.04 purified water qs 100
Exemple 5 : solution lipidique adaptée au ratEXAMPLE 5 Lipid Solution Suitable for the Rat
On a introduit, sous agitation lente, de 1 ' amisulpnde per se dans de l'acide oléique de sorte à obtenir une solution lipidique d' amisulpride per se à 10 mg/ml conforme à 1 ' invention.Amisulpide per se in oleic acid was introduced with slow stirring so as to obtain a lipid solution of amisulpride per se at 10 mg / ml in accordance with the invention.
Exemple 6 : solution lipidique pour usage humainEXAMPLE 6 Lipid Solution for Human Use
On a introduit, sous agitation lente, de 1 ' amisulpride per se dans de l'acide oléique de sorte à obtenir une solution lipidique d ' amisulpride à 25 mg/ml.Amisulpride per se was introduced with oleic acid under slow stirring so as to obtain a 25 mg / ml solution of amisulpride lipid.
Cette solution a été répartie en gélules taille 1 à raison de 0,4 g par gélule. Chaque gélule contenait 100 mg d ' amisulpride per se .This solution was divided into size 1 capsules at a rate of 0.4 g per capsule. Each capsule contained 100 mg of amisulpride per se.
Exemple 7:Example 7:
On a reproduit l'exemple 6 en remplaçant 1 ' amisulpride per se par le (D) -tartrate du (S) - { - ) - amisulpride, c'est à dire le composé de l'exemple IV du brevet FR 78 01632. On a ainsi obtenu des gélules contenant 100 mg de principe actif.Example 6 was reproduced by replacing 1 amisulpride per se with (D) -tartrate from (S) - (-) - amisulpride, that is to say the compound of Example IV of patent FR 78 01632. There were thus obtained capsules containing 100 mg of active principle.
Exemple 8Example 8
On a testé des compositions pharmaceutiques conformes à l'invention chez le rat, selon le protocole suivant:Pharmaceutical compositions in accordance with the invention were tested in rats, according to the following protocol:
Les rats étaient des Spragues Da ley OFA, mâles de 200 àThe rats were Spragues Da ley OFA, males from 200 to
220 g, âgés de 7 semaines.220 g, 7 weeks old.
Après administration de la composition pharmaceutique (T0) , conforme ou non à l'invention, on a replacé les animaux dans leur cage. Ils ont été maintenus à eun pendant quatre heures au maximum après traitement . On a effectué les prélèvements au niveau de la veine cave inférieure aux temps 0; 0,08; 0,25; 1; 2; 4; 6; 8; 16 et 24 heures. Les tubes contenant le sang prélevé ont été centrifugés et le plasma récupéré a été stocké au congélateur.After administration of the pharmaceutical composition (T 0 ), whether or not in accordance with the invention, the animals were replaced in their cage. They were kept on hold for a maximum of four hours after treatment. Samples were taken from the vena cava below time 0; 0.08; 0.25; 1; 2; 4; 6; 8; 16 and 24 hours. The tubes containing the collected blood were centrifuged and the recovered plasma was stored in the freezer.
La concentration en amisulpnde per se dans le plasma a été mesuré par HPLC avec détection fluorimétπque .The concentration of amisulpnde per se in the plasma was measured by HPLC with fluorimetric detection.
On a testé des compositions pharmaceutiques selon l'invention, comprenant chacune 10 mg/ml d ' amisulpride per se .Pharmaceutical compositions according to the invention were tested, each comprising 10 mg / ml of amisulpride per se.
Les compositions testées étaient celles des exemples 1, 3, 4 et 5.The compositions tested were those of Examples 1, 3, 4 and 5.
Ces compositions ont été comparées à une solution de référence, non conforme à l'invention, consistant en une solution aqueuse de chlorure de sodium à 0,9 % comprenant 10 mg/ml d ' amisulpnde per se, dont le pH a été ajusté à 3,5-6,5 au moyen d'acide chlorhydπque 1M.These compositions were compared with a reference solution, not in accordance with the invention, consisting of an aqueous 0.9% sodium chloride solution comprising 10 mg / ml of amisulpnde per se, the pH of which was adjusted to 3.5-6.5 using 1M hydrochloric acid.
Toutes les compositions testées ont été administrées par voie orale .All the compositions tested were administered orally.
Les résultats obtenus sont reportés sur la figure 1. Les concentrations plasmatiques en amisulpride per se sont exprimées en ng/ml .The results obtained are shown in FIG. 1. The plasma concentrations of amisulpride per are expressed in ng / ml.
Les Tmax, Cmax et les aires sous la courbe (AUC) obtenus pour chaque composition testée, sont regroupés dans le Tableau I ci-après. Tableau IThe T max , C max and the areas under the curve (AUC) obtained for each composition tested, are grouped in Table I below. Table I
Forme Tmax (heures) Cmax (ng/ml) AUC (ng/ml /h) pharmaceutîque (Tl T2) solution de 1 82 287 référence (0,08-16) solution 0, 08 108 410 lipidique (0,08-16) émulsion 0, 08 110 213 aqueuse (0, 08-8) émulsion 0,08 107 310 hydrophile (0,08-16) mélange auto- 4 63 324 émulsionnable (0,08-24)Form T max (hours) C max (ng / ml) AUC (ng / ml / h) pharmaceutical (Tl T2) solution of 1 82 287 reference (0.08-16) solution 0.08 108 410 lipid (0.08 -16) emulsion 0.08 110 213 aqueous (0.08-8) emulsion 0.08 107 310 hydrophilic (0.08-16) self-mixing 4 63 324 emulsifiable (0.08-24)
Ces résultats montrent la diminution du Tmax et/ou l'augmentation de l'AUC quand 1 ' amisulpride per se est administré conformément à l'invention; ceci démontre une intensification de l'absorption de 1 ' amisulpride per se, et donc une amélioration de sa Diodisponibilité .These results show the decrease in T max and / or the increase in AUC when 1 amisulpride per se is administered according to the invention; this demonstrates an intensification of the absorption of 1 amisulpride per se, and therefore an improvement in its availability.
Exemple 9Example 9
On a testé des solutions lipidiques comprenant des concentrations croissantes d ' amisulpnde per se selon le protocole décrit dans l'exemple 8.Lipid solutions comprising increasing concentrations of amisulpnde per se were tested according to the protocol described in Example 8.
Les solutions lipidiques ont été préparées par agitation jusqu'à dissolution de la dose requise d ' amisulpride per se dans 10 ml d'acide oléïque. Les solutions lipidiques ont été comparées à une solution de référence consistant en une solution aqueuse de chlorure de sodium comprenant 50 mg/ml d ' amisulpride per se, dont le pH a été ajusté à 3,5-6,5 au moyen d'acide chlorhydrique 1M. Les résultats obtenus sont reportés sur la figure 2. Les concentrations plasmatiques en amisulpride per se sont exprimées en ng/ml .The lipid solutions were prepared by stirring until the required dose of amisulpride per se was dissolved in 10 ml of oleic acid. The lipid solutions were compared with a reference solution consisting of an aqueous solution of sodium chloride comprising 50 mg / ml of amisulpride per se, the pH of which was adjusted to 3.5-6.5 using acid. hydrochloric 1M. The results obtained are shown in FIG. 2. The plasma concentrations of amisulpride per are expressed in ng / ml.
Les Tmax, Cmax et les aires sous la courbe (AUC) obtenus pour chaque composition testées, sont regroupés dans le Tableau II ci-après .The T max , C max and the areas under the curve (AUC) obtained for each composition tested, are grouped in Table II below.
Tableau IITable II
Forme T C "f-max AUC(ng/ml/h) pharmaceutique (heures) (ng/ml) Tl T2)TC form " f -max AUC (ng / ml / h) pharmaceutical (hours) (ng / ml) T1 T2)
Solution de 2 1075 3138 référence (0,08-6) 50 mg/ml solution lipidique 0,5 72 511 10 mg/ml (0,08-16) solution lipidique 2 1142 4981 50 mg/ml (0,08-6) solution lipidique 4 2871 15848 100 mg/ml (0,08-16)Solution of 2 1075 3138 reference (0.08-6) 50 mg / ml lipid solution 0.5 72 511 10 mg / ml (0.08-16) lipid solution 2 1142 4981 50 mg / ml (0.08-6 ) lipid solution 4 2871 15848 100 mg / ml (0.08-16)
Ces résultats montrent l'intensification et la prolongation de l'absorption, et donc l'augmentation de la biodisponibilité de 1 ' amisulpride per se administrée sous forme de solution lipidique conforme à l'invention. These results show the intensification and prolongation of absorption, and therefore the increase in bioavailability of 1 amisulpride per se administered in the form of lipid solution according to the invention.

Claims

Revendications claims
1. Composition pharmaceutique, principalement destinée à l'administration par voie orale, caractérisée en ce qu'elle comprend une phase lipophile et au moins un principe actif consistant en 1 ' amisulpride, un de ses isomères levogyre et dextrogyre ou un dérivé de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre, ce dérivé étant choisi parmi un sel d'addition avec un acide pharmacologiquement acceptable, un sel d'ammonium quaternaire ou un oxyde, de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre .1. Pharmaceutical composition, mainly intended for oral administration, characterized in that it comprises a lipophilic phase and at least one active principle consisting of 1 amisulpride, one of its levorotatory and dextrorotatory isomers or a derivative of 1 ' amisulpride or one of its levorotatory and dextrorotatory isomers, this derivative being chosen from an addition salt with a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide, 1 amisulpride or one of its levogyre and dextrogyre isomers.
2. Composition selon la revendication 1 caractérisée en ce que la phase lipophile comprend (i) un ou plusieurs acides gras, (il) un ou plusieurs monoglycérides ou dérivés acétylés ou polyéthoxylés de monoglycérides , (m) un ou plusieurs diglycérides ou dérivés acétylés ou polyéthoxylés de diglycérides, (iv) une ou plusieurs huiles, telles des huiles minérales, animales, végétales, végétales transestérifiées et/ou polyéthoxylées ou synthétiques ou (v) un mélange comprenant deux ou plus des composés mentionnés sous les points (i) , (ii) , (m) et (iv) .2. Composition according to claim 1 characterized in that the lipophilic phase comprises (i) one or more fatty acids, (it) one or more monoglycerides or acetylated or polyethoxylated derivatives of monoglycerides, (m) one or more diglycerides or acetylated derivatives or polyethoxylates of diglycerides, (iv) one or more oils, such as mineral, animal, vegetable, transesterified and / or polyethoxylated or synthetic oils or (v) a mixture comprising two or more of the compounds mentioned under points (i), ( ii), (m) and (iv).
3. Composition selon l'une des revendications 1 et 2 , caractérisée en ce que la phase lipophile comprend de l'acide oléique .3. Composition according to one of claims 1 and 2, characterized in that the lipophilic phase comprises oleic acid.
4. Composition selon l'une des revendications 1 à 3 caractérisée en ce qu'elle se présente sous forme d'une solution lipidique, d'une émulsion ou d'un mélange auto- émulsionnable .4. Composition according to one of claims 1 to 3 characterized in that it is in the form of a lipid solution, an emulsion or a self-emulsifiable mixture.
5. Composition selon l'une des revendications 1 à 4, caractérisée en ce que ledit principe actif consiste en 1 ' amisulpride, l' isomères levogyre de 1 ' amisulpride, l'isomère dextrogyre de 1 ' amisulpride et leurs tartrates.5. Composition according to one of claims 1 to 4, characterized in that said active principle consists of 1 Amisulpride, the levorotatory isomers of Amisulpride, the dextrorotatory isomer of Amisulpride and their tartrates.
6. Composition selon l'une des revendications 1 à 4, caractérisée en ce que ledit principe actif consiste en 1 ' isomères levogyre de 1 ' amisulpnde et ses tartrates, en particulier le (D) -tartrate du (S) - ( - ) - amisulpride.6. Composition according to one of claims 1 to 4, characterized in that the said active principle consists of the levorotatory isomers of the amisulpnde and its tartrates, in particular the (D) -tartrate of (S) - (-) - amisulpride.
7. Composition selon l'une des revendications 1 à 6, caractérisée en ce qu'elle comprend au moins un agent tensio- actif .7. Composition according to one of claims 1 to 6, characterized in that it comprises at least one surfactant.
8. Composition selon l'une des revendications 1 à 7, caractérisée en ce qu'elle comprend de 50 à 300 mg, plus généralement de 100 à 250 mg en ledit principe actif par dose .8. Composition according to one of claims 1 to 7, characterized in that it comprises from 50 to 300 mg, more generally from 100 to 250 mg of said active principle per dose.
9. Composition selon l'une des revendications 1 à 8, caractérisée en ce qu'elle se présente sous forme de gélules.9. Composition according to one of claims 1 to 8, characterized in that it is in the form of capsules.
10. Utilisation de 1 ' amisulpride, l'un de ses isomères levogyre ou dextrogyre ou un dérivé de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre, ce dérivé étant choisi parmi un sel d'addition avec un acide pharmacologiquement acceptable, un sel d'ammonium quaternaire ou un oxyde, de 1 'amisulpride ou de l'un de ses isomères levogyre et dextrogyre, pour préparer une composition pharmaceutique selon l'une des revendications 1 à 9, destinée au traitement de la dysthymie ou au traitement des psychoses, plus particulièrement au traitement des schizophrénies paranoides et productives, des psychoses délirantes aiguës, ainsi qu'au traitement des états déficitaires des schizophrénies, des évolutions psychotiques résiduelles et des états d' inhibition avec ralentissement. 10. Use of 1 amisulpride, one of its levorotatory or dextrorotatory isomers or a derivative of amisulpride or one of its levorotatory and dextrorotatory isomers, this derivative being chosen from an addition salt with a pharmacologically acid acceptable, a quaternary ammonium salt or an oxide, 1 amisulpride or one of its levorotatory and dextrorotatory isomers, for preparing a pharmaceutical composition according to one of claims 1 to 9, intended for the treatment of dysthymia or the treatment of psychoses, more particularly the treatment of paranoid and productive schizophrenia, acute delusional psychosis, as well as the treatment of deficit states of schizophrenia, residual psychotic changes and states of inhibition with slowing down.
11. Compositions pharmaceutiques comprenant de 1 ' amisulpride , l'un de ses isomères levogyre ou dextrogyre ou un dérivé de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre, ce dérivé étant cnoisi parmi un sel d'addition avec un acide pharmacologiquement acceptable, un sel d'ammonium quaternaire ou un oxyde, de 1 ' amisulpride ou de l'un de ses isomères levogyre et dextrogyre, et au moins un excipient pharmaceutiquement acceptable, lesdites compositions étant caractérisées en ce qu'elles autorisent la prolongation et l'intensification de l'absorption gastro- întest ale de 1 ' amisulpnde ou l'un de ses isomères, de sorte que la biodisponibilité de 1 ' amisulpride soit supérieure à 50 %, plus généralement comprise entre 60 et 75 %. 11. Pharmaceutical compositions comprising amisulpride, one of its levorotatory or dextrorotatory isomers or a derivative of amisulpride or one of its levorotatory and dextrorotatory isomers, this derivative being selected from an addition salt with a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide, 1 amisulpride or one of its levorotatory and dextrorotatory isomers, and at least one pharmaceutically acceptable excipient, said compositions being characterized in that they allow prolongation and the intensification of gastrointestinal absorption of amisulpide or one of its isomers, so that the bioavailability of amisulpride is greater than 50%, more generally between 60 and 75%.
EP97919108A 1996-09-18 1997-09-17 Pharmaceutical compositions containing amisulpride and their therapeutic applications Withdrawn EP0927026A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9611391 1996-09-18
FR9611391A FR2753376B1 (en) 1996-09-18 1996-09-18 PHARMACEUTICAL COMPOSITIONS COMPRISING AMISULPRIDE AND THERAPEUTIC APPLICATIONS THEREOF
PCT/FR1997/001633 WO1998011881A1 (en) 1996-09-18 1997-09-17 Pharmaceutical compositions containing amisulpride and their therapeutic applications

Publications (1)

Publication Number Publication Date
EP0927026A1 true EP0927026A1 (en) 1999-07-07

Family

ID=9495859

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97919108A Withdrawn EP0927026A1 (en) 1996-09-18 1997-09-17 Pharmaceutical compositions containing amisulpride and their therapeutic applications

Country Status (8)

Country Link
US (1) US6069165A (en)
EP (1) EP0927026A1 (en)
JP (1) JP2001501192A (en)
AU (1) AU729707B2 (en)
CA (1) CA2265894A1 (en)
FR (1) FR2753376B1 (en)
WO (1) WO1998011881A1 (en)
ZA (1) ZA978383B (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6423334B1 (en) 1997-10-01 2002-07-23 Elan Corporation, Plc Composition and method for enhancing transport across gastrointestinal tract cell layers
AU3843999A (en) * 1998-05-07 1999-11-23 Elan Corporation, Plc Solvent/cosolvent free microemulsion and emulsion preconcentrate drug delivery systems
US6169094B1 (en) * 1998-07-14 2001-01-02 Sanofi-Synthelabo Compositions of (S) (-)-amisulpride
FR2790388B1 (en) * 1999-03-04 2001-04-13 Synthelabo PHARMACEUTICAL COMPOSITIONS COMPRISING A BENZAMIDE AND AT LEAST ONE ABSORPTION PROMOTER
MX2011006307A (en) * 2008-12-15 2011-10-14 Banner Pharmacaps Inc Methods for enhancing the release and absorption of water insoluble active agents.
JP2014526509A (en) * 2011-09-13 2014-10-06 バイオメッド バレー ディスカバリーズ，インコーポレイティド Compositions and methods for treating metabolic disorders
MY205036A (en) 2016-11-28 2024-09-28 Lb Pharmaceuticals Inc Psychotropic agents and uses thereof
WO2018213813A2 (en) * 2017-05-18 2018-11-22 Lb Pharmaceuticals Inc. Inc. Psychotropic agents and uses thereof
US11377421B2 (en) 2016-11-28 2022-07-05 Lb Pharmaceuticals Inc. Psychotropic agents and uses thereof
WO2019113084A1 (en) 2017-12-05 2019-06-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
WO2019113079A1 (en) 2017-12-05 2019-06-13 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
FR3081350B1 (en) * 2018-05-24 2020-08-28 Paris Sciences Lettres Quartier Latin COLLOIDAL PARTICLES HOMOGENEOUSLY FUNCTIONALIZED BY BIOMOLECULES
EP3856156A2 (en) * 2018-09-28 2021-08-04 Medizinische Hochschule Hannover (MHH) 5-ht7 antagonist for the treatment of dementia-associated tauopathies
GB201904771D0 (en) * 2019-04-04 2019-05-22 Orexo Ab New pharmaceutical compositions
CA3142355A1 (en) 2019-06-04 2020-12-10 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2415099A1 (en) * 1978-01-20 1979-08-17 Ile De France NEW DERIVATIVES OF 4-AMINO-5-ALKYLSULFONYL ORTHO-ANISAMIDES, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS PSYCHOTROPES
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5980882A (en) * 1997-04-16 1999-11-09 Medeva Pharmaceuticals Manufacturing Drug-resin complexes stabilized by chelating agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9811881A1 *

Also Published As

Publication number Publication date
JP2001501192A (en) 2001-01-30
AU4305897A (en) 1998-04-14
US6069165A (en) 2000-05-30
CA2265894A1 (en) 1998-03-26
WO1998011881A1 (en) 1998-03-26
AU729707B2 (en) 2001-02-08
FR2753376B1 (en) 1998-10-16
FR2753376A1 (en) 1998-03-20
ZA978383B (en) 1998-03-24

Similar Documents

Publication Publication Date Title
CA2330500C (en) Pharmaceutical compositions capable of being gelled
EP1242047B1 (en) Fenofibrate galenic formulations and method for obtaining same
FR2737121A1 (en) NEW GALENIC FORMULATIONS OF FENOFIBRATE AND THEIR APPLICATIONS
EP0862423B1 (en) Pharmaceutical composition for oral administration
WO1998011881A1 (en) Pharmaceutical compositions containing amisulpride and their therapeutic applications
FR2550092A1 (en) TWO-PHASE SOLID DRUG PREPARATION AND METHOD OF OBTAINING THE SAME
FR2636534A1 (en) PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS
FR2678169A1 (en) NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOSPORINE FOR ORAL ADMINISTRATION.
FR2907012A1 (en) DERMATOLOGICAL COMPOSITION COMPRISING AVERMECTIN NANOCAPSULES, PROCESS FOR PREPARING THE SAME AND USE THEREOF
EP1035846B1 (en) Fatty acid uninterrupted by a methylene as anti-inflammatory agents in superficial tissues of mammals
CZ83498A3 (en) Preparation containing cyclosporin and process for preparing thereof
EP1173173A1 (en) Novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives
WO1998024430A1 (en) Pharmaceutical compositions containing n-sulphonyl indolin derivatives
FR2967067A1 (en) PHARMACEUTICAL COMPOSITION AND GALENIC FORM BASED ON DRONEDARONE AND PROCESS FOR PREPARING THE SAME
BE1012143A5 (en) New pharmaceutical.
CH685920A5 (en) Compositions agonist activity similar to 5HT receptors (1) selective.
EP0523153B1 (en) Oleaginous capsule of ketoprofen
CA2362480A1 (en) Pharmaceutical compositions for oral administration comprising a benzamide and at least an absorption promoter
WO2005046690A1 (en) Pharmaceutical composition for oral administration of a pyrazol-3-carboxamide derivative
LU87777A1 (en) NEW ORAL GALENIC FORM IMPROVING BIOAVAILABILITY
WO2001066109A1 (en) Oral pharmaceutical compositions containing n-sulphonylindoline derivatives
BE856652A (en) PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SLEEP DISORDERS
EP2303243A1 (en) Oral composition containing an anti-plaque agent of the thienopyridine family in the form of a base

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990419

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI-SYNTHELABO

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

17Q First examination report despatched

Effective date: 20010606

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020122