EP1100467A1 - Method for making coated gabapentine or pregabaline particles - Google Patents

Method for making coated gabapentine or pregabaline particles

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Publication number
EP1100467A1
EP1100467A1 EP99932956A EP99932956A EP1100467A1 EP 1100467 A1 EP1100467 A1 EP 1100467A1 EP 99932956 A EP99932956 A EP 99932956A EP 99932956 A EP99932956 A EP 99932956A EP 1100467 A1 EP1100467 A1 EP 1100467A1
Authority
EP
European Patent Office
Prior art keywords
particles
aminobutyric acid
gabapentin
analog
group
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.)
Ceased
Application number
EP99932956A
Other languages
German (de)
French (fr)
Inventor
Etienne Bruna
Edouard Gendrot
Charles Chauveau
Alain-Gilles Demichelis
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.)
Ethypharm SAS
Original Assignee
Ethypharm SAS
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 Ethypharm SAS filed Critical Ethypharm SAS
Publication of EP1100467A1 publication Critical patent/EP1100467A1/en
Ceased legal-status Critical Current

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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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to a process for manufacturing coated ⁇ -aminobutyric acid (GABA) analog particles containing less than 0.5% lactam by weight relative to the weight of GABA analog.
  • GABA coated ⁇ -aminobutyric acid
  • the invention also relates to the coated particles capable of being obtained by said process, as well as any dosage form using said coated particles.
  • the invention is more particularly described in relation to the analogs of ⁇ -aminobutyric acid chosen from the group comprising gabapentin and pregabalin.
  • the process applies to any analogue of ⁇ -aminobutyric acid capable of producing lactam molecules as a degradation product.
  • Gabapentin also known as 1-aminomethylcyclohexane acetic acid, is an analogue of ⁇ -aminobutyric acid (GABA). It has anti-convulsant properties and is used in the treatment of epilepsy. This well-known molecule is described in particular in documents US-A-4024175 and
  • gabapentin is currently marketed in France in the form of capsules filled with a powder mixture consisting of gabapentin, hydrated lactose, corn starch and talc.
  • the capsules are dosed at 100 mg, 300 mg or 400 mg of active principle and are marketed under the brand NEURONTIN® by PARKE-DAVIS.
  • gabapentin is capable of being degraded in aqueous solution to give, by intramolecular cyclization, a degradation product of the lactam type, the rate of which must not exceed 0.5% by weight relative to the weight of the principle active for any dosage form regardless of the dosage; _ and secondly, that gabapentin has a sufficiently bitter taste that it is essential to mask its taste.
  • document EP-A-0 458 751 has proposed to present gabapentin in the form of particles coated with a first hydrophilic layer of a polymer insoluble in water and with a second layer hydrophobic. Even if a satisfactory taste masking effect is obtained, the coating process of the first layer requires the presence of water, so that one can expect an intramolecular cyclization of gabapentin leading to the formation of lactam. within the finished product.
  • Pregabalin is also an analogue of ⁇ -aminobutyric acid known as an anti-epileptic and more particularly described in document WO 98/58641 for its application as an anti-inflammatory agent.
  • the Applicant has found that pregabalin exhibits a phenomenon identical to that of gabapentin with regard to its degradation in aqueous solution of lactam molecules.
  • pregabalin must reach a maximum plasma concentration in 2 to 3 hours.
  • this molecule also has a bitter taste making it difficult to use as such within a pharmaceutical formulation.
  • the first problem which the invention proposes to solve is to provide a galenic form of GABA analog, the lactam content of which is less than 0.5% by weight relative to the weight of GABA analog.
  • the second problem which the invention proposes to solve is to provide a galenic form of GABA analog, capable of being able to be used in pediatrics.
  • a third problem which the invention proposes to solve is to provide a galenic form of GABA analog in which the bitter taste of said analog is masked while leading to a maximum plasma concentration in 2 to 3 hours.
  • the invention provides a process for manufacturing coated particles of ⁇ -aminobutyric acid analog, the lactam content by weight relative to the weight of GABA analog is less than 0.5%.
  • This process is characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed onto said particles of ⁇ -aminobutyric acid analog.
  • the analogue of ⁇ -aminobutyric acid is gabapentin.
  • the analogue of ⁇ -aminobutyric acid is pregabalin.
  • the fact of coating the gabapentin or pregabalin particles with a polymer dissolved in an organic solvent makes it possible to obtain a level of lactam in the coated particle of less than 0, 5% by weight relative to the weight of gabapentin or pregabalin.
  • the coating of polymer also makes it possible to mask the taste of the analogue of ⁇ -aminobutyric acid without delaying its release, thus making it possible to obtain usual plasma concentrations.
  • the polymer represents between 60 and 80% by weight of the gabapentin.
  • the gabapentin particles are coated in an amount of 70% by weight of polymer.
  • the polymer represents between 15 and 30% by weight of pregabalin.
  • the pregabalin particles are coated in an amount of 20% by weight of polymer.
  • the various methods of manufacturing gabapentin or pregabalin lead to the production of particles whose size can vary between 2 micrometers and a few millimeters.
  • the spraying of the solution leads to an irregular coating of the particles.
  • the actual coating of gabapentin or pregabalin is carried out on agglomerated particles or not, whose size is between 100 and 400 micrometers, preferably around 250 micrometers by the same technique called the fluidized bed.
  • the coated gabapentin or pregabalin particle obtained is in the form of agglomerated or non-agglomerated particle, the size of which is between 100 and 450 micrometers, with a median of about 250 micrometers.
  • the organic solvent is chosen from the group comprising acetone, ethanol, isopropanol, alone or as a mixture.
  • the polymer is dissolved in a solvent comprising 50 parts of acetone and 50 parts of ethanol per 100 parts by mass / mass.
  • the binding agent is dissolved in an organic solvent identical or different from that used during spraying.
  • the polymer is chosen from the group comprising polymethacrylate, copolymers aminoethylmethacrylate, cellulosic polymers, alone or as a mixture.
  • the polymethacrylate is an EUDRAGIT, in particular the EUDRAGIT E® marketed by the company ROHM.
  • cellulose polymers it is possible to choose ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose acetophthalate, alone or as a mixture. Furthermore, it may be necessary to combine plasticizing agents with said polymer such as ethyl phthalate.
  • the coating solution can also contain a sweetening agent chosen from the group comprising aspartame, potassium acesulfam, sodium saccharinate, monoammonium glycyrrhizinate, sugars and derivatives , as well as polyols and derivatives, alone or as a mixture.
  • a sweetening agent chosen from the group comprising aspartame, potassium acesulfam, sodium saccharinate, monoammonium glycyrrhizinate, sugars and derivatives , as well as polyols and derivatives, alone or as a mixture.
  • the sweetening agent represents between 1 and 6% by weight of the analogue of ⁇ -aminobutyric acid.
  • the solution also comprises an antistatic agent chosen from the group comprising colloidal silica, precipitated silica and talc.
  • the antistatic agent represents between 2 and 8% by weight of the analogue of ⁇ -aminobutyric acid, advantageously between 5 and 6% by weight.
  • the spraying of both the polymer in solution and the binder in solution is carried out as already said by the fluidized bed technique.
  • the spraying air inlet temperature must be minimum and more particularly between 35 and 45 ° C, advantageously 40 ° C.
  • the atomizing air inlet temperature is higher and is more particularly between 40 and 80 ° C., advantageously 60 ° C.
  • the temperature of the particles agglomerated or not during the coating must be minimum and advantageously between 20 and 30 ° C.
  • the particles coated with gabapentin or pregabalin obtained can be used in any suitable dosage form, it being understood that the lactam content of said dosage form is less than 0.5% by weight relative to the weight of GABA analog .
  • the coated particles are used as such in the form of a sachet.
  • the coated particles can be subjected to a compression step after having previously dry-mixed said coated particles with the usual compression excipients.
  • excipients used for the manufacture of these tablets are known to those skilled in the art and are chosen in particular from the group comprising diluents, lubricants, flavoring agents, sweetening agents, alone or as a mixture.
  • the tablets capable of being obtained according to the process of the invention can advantageously be of two types.
  • the first type corresponds to multiparticulate tablets with rapid disintegration without supply of water, in less than 60 seconds in the oral cavity, also called FLASHTAB®, trademark registered by the Applicant and more particularly described in document EP-A-548 356. .
  • the excipients added during the compression step also comprise at least one disintegrating agent capable of allowing the active principle to disintegrate quickly.
  • the disintegrating agent is chosen from the group comprising sodium carboxymethylcellulose, crosslinked PVP (also called crospovidone) and carboxymethyl starch.
  • the polymer intended for coating the gabapentin or pregabalin particles must be chosen so that it is insoluble at neutral pH, corresponding to the salivary pH (therefore masking the taste) and that it is soluble or permeable. at a pH between 1 and 4 corresponding to the gastric pH.
  • the hardness of the tablet is between 30 and 70 N, advantageously 50 N.
  • the second type of tablet corresponds to so-called "fast dispersible” tablets, that is to say rapidly hydrodispersible tablets capable of disintegrate in a very short time ⁇ 1 minute, preferably ⁇ 15 seconds, in a minimum volume of water which will depend on the mass of the tablet.
  • the latter dosage form can therefore be advantageously used in pediatrics.
  • the excipients added during compression will further comprise not only a disintegrating agent but also a maintenance agent in suspension of the coated particles or swelling agent.
  • the hardness of the tablet obtained is between 30 and 100 N, advantageously 70 N.
  • the lactam level is measured by quantitative determination carried out by HPLC with respect to an external lactam standard.
  • Gabapentin particles are first agglomerated from the following mixture:
  • PVP polyvinyl providone marketed by BASF
  • the size of the particles of active principle is standardized by spraying on the gabapentin particles the binding agent in solution in ethanol, by the spray coating technique.
  • the fluidizing air temperature is adjusted to 40 ° C., the temperature of the particles during manufacture being 21 ° C.
  • the agglomerated particles thus formed are then coated according to the same process by spraying with a solution comprising: I Ludragit E lOO 280 mg
  • Aerosil R972 marketed by DEGUSSA
  • the percentage of lactam by weight relative to the weight of gabapentin present in the coated particles varies between 0.07 and 0.1% from one batch to another. 2 - Manufacture of rapidly hydrodispersible gabapentin tablets
  • the tablets are produced on a rotary press equipped with the 18 mm diameter punch.
  • the pressure exerted is 16 KNewton +/- 2.
  • the hardness of the tablets obtained is around 70 Newtons.
  • Tests were carried out for dissolving the tablets obtained in an acid medium (0.06 N of HCl) under standard conditions (apparatus 2, and paddle speed 50 rotations per minute).
  • the tablet is stable vis-à-vis the degradation product for six months under accelerated storage conditions.
  • this type of tablet has the advantage of being able to be used in pediatrics.
  • the production of the tablets is carried out on a rotary tablet equipped with a 16 mm diameter punch.
  • the pressure exerted is 12 KN +/- 2.
  • the hardness of the tablet obtained is around 55 N. a) Dissolution test
  • the percentage of lactam present in the tablet obtained according to the invention was also measured. The results are shown in the table below (by weight relative to the weight of gabapentin).
  • coated pregabalin particles are prepared, the composition of which is as follows:
  • coated particles are produced according to the process of the invention in a fluidized bed by spraying with a solution comprising Eudragit, potassium acesulfame and talc in 96% ethanol.
  • This fluidized bed technique is carried out in an apparatus of the GLATT / GPGC 1 type, the temperature of the product being between 20 and 25 ° C.
  • the percentage of lactam measured on the particles coated with pregabalin is:
  • said particles are mixed with a powder mixture comprising:
  • the hardness of the tablets obtained is 40 N.
  • coated particles also have the advantage, in addition to their conventional manufacturing process, of being able to be incorporated in particular into tablets of the FLASHTAB® or fast hydrodispersibility type, tablets which are not swallowed directly, but after having been disintegrated in contact with the saliva in the mouth in the first case, or in contact with water in the second case.
  • the invention is not limited to a process for the manufacture of particles coated with gabapentin or pregabalin, but relates to any analogue of ⁇ -aminobutyric acid capable of degrading into lactam molecules in aqueous solution.

Abstract

The invention concerns a method for making coated particles of η-aminobutyric acid analogue whereof the lactam content by weight relative to the weight of η-aminobutyric acid analogue is less than 0.5 %. The invention is characterised in that it consists in spraying a coating solution comprising at least a polymer in an organic solvent on said η-aminobutyric acid analogue particles.

Description

PROCEDE DE FABRICATION DE PARTICULES DE GABAPENTINE OU DE PREGABALINE ENROBEESPROCESS FOR THE MANUFACTURE OF COATED GABAPENTINE OR PREGABALINE PARTICLES
L'invention se rapporte à un procédé de fabrication de particules d'analogue d'acide γ-aminobutyrique (GABA) enrobées contenant moins de 0,5 % de lactame en poids par rapport au poids d'analogue de GABA.The invention relates to a process for manufacturing coated γ-aminobutyric acid (GABA) analog particles containing less than 0.5% lactam by weight relative to the weight of GABA analog.
L'invention concerne également les particules enrobées susceptibles d'être obtenues par ledit procédé, ainsi que toute forme galénique mettant en oeuvre lesdites particules enrobées.The invention also relates to the coated particles capable of being obtained by said process, as well as any dosage form using said coated particles.
Dans la suite de la description et dans les revendications, l'invention est plus particulièrement décrite en relation avec les analogues de l'acide γ-aminobutyrique choisis dans le groupe comprenant la gabapentine et la prégabaline. Cependant, comme déjà dit, le procédé s'applique à tout analogue de l'acide γ-aminobutyrique susceptible de produire des molécules de lactame en tant que produit de dégradation.In the following description and in the claims, the invention is more particularly described in relation to the analogs of γ-aminobutyric acid chosen from the group comprising gabapentin and pregabalin. However, as already said, the process applies to any analogue of γ-aminobutyric acid capable of producing lactam molecules as a degradation product.
La gabapentine encore dénommée acide 1-aminométhylcyclohexane acétique est un analogue de l'acide γ-aminobutyrique (GABA). Elle présente des propriétés anti-convulsivantes et est utilisée dans le traitement de l'épilepsie. Cette molécule bien connue est notamment décrite dans les documents US-A-4024175 etGabapentin, also known as 1-aminomethylcyclohexane acetic acid, is an analogue of γ-aminobutyric acid (GABA). It has anti-convulsant properties and is used in the treatment of epilepsy. This well-known molecule is described in particular in documents US-A-4024175 and
US-A-4087544.US-A-4087544.
Du point de vue pharmacocinétique, il est indispensable que la concentration plasmatique de la gabapentine atteigne son pic en 2 à 3 heures.From a pharmacokinetic point of view, it is essential that the plasma concentration of gabapentin reaches its peak in 2 to 3 hours.
C'est l'une des raisons pour laquelle la gabapentine est actuellement commercialisée en France sous forme de gélules remplies d'un mélange de poudre constituée de gabapentine, de lactose hydraté, d'amidon de maïs et de talc. Les gélules sont dosées à 100 mg, 300 mg ou 400 mg de principe actif et sont commercialisées sous la marque NEURONTIN® par PARKE-DAVIS.This is one of the reasons why gabapentin is currently marketed in France in the form of capsules filled with a powder mixture consisting of gabapentin, hydrated lactose, corn starch and talc. The capsules are dosed at 100 mg, 300 mg or 400 mg of active principle and are marketed under the brand NEURONTIN® by PARKE-DAVIS.
Même si les gélules permettent d'obtenir une concentration plasmatique de gabapentine satisfaisante, elles restent cependant inadaptées à l'usage pédiatrique. Pour résoudre ce problème, on a cherché à présenter la gabapentine sous forme de solution aqueuse.Even if the capsules make it possible to obtain a satisfactory plasma concentration of gabapentin, they nevertheless remain unsuitable for pediatric use. To resolve this problem, an attempt has been made to present gabapentin in the form of an aqueous solution.
Cependant, le document PHARMACEUTICAL RESEARCH, Volume 9, Numéro 5, de 1992 démontre :However, the document PHARMACEUTICAL RESEARCH, Volume 9, Number 5, from 1992 demonstrates:
_ d'une part, que la gabapentine est susceptible d'être dégradée en solution aqueuse pour donner par cyclisation intramoléculaire un produit de dégradation du type lactame, dont le taux ne doit pas dépasser 0,5 % en poids par rapport au poids du principe actif pour toute forme galénique quel que soit le dosage ; _ et d'autre part, que la gabapentine présente un goût suffisamment amer pour qu'il soit indispensable de masquer son goût._ on the one hand, that gabapentin is capable of being degraded in aqueous solution to give, by intramolecular cyclization, a degradation product of the lactam type, the rate of which must not exceed 0.5% by weight relative to the weight of the principle active for any dosage form regardless of the dosage; _ and secondly, that gabapentin has a sufficiently bitter taste that it is essential to mask its taste.
Pour résoudre le problème du masquage du goût, le document EP-A-0 458 751 a proposé de présenter la gabapentine sous forme de particules enrobées d'une première couche hydrophile d'un polymère insoluble dans l'eau et d'une seconde couche hydrophobe. Même si on obtient un effet de masquage du goût satisfaisant, le procédé d'enrobage de la première couche nécessite la présence d'eau, de sorte qu'on peut s'attendre à une cyclisation intramoléculaire de la gabapentine conduisant à la formation de lactame au sein même du produit fini.To solve the problem of masking the taste, document EP-A-0 458 751 has proposed to present gabapentin in the form of particles coated with a first hydrophilic layer of a polymer insoluble in water and with a second layer hydrophobic. Even if a satisfactory taste masking effect is obtained, the coating process of the first layer requires the presence of water, so that one can expect an intramolecular cyclization of gabapentin leading to the formation of lactam. within the finished product.
Le prégabaline est également un analogue de l'acide γ-aminobutyrique connu comme anti-épileptique et plus particulièrement décrit dans le document WO 98/58641 pour son application en tant qu'agent anti-inflammatoire. Le Demandeur a constaté que la prégabaline présentait un phénomène identique à celui de la gabapentine s'agissant de sa dégradation en solution aqueuse en molécules lactame. En outre, tout comme la gabapentine, la prégabaline doit atteindre une concentration plasmatique maximum en 2 à 3 heures. Enfin, cette molécule présente également un goût amer la rendant difficilement utilisable en tant que telle au sein d'une formulation galénique.Pregabalin is also an analogue of γ-aminobutyric acid known as an anti-epileptic and more particularly described in document WO 98/58641 for its application as an anti-inflammatory agent. The Applicant has found that pregabalin exhibits a phenomenon identical to that of gabapentin with regard to its degradation in aqueous solution of lactam molecules. In addition, like gabapentin, pregabalin must reach a maximum plasma concentration in 2 to 3 hours. Finally, this molecule also has a bitter taste making it difficult to use as such within a pharmaceutical formulation.
Le premier problème que se propose de résoudre l'invention est de fournir une forme galénique d'analogue de GABA, dont le contenu en lactame soit inférieur à 0,5 % en poids par rapport au poids d'analogue de GABA. Le second problème que se propose de résoudre l'invention est de fournir une forme galénique d'analogue de GABA, susceptible de pouvoir être utilisée en pédiatrie.The first problem which the invention proposes to solve is to provide a galenic form of GABA analog, the lactam content of which is less than 0.5% by weight relative to the weight of GABA analog. The second problem which the invention proposes to solve is to provide a galenic form of GABA analog, capable of being able to be used in pediatrics.
Un troisième problème que se propose de résoudre l'invention est de fournir une forme galénique d'analogue de GABA dans laquelle le goût amer dudit analogue soit masqué tout en conduisant à une concentration plasmatique maximale en 2 à 3 heures.A third problem which the invention proposes to solve is to provide a galenic form of GABA analog in which the bitter taste of said analog is masked while leading to a maximum plasma concentration in 2 to 3 hours.
Pour ce faire, l'invention propose un procédé de fabrication de particules d'analogue d'acide γ-aminobutyrique enrobées, dont la teneur en lactame en poids par rapport au poids d'analogue de GABA est inférieure à 0,5 %.To do this, the invention provides a process for manufacturing coated particles of γ-aminobutyric acid analog, the lactam content by weight relative to the weight of GABA analog is less than 0.5%.
Ce procédé se caractérise en ce que l'on pulvérise une solution d'enrobage comprenant au moins un polymère dans au moins un solvant organique sur lesdites particules d'analogue d'acide γ-aminobutyrique.This process is characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed onto said particles of γ-aminobutyric acid analog.
Dans une première forme de réalisation, l'analogue d'acide γ-aminobutyrique est la gabapentine.In a first embodiment, the analogue of γ-aminobutyric acid is gabapentin.
Dans une autre forme de réalisation de l'invention, l'analogue d'acide γ- aminobutyrique est la prégabaline.In another embodiment of the invention, the analogue of γ-aminobutyric acid is pregabalin.
On a en effet constaté que de façon tout à fait surprenante, le fait d'enrober les particules de gabapentine ou de prégabaline par un polymère solubilisé dans un solvant organique, permettait d'obtenir un taux de lactame dans la particule enrobée inférieur à 0,5 % en poids par rapport au poids de gabapentine ou de prégabaline. En outre, l'enrobage de polymère permet également de masquer le goût de l'analogue d'acide γ-aminobutyrique sans pour autant retarder sa libération, permettant ainsi d'obtenir des concentrations plasmatiques usuelles.It has in fact been found that, quite surprisingly, the fact of coating the gabapentin or pregabalin particles with a polymer dissolved in an organic solvent, makes it possible to obtain a level of lactam in the coated particle of less than 0, 5% by weight relative to the weight of gabapentin or pregabalin. In addition, the coating of polymer also makes it possible to mask the taste of the analogue of γ-aminobutyric acid without delaying its release, thus making it possible to obtain usual plasma concentrations.
Pour obtenir le masquage du goût tout en permettant la libération rapide de la gabapentine, le polymère représente entre 60 et 80 % en poids de la gabapentine.To obtain the masking of the taste while allowing the rapid release of the gabapentin, the polymer represents between 60 and 80% by weight of the gabapentin.
Pour une proportion de polymère inférieure à 60 %, on n'obtient pas un masquage du goût suffisant. A l'inverse, pour une proportion de polymère supérieure à 80 %, le goût de la gabapentine est parfaitement masqué, mais le principe actif peut ne pas être libéré suffisamment rapidement.For a proportion of polymer less than 60%, a sufficient taste masking is not obtained. Conversely, for a proportion of polymer greater than 80%, the taste of gabapentin is perfectly masked, but the active ingredient may not be released quickly enough.
Avantageusement, on enrobe les particules de gabapentine à raison de 70 % en poids de polymère.Advantageously, the gabapentin particles are coated in an amount of 70% by weight of polymer.
De même, concernant la prégabaline, pour obtenir le masquage du goût tout en permettant la libération rapide de la molécule, le polymère représente entre 15 et 30 % en poids de la prégabaline.Similarly, concerning pregabalin, to obtain the masking of the taste while allowing the rapid release of the molecule, the polymer represents between 15 and 30% by weight of pregabalin.
Pour une proportion de polymère inférieure à 15 %, on n'obtient pas un masquage de goût suffisant. A l'inverse, pour une proportion de polymère supérieure à 35 %, le goût de la gabapentine est parfaitement masqué, mais le principe actif peut ne pas être libéré suffisamment rapidement.For a proportion of polymer less than 15%, a sufficient taste masking is not obtained. Conversely, for a proportion of polymer greater than 35%, the taste of gabapentin is perfectly masked, but the active principle may not be released quickly enough.
Avantageusement, on enrobe les particules de prégabaline à raison de 20% en poids de polymère.Advantageously, the pregabalin particles are coated in an amount of 20% by weight of polymer.
Par ailleurs, les différents procédés de fabrication de gabapentine ou de prégabaline conduisent à l'obtention de particules dont la taille peut varier entre 2 micromètres et quelques millimètres.Furthermore, the various methods of manufacturing gabapentin or pregabalin lead to the production of particles whose size can vary between 2 micrometers and a few millimeters.
Si la taille des particules d'analogue de principe actif est trop faible, c'est-à- dire de l'ordre de 50 micromètres, la pulvérisation de la solution conduit à un enrobage irrégulier des particules.If the size of the particles of analog of active principle is too small, that is to say of the order of 50 micrometers, the spraying of the solution leads to an irregular coating of the particles.
Pour résoudre ce problème, on cherche à augmenter la taille des particules en pulvérisant sur lesdites particules une solution d'un agent liant hydrosoluble dans un solvant organique par la technique dite du lit d'air fluidisé encore dénommée "spray coating", puis on tamise et on calibre les particules agglomérées obtenues.To solve this problem, we seek to increase the size of the particles by spraying on said particles a solution of a water-soluble binding agent in an organic solvent by the technique known as the fluidized air bed also called "spray coating", then sieving and calibrating the agglomerated particles obtained.
L'enrobage proprement dit de la gabapentine ou prégabaline est effectué sur les particules agglomérées ou non, dont la taille est comprise entre 100 et 400 micromètres, de préférence aux alentours de 250 micromètres par la même technique dite du lit fluidisé. La particule de gabapentine ou de prégabaline enrobée obtenue se présente sous la forme de particule agglomérée ou non, enrobée, dont la taille est comprise entre 100 et 450 micromètres, avec une médiane d'environ 250 micromètres.The actual coating of gabapentin or pregabalin is carried out on agglomerated particles or not, whose size is between 100 and 400 micrometers, preferably around 250 micrometers by the same technique called the fluidized bed. The coated gabapentin or pregabalin particle obtained is in the form of agglomerated or non-agglomerated particle, the size of which is between 100 and 450 micrometers, with a median of about 250 micrometers.
Pour dissoudre le polymère, le solvant organique est choisi dans le groupe comprenant l'acétone, l'éthanol, l'isopropanol, seuls ou en mélange.To dissolve the polymer, the organic solvent is chosen from the group comprising acetone, ethanol, isopropanol, alone or as a mixture.
Selon un mode de réalisation avantageux, le polymère est mis en solution dans un solvant comprenant 50 parties d'acétone et 50 parties d'éthanol pour 100 parties en masse/masse.According to an advantageous embodiment, the polymer is dissolved in a solvent comprising 50 parts of acetone and 50 parts of ethanol per 100 parts by mass / mass.
De même, lorsqu'on effectue une étape préalable d'uniformisation de la taille des particules de gabapentine ou prégabaline, l'agent liant est mis en solution dans un solvant organique identique ou différent de celui mis en œuvre lors de la pulvérisation.Likewise, when a preliminary stage of uniformization of the size of the gabapentin or pregabalin particles is carried out, the binding agent is dissolved in an organic solvent identical or different from that used during spraying.
Par ailleurs, pour obtenir un enrobage polymérique permettant à la fois de libérer rapidement l'analogue de l'acide γ-aminobutyrique, mais également de masquer le goût de la molécule active, le polymère est choisi dans le groupe comprenant le polyméthacrylate, les copolymères d'aminoéthylméthacrylate, les polymères cellulosiques, seuls ou en mélange.Furthermore, to obtain a polymeric coating allowing both to rapidly release the analogue of γ-aminobutyric acid, but also to mask the taste of the active molecule, the polymer is chosen from the group comprising polymethacrylate, copolymers aminoethylmethacrylate, cellulosic polymers, alone or as a mixture.
Avantageusement, le polyméthacrylate est un EUDRAGIT, notamment l'EUDRAGIT E ® commercialisé par la société ROHM.Advantageously, the polymethacrylate is an EUDRAGIT, in particular the EUDRAGIT E® marketed by the company ROHM.
Parmi les polymères cellulosiques, on peut choisir l'éthyl cellulose, l'hydroxypropylméthyl cellulose, l'hydroxypropyl cellulose, l'acétophtalate de cellulose, seuls en ou mélange. Par ailleurs, il peut être nécessaire d'associer des agents plastifiants audit polymère tels que le phtalate d'éthyle.Among the cellulose polymers, it is possible to choose ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose acetophthalate, alone or as a mixture. Furthermore, it may be necessary to combine plasticizing agents with said polymer such as ethyl phthalate.
Pour optimiser le masquage du goût du principe actif, la solution d'enrobage peut contenir en outre un agent édulcorant choisi dans le groupe comprenant l'aspartam, l'acésulfam de potassium, le saccharinate de sodium, le monoammonium glycyrrhizinate, les sucres et dérivés, ainsi que les polyols et dérivés, seuls ou en mélange. En pratique, l'agent édulcorant représente entre 1 et 6 % en poids de l'analogue d'acide γ-aminobutyrique.To optimize the masking of the taste of the active principle, the coating solution can also contain a sweetening agent chosen from the group comprising aspartame, potassium acesulfam, sodium saccharinate, monoammonium glycyrrhizinate, sugars and derivatives , as well as polyols and derivatives, alone or as a mixture. In practice, the sweetening agent represents between 1 and 6% by weight of the analogue of γ-aminobutyric acid.
Par ailleurs, pour éviter les phénomènes d'électrostatisme durant l'enrobage et par là même conduire à une meilleure maîtrise du procédé, la solution comprend en outre un agent antistatique choisi dans le groupe comprenant la silice colloïdale, la silice précipitée et le talc.Furthermore, to avoid the phenomena of electrostatism during coating and thereby lead to better control of the process, the solution also comprises an antistatic agent chosen from the group comprising colloidal silica, precipitated silica and talc.
En pratique, l'agent antistatique représente entre 2 et 8 % en poids de l'analogue de l'acide γ-aminobutyrique, avantageusement entre 5 et 6 % en poids.In practice, the antistatic agent represents between 2 and 8% by weight of the analogue of γ-aminobutyric acid, advantageously between 5 and 6% by weight.
Selon une autre caractéristique du procédé de l'invention, la pulvérisation aussi bien du polymère en solution que de l'agent liant en solution est effectuée comme déjà dit par la technique du lit fluidisé.According to another characteristic of the process of the invention, the spraying of both the polymer in solution and the binder in solution is carried out as already said by the fluidized bed technique.
A échelle du laboratoire, la température d'entrée d'air de pulvérisation doit être minimale et plus particulièrement comprise entre 35 et 45°C, avantageusement 40°C.At laboratory scale, the spraying air inlet temperature must be minimum and more particularly between 35 and 45 ° C, advantageously 40 ° C.
A échelle industrielle, la température d'entrée d'air de pulvérisation est plus élevée et est plus particulièrement comprise entre 40 et 80°C, avantageusement 60°C.On an industrial scale, the atomizing air inlet temperature is higher and is more particularly between 40 and 80 ° C., advantageously 60 ° C.
Quoiqu'il en soit, et dans les deux cas, la température des particules agglomérées ou non pendant l'enrobage doit être minimale et avantageusement comprise entre 20 et 30°C.Anyway, and in both cases, the temperature of the particles agglomerated or not during the coating must be minimum and advantageously between 20 and 30 ° C.
Les particules enrobées de gabapentine ou prégabaline obtenues peuvent être mises en œuvre au sein de toute forme galénique adéquate, étant entendu que la teneur en lactame de ladite forme galénique est inférieure à 0,5 % en poids par rapport au poids d'analogue de GABA.The particles coated with gabapentin or pregabalin obtained can be used in any suitable dosage form, it being understood that the lactam content of said dosage form is less than 0.5% by weight relative to the weight of GABA analog .
Dans une première forme de réalisation, les particules enrobées sont mises en œuvre telles quelles sous forme de sachet. Selon un mode avantageux de réalisation de l'invention, on peut soumettre les particules enrobées à une étape de compression après avoir préalablement mélangé à sec lesdites particules enrobées avec les excipients usuels de compression.In a first embodiment, the coated particles are used as such in the form of a sachet. According to an advantageous embodiment of the invention, the coated particles can be subjected to a compression step after having previously dry-mixed said coated particles with the usual compression excipients.
Les excipients mis en oeuvre pour la fabrication de ces comprimés sont connus de l'homme du métier et sont notamment choisis dans le groupe comprenant les agents diluants, les agents lubrifiants, les agents aromatisants, les agents édulcorants, seuls ou en mélange.The excipients used for the manufacture of these tablets are known to those skilled in the art and are chosen in particular from the group comprising diluents, lubricants, flavoring agents, sweetening agents, alone or as a mixture.
Les comprimés susceptibles d'être obtenus selon le procédé de l'invention peuvent être avantageusement de deux types.The tablets capable of being obtained according to the process of the invention can advantageously be of two types.
Le premier type correspond à des comprimés multiparticulaires à délitement rapide sans apport d'eau, en moins de 60 secondes dans la cavité buccale, encore dénommés FLASHTAB ®, marque déposée par le Demandeur et plus particulièrement décrit dans le document EP-A-548 356.The first type corresponds to multiparticulate tablets with rapid disintegration without supply of water, in less than 60 seconds in the oral cavity, also called FLASHTAB®, trademark registered by the Applicant and more particularly described in document EP-A-548 356. .
Dans ce cas, les excipients rajoutés lors de l'étape de compression comprennent en outre au moins un agent désintégrant apte à permettre le délitement rapide du principe actif.In this case, the excipients added during the compression step also comprise at least one disintegrating agent capable of allowing the active principle to disintegrate quickly.
Avantageusement, l'agent désintégrant est choisi dans le groupe comprenant la carboxyméthylcellulose sodique, le PVP réticulé (encore dénommée crospovidone) et le carboxyméthylamidon.Advantageously, the disintegrating agent is chosen from the group comprising sodium carboxymethylcellulose, crosslinked PVP (also called crospovidone) and carboxymethyl starch.
Par ailleurs, le polymère destiné à l'enrobage des particules de gabapentine ou prégabaline doit être choisi de sorte à ce qu'il soit insoluble à pH neutre, correspondant au pH salivaire (donc masquage du goût) et qu'il soit soluble ou perméable à un pH compris entre 1 et 4 correspondant au pH gastrique.Furthermore, the polymer intended for coating the gabapentin or pregabalin particles must be chosen so that it is insoluble at neutral pH, corresponding to the salivary pH (therefore masking the taste) and that it is soluble or permeable. at a pH between 1 and 4 corresponding to the gastric pH.
De plus, la dureté du comprimé est comprise entre 30 et 70 N, avantageusement 50 N.In addition, the hardness of the tablet is between 30 and 70 N, advantageously 50 N.
Le second type de comprimé correspond à des comprimés dits "fast dispersible", c'est-à-dire des comprimés à hydrodispersibilité rapide susceptibles de se déliter en un temps très court < 1 minute, de préférence < à 15 secondes, dans un volume d'eau minimum qui dépendra de la masse du comprimé.The second type of tablet corresponds to so-called "fast dispersible" tablets, that is to say rapidly hydrodispersible tablets capable of disintegrate in a very short time <1 minute, preferably <15 seconds, in a minimum volume of water which will depend on the mass of the tablet.
Cette dernière forme galénique peut donc être avantageusement utilisée en pédiatrie.The latter dosage form can therefore be advantageously used in pediatrics.
Dans ce cas, les excipients ajoutés lors de la compression comprendront en outre non seulement un agent de délitement mais également un agent de maintien en suspension des particules enrobées ou agent gonflant.In this case, the excipients added during compression will further comprise not only a disintegrating agent but also a maintenance agent in suspension of the coated particles or swelling agent.
De même, la dureté du comprimé obtenu est comprise entre 30 et 100 N, avantageusement 70 N.Likewise, the hardness of the tablet obtained is between 30 and 100 N, advantageously 70 N.
L'invention et les avantages qui en découlent ressortiront mieux des exemples de réalisation suivants.The invention and the advantages which result therefrom will emerge more clearly from the following exemplary embodiments.
L'ensemble des exemples étant réalisés à l'échelle de laboratoire, les différents paramètres sont réglés en conséquence.All the examples being carried out on a laboratory scale, the various parameters are adjusted accordingly.
Dans les trois exemples suivants, la mesure du taux de lactame se fait par détermination quantitative effectuée par HPLC par rapport à un étalon externe de lactame.In the following three examples, the lactam level is measured by quantitative determination carried out by HPLC with respect to an external lactam standard.
EXEMPLE 1 1 - Fabrication de particules de gabapentine enrobéesEXAMPLE 1 1 - Manufacture of coated gabapentin particles
a) Fabrication de particules aggloméréesa) Manufacture of agglomerated particles
On agglomère tout d'abord des particules de gabapentine à partir du mélange suivant :Gabapentin particles are first agglomerated from the following mixture:
PVP = polyvinyl providone commercialisé par BASF Conformément au procédé de l'invention, on uniformise la taille des particules de principe actif en pulvérisant sur les particules de gabapentine l'agent liant en solution dans l'éthanol, par la technique du spray coating.PVP = polyvinyl providone marketed by BASF In accordance with the process of the invention, the size of the particles of active principle is standardized by spraying on the gabapentin particles the binding agent in solution in ethanol, by the spray coating technique.
On règle la température d'air de fluidisation à 40°C, la température des particules en cours de fabrication étant de 21°C.The fluidizing air temperature is adjusted to 40 ° C., the temperature of the particles during manufacture being 21 ° C.
On procède ensuite à un tamisage, puis calibrage des particules agglomérées obtenues pour obtenir une majorité de particules de taille comprise entre 250 et 350 microns.We then proceed to sieving, then calibrating the agglomerated particles obtained to obtain a majority of particles of size between 250 and 350 microns.
h) Enrobage des particules aggloméréesh) Coating of agglomerated particles
Les particules agglomérées ainsi formées sont ensuite enrobées selon le même procédé par pulvérisation d'une solution comprenant : I Ludragit E lOO 280 mgThe agglomerated particles thus formed are then coated according to the same process by spraying with a solution comprising: I Ludragit E lOO 280 mg
Ethanol QSP 1 027 mg Acétone QSP 1 027 mgEthanol QSP 1,027 mg Acetone QSP 1,027 mg
Silice colloïdale 42 mgColloidal silica 42 mg
1 : Aérosil R972 commercialisé par DEGUSSA1: Aerosil R972 marketed by DEGUSSA
c) Pourcentage de lactame produit en fin de fabrication des particules enrobéesc) Percentage of lactam produced at the end of the manufacture of the coated particles
Le pourcentage de lactame en poids par rapport au poids de la gabapentine présent dans les particules enrobées varie entre 0,07 et 0,1 % d'un lot à l'autre. 2 - Fabrication de comprimés de gabapentine à hydrodispersibilité rapideThe percentage of lactam by weight relative to the weight of gabapentin present in the coated particles varies between 0.07 and 0.1% from one batch to another. 2 - Manufacture of rapidly hydrodispersible gabapentin tablets
Une fois les particules de gabapentine enrobées, on mélange lesdites particules avec le mélange de poudre comprenantOnce the gabapentin particles have been coated, said particles are mixed with the powder mixture comprising
1 : Pearlitol : commercialisé par ROQUETTE1: Pearlitol: marketed by ROQUETTE
2 : Avicel CE 15 : commercialisé par FMC2: Avicel CE 15: marketed by FMC
3 : Kollidon CL commercialisé par BASF3: Kollidon CL marketed by BASF
Les comprimés sont réalisés sur comprimeuse rotative équipée du poinçon de diamètre 18 mm. La pression exercée est de 16 KNewton +/- 2.The tablets are produced on a rotary press equipped with the 18 mm diameter punch. The pressure exerted is 16 KNewton +/- 2.
La dureté des comprimés obtenus est de l'ordre de 70 Newtons.The hardness of the tablets obtained is around 70 Newtons.
a) Essais de dissolutiona) Dissolution tests
On a réalisé des essais de dissolution des comprimés obtenus en milieu acide (0,06 N de HCl) dans les conditions standard (apparatus 2, et vitesse de pâles 50 rotations par minute).Tests were carried out for dissolving the tablets obtained in an acid medium (0.06 N of HCl) under standard conditions (apparatus 2, and paddle speed 50 rotations per minute).
Les essais ont été effectués dans des conditions de stockage des comprimés à 25°C et 60 % d'humidité relative. Les résultats figurent dans le tableau ci-après.The tests were carried out under storage conditions of the tablets at 25 ° C. and 60% relative humidity. The results are shown in the table below.
Comme le montre le tableau ci-dessus, 96 % du comprimé est dissous en 5 minutes, ce qui prouve la capacité du polymère à libérer rapidement le principe actif. As shown in the table above, 96% of the tablet is dissolved in 5 minutes, which proves the ability of the polymer to rapidly release the active ingredient.
b) Pourcentage de lactame contenu dans le comprimé à hydrodispersibilité rapideb) Percentage of lactam contained in the rapidly water-dispersible tablet
On a par ailleurs mesuré le pourcentage de lactame présent dans le comprimé en fin de fabrication (T0), au bout de 42 jours, 3 et 6 mois de stockage. Les résultats figurent dans le tableau ci-après (pourcentage de lactame en poids par rapport au poids de gabapentine)We also measured the percentage of lactam present in the tablet at the end of manufacture (T 0 ), after 42 days, 3 and 6 months of storage. The results are shown in the table below (percentage of lactam by weight relative to the weight of gabapentin)
On constate que le comprimé est stable vis-à-vis du produit de dégradation pendant six mois dans des conditions accélérées de stockage. Comme déjà dit, ce type de comprimé présente l'avantage de pouvoir être utilisé en pédiatrie.It is found that the tablet is stable vis-à-vis the degradation product for six months under accelerated storage conditions. As already said, this type of tablet has the advantage of being able to be used in pediatrics.
EXEMPLE 2EXAMPLE 2
1/ Fabrication de particules de gabapentine enrobées1 / Manufacture of coated gabapentin particles
a) On suit le même processus de fabrication que celui décrit dans l'exemple 1 en partant d'une masse de gabapentine égale à 300 mg, les autres constituants étant mis en œuvre au prorata.a) The same manufacturing process as that described in Example 1 is followed, starting with a mass of gabapentin equal to 300 mg, the other constituents being used in proportion.
b) Le pourcentage de lactame dosé dans les particules enrobées en fin de procédé varie entre 0,07 et 0,10 % en poids par rapport au poids de gabapentine d'un lot à l'autre.b) The percentage of lactam dosed in the particles coated at the end of the process varies between 0.07 and 0.10% by weight relative to the weight of gabapentin from one batch to another.
2/ Fabrication du comprimé à hydrodispersibilité rapide2 / Manufacture of the rapidly hydrodispersible tablet
On fabrique ensuite des comprimés à hydrodispersibilité rapide de gabapentine dosés à 300 mg en mélangeant les particules enrobées obtenues et le mélange de poudre suivant :Next, quick-dispersing gabapentin tablets 300 mg are made by mixing the coated particles obtained and the following powder mixture:
La fabrication des comprimés est réalisée sur comprimeuse rotative équipée de poinçon diamètre 16 mm. La pression exercée est de 12 KN +/- 2. La dureté du comprimé obtenu est de l'ordre de 55 N. a) Essai de dissolutionThe production of the tablets is carried out on a rotary tablet equipped with a 16 mm diameter punch. The pressure exerted is 12 KN +/- 2. The hardness of the tablet obtained is around 55 N. a) Dissolution test
Comme précédemment, on a ensuite calculé les pourcentages de dissolution de la gabapentine en milieu acide. Les résultats figurent dans le tableau ci-après.As before, the percentages of dissolution of gabapentin in an acid medium were then calculated. The results are shown in the table below.
b) Pourcentage de lactame b) Percentage of lactam
On a également mesuré le pourcentage de lactame présent dans le comprimé obtenu selon l'invention. Les résultats figurent dans le tableau ci-après (en poids par rapport au poids de gabapentine).The percentage of lactam present in the tablet obtained according to the invention was also measured. The results are shown in the table below (by weight relative to the weight of gabapentin).
EXEMPLE 3 EXAMPLE 3
1/ Fabrication de particules de prégabaline enrobées1 / Manufacture of coated pregabalin particles
On prépare dans cette étape des particules de prégabaline enrobées dont la composition est la suivante :In this step, coated pregabalin particles are prepared, the composition of which is as follows:
Les particules enrobées sont fabriquées selon le procédé de l'invention en lit fluidisé par pulvérisation d'une solution comprenant l'Eudragit, l'Acésulfame de potassium et le talc dans de l'éthanol à 96 %.The coated particles are produced according to the process of the invention in a fluidized bed by spraying with a solution comprising Eudragit, potassium acesulfame and talc in 96% ethanol.
Cette technique en lit fluidisé est réalisée au sein d'un appareil du type GLATT/GPGC 1, la température du produit étant comprise entre 20 et 25° C.This fluidized bed technique is carried out in an apparatus of the GLATT / GPGC 1 type, the temperature of the product being between 20 and 25 ° C.
Le pourcentage de lactame mesuré sur les particules enrobées de prégabaline est :The percentage of lactam measured on the particles coated with pregabalin is:
2/ Fabrication du comprimé multiparticulaire à délitement rapide 2 / Manufacture of the fast disintegrating multiparticulate tablet
Une fois les particules de prégabaline enrobées, on mélange lesdites particules avec un mélange de poudre comprenant :Once the pregabalin particles have been coated, said particles are mixed with a powder mixture comprising:
La dureté des comprimés obtenus est de 40 N.The hardness of the tablets obtained is 40 N.
a) Essai de dissolution On a calculé les pourcentages de dissolution de la prégabaline en milieu acide dans les mêmes conditions que pour les exemples 1 et 2. Les résultats figurent dans le tableau ci-après.a) Dissolution test The percentages of dissolution of pregabalin in an acid medium were calculated under the same conditions as for Examples 1 and 2. The results are shown in the table below.
b) Pourcentage de lactame b) Percentage of lactam
Le pourcentage de lactame calculé sur les comprimés sont représentés dans le tableau ci-dessous.The percentage of lactam calculated on the tablets is shown in the table below.
Les avantages de l'invention ressortent bien de la description. On note en particulier que l'invention permet de résoudre simultanément les trois problèmes, à savoir : The advantages of the invention appear clearly from the description. It should be noted in particular that the invention makes it possible to simultaneously solve the three problems, namely:
• proposer une forme galénique d'analogue de GABA dont le pourcentage de lactame toxique est inférieur à 0,5 % ;• propose a galenic form of analog of GABA whose percentage of toxic lactam is less than 0.5%;
• masquer le goût amer des analogues de l'acide γ-aminobutyrique ;• mask the bitter taste of analogs of γ-aminobutyric acid;
• et obtenir une concentration plasmatique de la molécule active maximale en 2 à 3 heures après ingestion.• and obtain a maximum plasma concentration of the active molecule in 2 to 3 hours after ingestion.
Les particules enrobées présentent également l'avantage, outre leur procédé de fabrication conventionnel, de pouvoir être incorporés notamment au sein de comprimés type FLASHTAB ® ou à hydrodispersibilité rapide, comprimés qui ne sont pas avalés directement, mais après avoir été délités au contact de la salive dans la bouche dans le premier cas, ou au contact de l'eau dans le second cas.The coated particles also have the advantage, in addition to their conventional manufacturing process, of being able to be incorporated in particular into tablets of the FLASHTAB® or fast hydrodispersibility type, tablets which are not swallowed directly, but after having been disintegrated in contact with the saliva in the mouth in the first case, or in contact with water in the second case.
Il n'est donc dans ce cas plus nécessaire d'ingérer des formes solides, lesquelles peuvent s'avérer inadéquates, notamment chez les enfants et les personnes âgées, et compliquées dans le cas du traitement d'une personne souffrant d'épilepsie.It is therefore no longer necessary in this case to ingest solid forms, which may prove to be inadequate, in particular in children and the elderly, and complicated in the case of the treatment of a person suffering from epilepsy.
Comme déjà dit, l'invention ne se limite pas à un procédé de fabrication de particules enrobées de gabapentine ou prégabaline, mais concerne tout analogue de l'acide γ-aminobutyrique susceptible de se dégrader en molécules de lactame en solution aqueuse. As already stated, the invention is not limited to a process for the manufacture of particles coated with gabapentin or pregabalin, but relates to any analogue of γ-aminobutyric acid capable of degrading into lactam molecules in aqueous solution.

Claims

REVENDICATIONS
1/ Procédé pour la fabrication de particules d'analogue d'acide γ- aminobutyrique enrobées dont la teneur en lactame en poids par rapport au poids d'analogue d'acide γ-aminobutyrique est inférieure à 0,5%, caractérisé en ce que l'on pulvérise une solution d'enrobage comprenant au moins un polymère dans au moins un solvant organique sur lesdites particules d'analogue d'acide γ- aminobutyrique .1 / Process for the manufacture of coated particles of γ-aminobutyric acid analog whose lactam content by weight relative to the weight of γ-aminobutyric acid analog is less than 0.5%, characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed onto said particles of analog of γ-aminobutyric acid.
2/ Procédé selon la revendication 1, caractérisé en ce que l'analogue d'acide γ-aminobutyrique est la gabapentine.2 / A method according to claim 1, characterized in that the analog of γ-aminobutyric acid is gabapentin.
3/ Procédé selon la revendication 1 , caractérisé en ce que l'analogue d'acide γ-aminobutyrique est la prégabaline.3 / A method according to claim 1, characterized in that the analog of γ-aminobutyric acid is pregabalin.
4/ Procédé selon la revendication 2, caractérisé en ce que le polymère représente entre 60 et 80 % en poids de la gabapentine.4 / A method according to claim 2, characterized in that the polymer represents between 60 and 80% by weight of gabapentin.
5/ Procédé selon la revendication 3, caractérisé en ce que le polymère représente entre 15 et 30 % en poids de la prégabaline.5 / A method according to claim 3, characterized in that the polymer represents between 15 and 30% by weight of pregabalin.
6/ Procédé selon l'une des revendications 1 à 5, caractérisé en ce que les particules d'analogue d'acide γ-aminobutyrique sont préalablement uniformisées en taille, par pulvérisation sur lesdites particules d'une solution d'un agent liant hydrosoluble dans un solvant organique, puis tamisage et calibrage des particules agglomérées obtenues.6 / A method according to one of claims 1 to 5, characterized in that the particles of analog of γ-aminobutyric acid are previously uniform in size, by spraying onto said particles a solution of a water-soluble binding agent in an organic solvent, then sieving and sizing of the agglomerated particles obtained.
Il Procédé selon l'une des revendications 1 à 6, caractérisé en ce que la pulvérisation de la solution d'enrobage est effectué en lit fluidisé.Il Method according to one of claims 1 to 6, characterized in that the spraying of the coating solution is carried out in a fluidized bed.
8/ Procédé selon l'une des revendications 1 à 7, caractérisé en ce que le solvant organique est choisi dans le groupe comprenant l'acétone, l'éthanol, l'isopropanol, seul ou en mélange. 9/ Procédé selon la revendication 8, caractérisé en ce que le solvant organique comprend 50 parties d'acétone et 50 parties d'éthanol pour 100 parties en masse/masse.8 / A method according to one of claims 1 to 7, characterized in that the organic solvent is chosen from the group comprising acetone, ethanol, isopropanol, alone or as a mixture. 9 / A method according to claim 8, characterized in that the organic solvent comprises 50 parts of acetone and 50 parts of ethanol per 100 parts by mass / mass.
10/ Procédé selon la revendication 6, caractérisé en ce que l'agent liant est mis en solution dans de l'éthanol.10 / A method according to claim 6, characterized in that the binding agent is dissolved in ethanol.
11/ Procédé selon l'une des revendications 1 à 10, caractérisé en ce que le polymère est choisi dans le groupe comprenant le polyméthacrylate, les copolymères d'amino ethylméthacrylate, les polymères cellulosiques, seuls ou en mélange.11 / A method according to one of claims 1 to 10, characterized in that the polymer is chosen from the group comprising polymethacrylate, amino ethylmethacrylate copolymers, cellulose polymers, alone or as a mixture.
12/ Procédé selon l'une des revendications 1 à 11, caractérisé en ce que la solution d'enrobage contient en outre un agent édulcorant choisi dans le groupe comprenant l'aspartam, l'acésulfam de potassium, le monoammonium glycyrrhizinate, le saccharinate de sodium, les sucres et dérivés, les polyols et dérivés, seuls ou en mélange.12 / A method according to one of claims 1 to 11, characterized in that the coating solution also contains a sweetening agent selected from the group comprising aspartame, potassium acesulfam, monoammonium glycyrrhizinate, saccharin sodium, sugars and derivatives, polyols and derivatives, alone or as a mixture.
13/ Procédé selon l'une des revendications 1 à 12, caractérisé en ce que la solution d'enrobage contient en outre un agent antistatique choisi dans le groupe comprenant la silice colloïdale, la silice précipitée et le talc.13 / A method according to one of claims 1 to 12, characterized in that the coating solution further contains an antistatic agent selected from the group comprising colloidal silica, precipitated silica and talc.
14/ Procédé selon l'une des revendications 1 à 13, caractérisé en ce que l'on mélange à sec les particules enrobées obtenues avec des excipients de compression avant de les soumettre à une étape de compression pour obtenir des comprimés.14 / A method according to one of claims 1 to 13, characterized in that the coated particles obtained are dry mixed with compression excipients before subjecting them to a compression step to obtain tablets.
15/ Procédé selon la revendication 14, caractérisé en ce que les excipients de compression sont choisis dans le groupe comprenant les agents diluants, les agents lubrifiants, les agents aromatisants, les agents édulcorants, seuls ou en mélange.15 / A method according to claim 14, characterized in that the compression excipients are chosen from the group comprising diluents, lubricants, flavoring agents, sweetening agents, alone or as a mixture.
16/ Procédé selon la revendication 15, caractérisé en ce que les excipients de compression comprennent en outre au moins un agent désintégrant choisi dans le groupe comprenant la carboxyméthylcellulose sodique, la crospovidone et le carboxyméthylamidon. 111 Procédé selon la revendication 16, caractérisé en ce que les excipients de compression comprennent en outre un agent de maintien en suspension des particules enrobées.16 / A method according to claim 15, characterized in that the compression excipients further comprise at least one disintegrating agent selected from the group comprising sodium carboxymethylcellulose, crospovidone and carboxymethyl starch. 111 Method according to claim 16, characterized in that the compression excipients further comprise an agent for keeping the coated particles in suspension.
18/ Particules enrobées susceptibles d'être obtenues par le procédé selon l'une des revendications 1 à 13.18 / coated particles capable of being obtained by the method according to one of claims 1 to 13.
19/ Comprimé susceptible d'être obtenu par le procédé selon l'une des revendications 1 à 15.19 / Tablet capable of being obtained by the method according to one of claims 1 to 15.
20/ Comprimé multiparticulaire pour administration orale sans utilisation d'eau, dont la vitesse de délitement entraîne la désagrégation en moins de 60 secondes dans la cavité buccale susceptible d'être obtenu par le procédé selon l'une des revendications 1 à 16.20 / Multiparticulate tablet for oral administration without the use of water, the disintegration speed of which causes disintegration in less than 60 seconds in the oral cavity capable of being obtained by the method according to one of claims 1 to 16.
21/ Comprimé multiparticulaire à hydrodispersibilité rapide apte à former une suspension stable dans un faible volume d'eau, susceptible d'être obtenu par le procédé selon l'une des revendications 1 à 17. 21 / Multiparticulate tablet with rapid hydrodispersibility capable of forming a stable suspension in a small volume of water, capable of being obtained by the process according to one of claims 1 to 17.
EP99932956A 1998-08-03 1999-07-23 Method for making coated gabapentine or pregabaline particles Ceased EP1100467A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9810091 1998-08-03
FR9810091A FR2781793B1 (en) 1998-08-03 1998-08-03 PROCESS FOR PRODUCING COATED GABAPENTINE GRANULES
PCT/FR1999/001811 WO2000007568A1 (en) 1998-08-03 1999-07-23 Method for making coated gabapentine or pregabaline particles

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EP (1) EP1100467A1 (en)
JP (1) JP2002522375A (en)
CN (1) CN1321083A (en)
AR (1) AR021746A1 (en)
AU (1) AU742701B2 (en)
CA (1) CA2338173A1 (en)
FR (1) FR2781793B1 (en)
NZ (1) NZ509980A (en)
PE (1) PE20001030A1 (en)
WO (1) WO2000007568A1 (en)
ZA (1) ZA200100943B (en)

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WO2000007568A1 (en) 2000-02-17
US20020012679A1 (en) 2002-01-31
AU4916099A (en) 2000-02-28
JP2002522375A (en) 2002-07-23
AU742701B2 (en) 2002-01-10
NZ509980A (en) 2003-07-25
FR2781793A1 (en) 2000-02-04
PE20001030A1 (en) 2000-10-12
US6488964B2 (en) 2002-12-03
FR2781793B1 (en) 2001-07-20
CN1321083A (en) 2001-11-07
AR021746A1 (en) 2002-08-07
CA2338173A1 (en) 2000-02-17

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