EP1781295A1 - Pharmaceutical composition in the form of a gastric-resident tablet containing an active principle - Google Patents

Pharmaceutical composition in the form of a gastric-resident tablet containing an active principle

Info

Publication number
EP1781295A1
EP1781295A1 EP05798249A EP05798249A EP1781295A1 EP 1781295 A1 EP1781295 A1 EP 1781295A1 EP 05798249 A EP05798249 A EP 05798249A EP 05798249 A EP05798249 A EP 05798249A EP 1781295 A1 EP1781295 A1 EP 1781295A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
matrix tablet
tablet
tablets
weight
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Withdrawn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
EP05798249A
Other languages
German (de)
French (fr)
Inventor
Gérard Alaux
Estelle Chouin
Nathalie Dufresne-Arokiassamy
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 SA
Original Assignee
Sanofi Aventis France
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
Family has litigation
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Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1781295A1 publication Critical patent/EP1781295A1/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Withdrawn legal-status Critical Current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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • the present invention relates to a pharmaceutical composition in tablet form, containing an active ingredient, used for administration once a day.
  • the conventional sustained-release dosage forms are hardly suitable for certain active principles which have an absorption window in the upper parts of the gastrointestinal tract, that is to say which are absorbed in the stomach, the upper parts. small intestine, duodenum, jejunum and ilium, and less or less at the colonic level. Indeed, the conventional administration unit releases the active substance throughout its passage in the gastrointestinal tract and not only in the part where the absorption of the active ingredient is maximum.
  • the present invention relates to a pharmaceutical composition in tablet form containing an active ingredient, used for administration once a day, overcoming the disadvantages mentioned above.
  • the invention is characterized in that in contact with the gastric fluid, the pharmaceutical composition rapidly increases its volume. It is indeed clearly advantageous that this composition increases its volume not only considerably but also very rapidly, as soon as it comes into contact with the gastric fluid. This makes it possible to ensure a longer residence time of this pharmaceutical composition in the stomach, to avoid premature gastric emptying and thus to ensure that most of the active ingredient contained in the pharmaceutical composition is released and absorbed. in the portion of the gastrointestinal tract where the absorption capacity is highest.
  • An object of the invention is a pharmaceutical composition under form of a matrix tablet, comprising an active ingredient, and allowing a prolonged release of the latter, which after fifteen minutes in contact with a representative medium of the gastric fluid rapidly increases in volume, with a swelling rate of at least 200 %, more particularly at least 250%.
  • matrix tablet is meant a pharmaceutical composition for oral administration containing an active substance dispersed uniformly in one or more suitable excipients which, after compression, allow the formation of a matrix capable of controlling the release of the active principle.
  • representative medium of the gastric fluid is meant a 0.01 M aqueous solution of hydrochloric acid and 0.1 M sodium chloride at 37 ° C.
  • the rate of swelling of the tablets is determined by measuring the thickness and the diameter of the dry tablet and the tablet remained fifteen minutes immersed in the representative medium of the gastric fluid and using a suitable measuring instrument.
  • the degree of swelling (in percent) can thus be expressed in terms of thickness, diameter or volume, according to the following formulas:
  • Vto Volume of the tablet at TO
  • Seen 5 Volume of the tablet at 15 minutes. the volume of the tablet being calculated according to the following formula
  • D is the tablet diameter
  • e is the thickness of the tablet wafer
  • h is the half difference between the total tablet thickness and the wafer thickness
  • R is the tablet radius of curvature.
  • the pharmaceutical composition is in the form of a single-phase matrix tablet.
  • the pharmaceutical composition is in the form of a matrix tablet having at least two phases.
  • the pharmaceutical composition may comprise one or more active ingredients in one or more phases.
  • the pharmaceutical composition will more particularly comprise one or two active subtances.
  • phase is meant a homogeneous mixture of one or more excipients, in the form of a powder or granule, which may contain an active ingredient.
  • a pharmaceutical composition according to the invention comprising two or more phases may be in the form of a multi-layer tablet (bilayer, tri-layer, etc.), more particularly a bilayer, or in the form of a core. covered with one or more phases.
  • the invention consists of a pharmaceutical composition in the form of a gastric residence matrix tablet comprising an active ingredient, and at least one phase containing, at least, as excipients: a) povidone and / or polyvinyl acetate in proportions ranging from 30 to 80% by weight of the phase,
  • crospovidone may be replaced or combined with another super-disintegrant such as low-substituted hydroxypropylcellulose (L-HPC), sodium carboxymethyl starch and / or croscarmellose sodium.
  • L-HPC low-substituted hydroxypropylcellulose
  • sodium carboxymethyl starch sodium carboxymethyl starch
  • croscarmellose sodium another super-disintegrant
  • the matrix tablet according to the invention has the advantage of swelling very quickly in contact with gastric fluids. Indeed, the presence of excipients a), b) and c) in the proportions according to the invention makes it possible to obtain a synergy of swelling. The tablet could thus reside for several hours in the stomach.
  • the matrix compound comprises at least two phases, one or more of the phases may comprise an active ingredient.
  • each phase may have an identical or different composition in excipients of another phase, it being understood that at least one of the phases comprises the excipients a), b) and c) in the proportions as indicated according to the invention.
  • one of the phases does not include the excipients a), b) and c), each in the proportions as indicated according to the invention, the skilled person can determine its composition according to the biopharmaceutical requirements, such as control release of the active ingredient, increased swelling rate.
  • povidone and polyvinyl acetate excipients or the povidone / polyvinyl acetate mixture are commercially available or, more particularly, the mixture is chosen from those sold under the name Kollidon® SR.
  • the povidone and / or the polyvinyl acetate are in an amount ranging from 30 to 80% by weight of the phase containing it and more particularly from 30 to 65%.
  • Crospovidone is a crosslinked homopolymer of ⁇ -vinyl-2-pyrrolidinone of molecular weight greater than 1,000,000DA. This polymer belongs to the category of super-disintegrants, able to quickly and intensively capture the surrounding liquid.
  • crospovidone sold commercially under the name Kollidon® CL (BASF) or Plasdone® XL (ISP).
  • Hydroxypropylcellulose is a low-substituted hydroxypropyl ether of cellulose, insoluble in water and alcohols but capable of swelling in these solvents.
  • L-HPC LH-11 grade provided by Shin Etsu.
  • Sodium carboxymethyl starch or sodium starch glycolate is the sodium salt of a carboxymethyl starch ether. There are three grades, A, B and C, which differs in sodium content. By way of example, mention may be made of sodium starch glycolate sold under the trade name Primojel® (Avebe) or Explotab® (JRS Pharma).
  • Croscarmellose sodium is a cellulosic polymer obtained by crosslinking carmellose sodium.
  • Ad-Di-Sol® Ad-Di-Sol®
  • Crospovidone or super-disintegrants such as low-substituted hydroxypropylcellulose, sodium carboxymethyl starch or sodium starch glycolate, croscarmellose sodium, are present in an amount ranging from 5 to 25% by weight of the phase containing them and more particularly of
  • the carbomer is a polymer of acrylic acid crosslinked with an allyl ether of sucrose or pentaerythritol having a very high molecular weight (of the order of one million).
  • Carbopol® 974 or Carbopol® 71G NOVEON
  • Carbopol® 71G which makes it possible to obtain aqueous dispersions having a viscosity of between 4000 and 11000 cps (dispersion at 0.5%).
  • the carbomer is in the tablet or in a phase in proportions in an amount ranging from 5 to 40% by weight respectively of the tablet or the phase and more particularly from 10 to 35%.
  • the excipients a), b) and c) are respectively in amounts of 40 to 70% for povidone and / or polyvinyl acetate, 10 to 20% for crospovidone and 10 to 30% for the carbomer.
  • the tablet may also include any suitable excipient necessary for the manufacture of the tablet, such as:
  • soluble or insoluble diluents microcrystalline cellulose, lactose, mannitol, dicalcium phosphate, etc.
  • insoluble diluents in an amount ranging from 5 to 30% by weight of the phase containing it;
  • lubricants magnesium stearate, talc, hydrogenated castor oil, PEG 6000, glycerol behenate, stearic acid, etc.
  • flow agents colloidal silica, precipitated silica, etc.
  • compositions according to the invention may for example be useful for benzamides and ⁇ 1 -antagonists, as well as the following active ingredients: captopril, furosemide, ursodesoxycholic acid, amoxicillin, (+) - ⁇ - aminomethyl-2-methoxysulfonamidobenzenemethanol (disclosed in patent application EP 842 148 to Example 3.6) or 3'- (2-amino-hydroxyethyl) -4'-fluoromethanesulfonanilide (NS 49).
  • the benzamides are in particular metoclopramide, veralipride, alizapride, and clébopride, especially in amisulpride, tiapride, sulpiride and their salts.
  • ⁇ 1 -antagonists are in particular terazosin and alfuzosin and their salts, in particular alfuzosin hydrochloride. They are intended in particular for the treatment of benign prostatic hypertrophy.
  • Captopril is used especially for the treatment of hypertension, furosemide as a diuretic, arnoxicillin and its salts as an antibiotic, and ursodesoxycholic acid and its salts is used for the treatment of cholelithiases, hepatic disorders and syphilis.
  • Benzamides, ⁇ 1-antagonists are also covered, including their mixtures, in particular their racemic mixtures, but also their salts.
  • active ingredients which are more particularly suitable for the compositions according to the invention, mention may be made of amisulpride (D) -tartrate, (S) - (-)
  • the amount of active ingredient in the pharmaceutical composition is generally from 0.1 mg to 200 mg.
  • the tablets of the invention can be produced by direct compression of a mixture of powders or by granulation and compression using the usual production technologies.
  • the chosen compression format can be optimized according to the general knowledge of the skilled person.
  • the working compression force varies between 500 DaN and 3000 DaN so as to obtain tablets with a tensile strength that allows them to be handled and administered without any problem (between 80 and 300N for 10R10 mm tablets, for example) . Obtained, according to the methods to be described in more detail in the examples, mono tablets, or at least two phases having a shape that allows easy administration and swallowing.
  • each phase of the tablet may have a different thickness ranging from 1 to 8 mm, but preferably from 2 mm to 6 mm. These dimensions may vary depending on the compression format.
  • Example 1 Preparation of a monolayer tablet comprising 10 mg of alfuzosin hydrochloride
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression machine.
  • the rate of swelling of the tablets is determined by measuring the thickness and the diameter of the dry tablet and the tablet which has been left for 15 minutes immersed in gastric liquid at 37 ° C. (0.01 M HCl + 0.1 M NaCl), and this using a suitable measuring instrument.
  • the swelling ratio is 80% by thickness and 25% by diameter, ie about 200% by volume.
  • the release profile an active ingredient in the gastric medium (pH2 + 0.1 M NaCl) obtained with this formulation is a profile of order 0 is: - 10 to 20% released in 1 hour.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression machine. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® mixer. The mixture flows freely and facilitates the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above.
  • the swelling is 80% in thickness and 30% in diameter, ie about 300% by volume.
  • the release profile an active ingredient in the gastric medium (pH2 + 0.1 M NaCl) obtained with this formulation is a profile of order 0 is: - 10 to 20% released in 1 hour.
  • Example 3 Preparation of a bi-layer tablet comprising 10 mg of alfuzosin hydrochloride
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula ® inverting mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above in Example 1. In this example, the swelling is 350% by volume.
  • Example 5 Preparation of a 500 mg two-layer tablet comprising 10 mg of alfuzosin hydrochloride
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • Flow of the mixture ⁇ 10 seconds per 100g of mixture.
  • Hardness of the tablets 150N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 360% by volume.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is. 2Z0 ._% by volume.
  • Example 7 Preparation of a bi-layer tablet comprising 10 mg of alfuzosin hydrochloride
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
  • Examples 9 and 10 below show single-layer monosaccharide tablet compositions. These compositions can be used as a swelling placebo layer in the manufacture of multilayer tablets. It is also possible to incorporate the active ingredient in these compositions, for example at a height of 10 mg, in order to obtain a pharmaceutical composition according to the invention.
  • Example 9 Preparation of a 500 mg monolayer placebo tablet.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 340% by volume.
  • Example 10 Preparation of a 500 mg monolayer placebo tablet.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above. In this example, the swelling is 470% by volume.
  • Example 11 Preparation of a tri-layer tablet of 700 mg containing 10 mg of alfuzosin hydrochloride.
  • the tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
  • the swelling rate of the tablets is determined by the method described above.
  • the swelling is 104% in thickness, 41% in width and 36% in length.

Abstract

The invention concerns a pharmaceutical composition in the form of a gastric resident matrix tablet, comprising an active principle, characterized in that when contacted with an environment representing a gastric fluid, it increases after fifteen minutes in volume, by a swelling rate of at least 200 %.

Description

COMPOSITION PHARMACEUTIQUE SOUS FORME DE COMPRIME A RESIDENCE GASTRIQUE CONTENANT UN PRINCIPE ACTIF PHARMACEUTICAL COMPOSITION IN THE FORM OF A GASTRIC RESISTANCE COMPRESSOR CONTAINING AN ACTIVE INGREDIENT
La présente invention a pour objet une composition pharmaceutique sous forme de comprimé, contenant un principe actif, utilisable pour une administration une fois par jour.The present invention relates to a pharmaceutical composition in tablet form, containing an active ingredient, used for administration once a day.
Les formes pharmaceutiques à libération prolongée classiques conviennent difficilement pour certains principes actifs qui présentent une fenêtre d'absorption dans les parties hautes du tractus gastro-intestinal, c'est-à-dire qui sont absorbés au niveau de l'estomac, des parties hautes de l'intestin grêle, duodénum, jéjunum et ilium, et moins ou peu au niveau colonique. Effectivement, l'unité d'administration classique libère la substance active tout au long de son passage dans le tractus gastro-intestinal et non pas uniquement dans la partie où l'absorption du principe actif est maximale.The conventional sustained-release dosage forms are hardly suitable for certain active principles which have an absorption window in the upper parts of the gastrointestinal tract, that is to say which are absorbed in the stomach, the upper parts. small intestine, duodenum, jejunum and ilium, and less or less at the colonic level. Indeed, the conventional administration unit releases the active substance throughout its passage in the gastrointestinal tract and not only in the part where the absorption of the active ingredient is maximum.
La présente invention a pour objet une composition pharmaceutique sous forme de comprimé contenant un principe actif, utilisable pour une administration une fois par jour, remédiant aux inconvénients mentionnés ci-dessus.The present invention relates to a pharmaceutical composition in tablet form containing an active ingredient, used for administration once a day, overcoming the disadvantages mentioned above.
L'invention est caractérisée par le fait qu'au contact avec le fluide gastrique, la composition pharmaceutique augmente rapidement son volume. Il est effectivement clairement avantageux que cette composition augmente son volume non seulement considérablement mais aussi très rapidement, dès qu'elle entre au contact du fluide gastrique. Ceci permet d'assurer un temps de séjour plus long de cette composition pharmaceutique dans l'estomac, d'éviter une vidange gastrique prématurée et d'assurer ainsi que la plus grande partie du principe actif contenue dans la composition pharmaceutique, soit libérée et absorbée dans la portion du tractus gastro-intestinal où la capacité d'absorption est la plus élevée.The invention is characterized in that in contact with the gastric fluid, the pharmaceutical composition rapidly increases its volume. It is indeed clearly advantageous that this composition increases its volume not only considerably but also very rapidly, as soon as it comes into contact with the gastric fluid. This makes it possible to ensure a longer residence time of this pharmaceutical composition in the stomach, to avoid premature gastric emptying and thus to ensure that most of the active ingredient contained in the pharmaceutical composition is released and absorbed. in the portion of the gastrointestinal tract where the absorption capacity is highest.
Un objet de l'invention consiste en une composition pharmaceutique sous forme d'un comprimé matriciel, comprenant un principe actif, et permettant une libération prolongée de ce dernier, qui après quinze minutes au contact avec un milieu représentatif du fluide gastrique augmente rapidement en volume, d'un taux de gonflement d'au moins 200%, plus particulièrement d'au moins 250%.An object of the invention is a pharmaceutical composition under form of a matrix tablet, comprising an active ingredient, and allowing a prolonged release of the latter, which after fifteen minutes in contact with a representative medium of the gastric fluid rapidly increases in volume, with a swelling rate of at least 200 %, more particularly at least 250%.
On entend par comprimé matriciel une composition pharmaceutique pour administration orale renfermant une substance active dispersée uniformément dans un ou des excipients appropriés qui, après compression, permettent la formation d'une matrice capable de contrôler la libération du principe actif.By matrix tablet is meant a pharmaceutical composition for oral administration containing an active substance dispersed uniformly in one or more suitable excipients which, after compression, allow the formation of a matrix capable of controlling the release of the active principle.
On entend par milieu représentatif du fluide gastrique, une solution aqueuse 0,01 M en acide chlorhydrique et 0,1 M en chlorure de sodium à 37°C.By representative medium of the gastric fluid is meant a 0.01 M aqueous solution of hydrochloric acid and 0.1 M sodium chloride at 37 ° C.
. Le taux de gonflement des comprimés est déterminé par mesure de l'épaisseur et du diamètre du comprimé sec et du comprimé resté quinze minutes en immersion dans le milieu représentatif du fluide gastrique et ce à l'aide d'un instrument de mesure adapté. Le taux de gonflement (en pourcent) peut ainsi être exprimé en épaisseur, diamètre ou volume, selon les formules suivantes :. The rate of swelling of the tablets is determined by measuring the thickness and the diameter of the dry tablet and the tablet remained fifteen minutes immersed in the representative medium of the gastric fluid and using a suitable measuring instrument. The degree of swelling (in percent) can thus be expressed in terms of thickness, diameter or volume, according to the following formulas:
Taux de gonflement en épaisseur :Swelling rate in thickness:
((Epti5- Epto)/Epto)x 1OO Epto = Epaisseur du comprimé à TO Epti5 = Epaisseur du comprimé à15 minutes.((Epti 5 - Epto) / Epto) x 100 Epto = Thickness of tablet at TO Epti 5 = Thickness of tablet at 15 minutes.
Taux de gonflement en diamètre:Swelling rate in diameter:
((Dti5- Dto)/Dto)x1OO Dto = Diamètre du comprimé à TO Df-)5 = Diamètre du comprimé à15 minutes. Taux de gonflement en volume:((Dti 5 - Dto) / D to ) x 100 D t o = Diameter of the tablet at TO D f -) 5 = Diameter of the tablet at 15 minutes. Bulking rate by volume:
((Vti5-Vto)/Vto)x1OO((Vti 5 -Vto) / V t o) x100
Vto = Volume du comprimé à TOVto = Volume of the tablet at TO
Vu 5 = Volume du comprimé à15 minutes. le volume du comprimé étant calculé selon la formule suivanteSeen 5 = Volume of the tablet at 15 minutes. the volume of the tablet being calculated according to the following formula
- pour un comprimé bombé : |V = ((π x D^ x e)/4) + π x h x ((Dz/4) + (tτV3))l- for a curved tablet: | V = ((π x D x xe) / 4) + π xhx ((D z / 4) + (tτV3)) l
RR
Où D est le diamètre du comprimé, e représente l'épaisseur de la tranche du comprimé, h représente la demi-différence entre l'épaisseur totale du comprimé et l'épaisseur de la tranche et R représente le rayon de courbure du comprimé.Where D is the tablet diameter, e is the thickness of the tablet wafer, h is the half difference between the total tablet thickness and the wafer thickness, and R is the tablet radius of curvature.
- pour un comprimé dont le rayon de courbure est égal au diamètre (par exemple, format 10R10 mm, 12R12 mm, etc.) :- for a tablet whose radius of curvature is equal to the diameter (for example, 10R10 mm, 12R12 mm, etc.):
[V = ((π x D* x e) / 4) + 0,0359 x π x Dl Où e = E - 0,28D.[V = ((π x D * x e) / 4) + 0.0359 x π x D1 Where e = E - 0.28D.
Selon un aspect de l'invention, la composition pharmaceutique se présente sous forme d'un comprimé matriciel monophase.According to one aspect of the invention, the pharmaceutical composition is in the form of a single-phase matrix tablet.
Selon un autre aspect de l'invention, la composition pharmaceutique se présente sous forme d'un comprimé matriciel ayant au moins deux phases.According to another aspect of the invention, the pharmaceutical composition is in the form of a matrix tablet having at least two phases.
Selon un autre aspect de l'invention, la composition pharmaceutique peut comprendre un ou plusieurs principes actifs dans une ou plusieurs phases. La composition pharmaceutique comprendra plus particulièrement un ou deux principes actifs.According to another aspect of the invention, the pharmaceutical composition may comprise one or more active ingredients in one or more phases. The pharmaceutical composition will more particularly comprise one or two active subtances.
On entend par phase un mélange homogène d'un ou plusieurs excipients, sous forme de poudre ou de granulé, pouvant contenir un principe actif.By phase is meant a homogeneous mixture of one or more excipients, in the form of a powder or granule, which may contain an active ingredient.
Une compositions pharmaceutique selon l'invention comprenant deux ou plusieurs phases peut se présenter sous forme d'un comprimé multi-couche (bi- couche, tri-couche, ..), plus particulièrement bi-couche, ou sous forme d'un noyau recouvert d'une ou plusieurs phases.A pharmaceutical composition according to the invention comprising two or more phases may be in the form of a multi-layer tablet (bilayer, tri-layer, etc.), more particularly a bilayer, or in the form of a core. covered with one or more phases.
Selon un autre objet, l'invention consiste en une composition pharmaceutique sous forme d'un comprimé matriciel à résidence gastrique comprenant un principe actif, et au moins une phase contenant, au moins, en tant qu'excipients: - a) de la povidone et/ ou acétate de polyvinyle dans des proportions allant de 30 à 80% en poids de la phase,According to another object, the invention consists of a pharmaceutical composition in the form of a gastric residence matrix tablet comprising an active ingredient, and at least one phase containing, at least, as excipients: a) povidone and / or polyvinyl acetate in proportions ranging from 30 to 80% by weight of the phase,
- b) de la crospovidone dans des proportions allant de 5 à 25% en poids de la phase etb) crospovidone in proportions ranging from 5 to 25% by weight of the phase and
- c) du carbomer dans des proportions allant de 5 à 40% en poids de la phase.- c) carbomer in proportions ranging from 5 to 40% by weight of the phase.
Alternativement, selon un autre objet de l'invention, la crospovidone peut être remplacée ou associée à un autre superdésintégrant tel que l'hydroxypropylcellulose faiblement substitué (L-HPC), le carboxyméthyl amidon sodique et/ou la croscarmellose sodique.Alternatively, according to another subject of the invention, crospovidone may be replaced or combined with another super-disintegrant such as low-substituted hydroxypropylcellulose (L-HPC), sodium carboxymethyl starch and / or croscarmellose sodium.
Le comprimé matriciel selon l'invention a pour avantage de gonfler très rapidement au contact des fluides gastriques. Effectivement, la présence des excipients a), b) et c) dans les proportions selon l'invention permet d'obtenir une synergie de gonflement. Le comprimé pourrait ainsi résider plusieurs heures au niveau de l'estomac. Lorsque le composé matriciel comprend au moins deux phases, une ou plusieurs des phases peut comprendre un principe actif. D'autre part, chaque phase peut avoir une composition identique ou différente en excipients d'une autre phase, étant entendu qu'au moins une des phases comprend les excipients a), b) et c) dans les proportions telles qu'indiquées selon l'invention. Lorsqu'une des phases ne comprend pas les excipients a), b) et c), chacun dans les proportions telles qu'indiquées selon l'invention, l'homme du métier pourra déterminer sa composition en fonction des besoins biopharmaceutiques, tels que contrôle de la libération du principe actif, augmentation du taux de gonflement.The matrix tablet according to the invention has the advantage of swelling very quickly in contact with gastric fluids. Indeed, the presence of excipients a), b) and c) in the proportions according to the invention makes it possible to obtain a synergy of swelling. The tablet could thus reside for several hours in the stomach. When the matrix compound comprises at least two phases, one or more of the phases may comprise an active ingredient. On the other hand, each phase may have an identical or different composition in excipients of another phase, it being understood that at least one of the phases comprises the excipients a), b) and c) in the proportions as indicated according to the invention. When one of the phases does not include the excipients a), b) and c), each in the proportions as indicated according to the invention, the skilled person can determine its composition according to the biopharmaceutical requirements, such as control release of the active ingredient, increased swelling rate.
Les excipients povidone et acétate de polyvinyle ou le mélange povidone/ acétate de polyvinyle se trouvent dans le commerce ou plus particulièrement le mélange est choisi parmi ceux commercialisés sous la dénomination Kollidon® SR.The povidone and polyvinyl acetate excipients or the povidone / polyvinyl acetate mixture are commercially available or, more particularly, the mixture is chosen from those sold under the name Kollidon® SR.
La povidone et/ou l'acétate de polyvinyle se trouvent en une quantité allant de 30 à 80% en poids de la phase le contenant et plus particulièrement de 30 à 65%.The povidone and / or the polyvinyl acetate are in an amount ranging from 30 to 80% by weight of the phase containing it and more particularly from 30 to 65%.
La crospovidone est un homopolymère réticulé de Λ/-vinyl-2-pyrrolidinone de poids moléculaire supérieur à 1 000 000DA. Ce polymère appartient à la catégorie des superdésintégrants, capables de capter rapidement et intensément le liquide environnant. A titre d'exemple, on peu citer la crospovidone vendue dans le commerce sous le nom de Kollidon® CL (BASF) ou Plasdone® XL (ISP) .Crospovidone is a crosslinked homopolymer of β-vinyl-2-pyrrolidinone of molecular weight greater than 1,000,000DA. This polymer belongs to the category of super-disintegrants, able to quickly and intensively capture the surrounding liquid. By way of example, mention may be made of crospovidone sold commercially under the name Kollidon® CL (BASF) or Plasdone® XL (ISP).
L'hydroxypropylcellulose est un hydroxypropyl ether de cellulose faiblement substitué, insoluble dans l'eau et les alcools mais capable de gonfler dans ces solvants. A titre d'exemple, on peut citer le grade L-HPC LH-11 fourni par Shin Etsu.Hydroxypropylcellulose is a low-substituted hydroxypropyl ether of cellulose, insoluble in water and alcohols but capable of swelling in these solvents. By way of example, mention may be made of the L-HPC LH-11 grade provided by Shin Etsu.
Le carboxyméthyl amidon sodique ou glycolate d'amidon sodique est le sel de sodium d'un ether carboxyméthylé d'amidon. Il en existe trois grades, A, B et C, qui différent par leur contenu en sodium. A titre d'exemple, on peut citer Ie glycolate d'amidon sodique vendu sous la dénomination commerciale Primojel® (Avebe) ou Explotab® (JRS Pharma).Sodium carboxymethyl starch or sodium starch glycolate is the sodium salt of a carboxymethyl starch ether. There are three grades, A, B and C, which differs in sodium content. By way of example, mention may be made of sodium starch glycolate sold under the trade name Primojel® (Avebe) or Explotab® (JRS Pharma).
La croscarmellose sodique est un polymère cellulosique obtenu par réticulation de la carmellose sodique. A titre d'exemple, on peut citer l'Ad-Di-Sol® (FMC). " Croscarmellose sodium is a cellulosic polymer obtained by crosslinking carmellose sodium. By way of example, mention may be made of Ad-Di-Sol® (FMC). "
La crospovidone ou les superdésintégrants, tels que hydroxypropylcellulose faiblement substituée, carboxyméthyl amidon sodique ou glycolate d'amidon sodique, croscarmellose sodique, se trouvent en une quantité allant de 5 à 25% en poids de la phase les contenant et plus particulièrement deCrospovidone or super-disintegrants, such as low-substituted hydroxypropylcellulose, sodium carboxymethyl starch or sodium starch glycolate, croscarmellose sodium, are present in an amount ranging from 5 to 25% by weight of the phase containing them and more particularly of
10% à 25%.10% to 25%.
Le carbomer est un polymère d'acide acrylique réticulé par un éther allylique de saccharose ou de pentaérythritol ayant un poids moléculaire très élevé (de l'ordre du million). A titre d'exemple, on peut citer le Carbopol® 974 ou le Carbopol® 71 G (NOVEON), plus particulièrement le Carbopol® 71 G qui permet d'obtenir des dispersions aqueuses ayant une viscosité comprise entre 4000 et 11000 cps (dispersion à 0,5%). Le carbomer se trouve dans le comprimé ou dans une phase dans des proportions en une quantité allant de 5 à 40% en poids respectivement du comprimé ou de la phase et plus particulièrement de 10 à 35%.The carbomer is a polymer of acrylic acid crosslinked with an allyl ether of sucrose or pentaerythritol having a very high molecular weight (of the order of one million). By way of example, mention may be made of Carbopol® 974 or Carbopol® 71G (NOVEON), more particularly Carbopol® 71G, which makes it possible to obtain aqueous dispersions having a viscosity of between 4000 and 11000 cps (dispersion at 0.5%). The carbomer is in the tablet or in a phase in proportions in an amount ranging from 5 to 40% by weight respectively of the tablet or the phase and more particularly from 10 to 35%.
Selon un autre objet de l'invention, les excipients a), b) et c) se trouvent respectivement dans des quantités de 40 à 70% pour la povidone et/ou l'acétate de polyvinyle, 10 à 20% pour la crospovidone et 10 à 30% pour le carbomer.According to another subject of the invention, the excipients a), b) and c) are respectively in amounts of 40 to 70% for povidone and / or polyvinyl acetate, 10 to 20% for crospovidone and 10 to 30% for the carbomer.
Le comprimé peut comprendre également tout excipient adéquat et nécessaire à la fabrication du comprimé, tel que :The tablet may also include any suitable excipient necessary for the manufacture of the tablet, such as:
- des diluants, solubles ou insolubles, (cellulose microcristalline, lactose, mannitol, phosphate dicalcique,...), plus particulièrement les diluants insolubles tels que la cellulose microcristalline, en une quantité allant de 5 à 30 % en poids de la phase le contenant ;soluble or insoluble diluents (microcrystalline cellulose, lactose, mannitol, dicalcium phosphate, etc.), more particularly the insoluble diluents such as microcrystalline cellulose, in an amount ranging from 5 to 30% by weight of the phase containing it;
- des lubrifiants (stéarate de magnésium, talc, huile de ricin hydrogénée, PEG 6000, béhénate de glycérol, acide stéarique,...) et - des agents d'écoulement (silice colloïdale, silice précipitée,...).lubricants (magnesium stearate, talc, hydrogenated castor oil, PEG 6000, glycerol behenate, stearic acid, etc.) and flow agents (colloidal silica, precipitated silica, etc.).
Les compositions pharmaceutiques selon l'invention peuvent par exemple être utiles pour les benzamides et les α1 -antagonistes, ainsi que les principes actifs suivants : le captopril, le furosémide, l'acide ursodesoxycholique, l'amoxicilline, le (+)-α-aminomethyl-2-methoxysulfonamidobenzèneméthanol (divulgue dans la demande de brevet EP 842 148 à l'exemple 3.6) ou le 3'- (2- amino1-hydroxyethyl)-4'-fluoromethanesulfonanilide (NS 49).The pharmaceutical compositions according to the invention may for example be useful for benzamides and α1 -antagonists, as well as the following active ingredients: captopril, furosemide, ursodesoxycholic acid, amoxicillin, (+) - α- aminomethyl-2-methoxysulfonamidobenzenemethanol (disclosed in patent application EP 842 148 to Example 3.6) or 3'- (2-amino-hydroxyethyl) -4'-fluoromethanesulfonanilide (NS 49).
Les benzamides sont en particulier le métoclopramide, le véralipride, l'alizapride, le clébopride et plus, particulièrement en l'amisulpride, le tiapride, le sulpiride et leurs sels.The benzamides are in particular metoclopramide, veralipride, alizapride, and clébopride, especially in amisulpride, tiapride, sulpiride and their salts.
Les α1 -antagonistes sont en particulier la térazosine et l'alfuzosine ainsi que leurs sels, en particulier le chlorhydrate d'alfuzosine. Ils sont destinés notamment au traitement de l'hypertrophie bénigne de la prostate.Α 1 -antagonists are in particular terazosin and alfuzosin and their salts, in particular alfuzosin hydrochloride. They are intended in particular for the treatment of benign prostatic hypertrophy.
Le captopril est utilisé notamment pour le traitement de l'hypertension, le furosémide comme diurétique, l'arnoxicilline et ses sels comme antibiotique, et l'acide ursodesoxycholique et ses sels est utilisé pour le traitement des cholélithiases, désordres hépatiques et syphilis.Captopril is used especially for the treatment of hypertension, furosemide as a diuretic, arnoxicillin and its salts as an antibiotic, and ursodesoxycholic acid and its salts is used for the treatment of cholelithiases, hepatic disorders and syphilis.
Au sens de la présente invention, les différents énantiomères ou diastéréoisomères des différents principes actifs ou familles de principes actifsFor the purposes of the present invention, the different enantiomers or diastereoisomers of the different active principles or families of active principles
(benzamides, α1 -antagonistes) sont également couverts, y compris leurs mélanges, en particulier leurs mélanges racémiques, mais également leurs sels. Parmi les principes actifs qui conviennent plus particulièrement aux compositions selon l'invention, on peut citer le (D)-tartrate d'amisulpride, le (S)- (-(Benzamides, α1-antagonists) are also covered, including their mixtures, in particular their racemic mixtures, but also their salts. Among the active ingredients which are more particularly suitable for the compositions according to the invention, mention may be made of amisulpride (D) -tartrate, (S) - (-)
)-amisulpride, le (D)-tartrate du (S)- (-)-amisulpride, le chlorhydrate de tiapride, le chlorhydrate d'alfuzosine et le chlorhydrate de 3'- (2-amino-1-hydroxyethyl)-4'- fluoromethanesulfonanilide.) -amisulpride, (S) - (-) - amisulpride (D) -tartrate, tiapride hydrochloride, alfuzosin hydrochloride and 3 '- (2-amino-1-hydroxyethyl) -4' hydrochloride fluoromethanesulfonanilide.
La quantité véhiculée de principe actif dans la composition pharmaceutique est en général de 0,1 mg à 200 mg.The amount of active ingredient in the pharmaceutical composition is generally from 0.1 mg to 200 mg.
Les comprimés de l'invention peuvent être produits par compression directe d'un mélange des poudres ou par granulation puis compression en utilisant les technologies de production habituelles. Le format de compression choisi peut être optimisé selon les connaissances générales de l'homme du métier.The tablets of the invention can be produced by direct compression of a mixture of powders or by granulation and compression using the usual production technologies. The chosen compression format can be optimized according to the general knowledge of the skilled person.
La force de compression de travail varie entre 500 DaN et 3000 DaN de manière à obtenir des comprimés présentant une résistance à la rupture qui permette de les manipuler et de les administrer sans problème (entre 80 et 300N pour des comprimés 10R10 mm, par exemple). On obtient, selon les procédés qui seront décrits d'une façon plus détaillée dans les exemples, des comprimés mono, ou à au moins deux phases ayant une forme qui permette une administration et une déglutition faciles.The working compression force varies between 500 DaN and 3000 DaN so as to obtain tablets with a tensile strength that allows them to be handled and administered without any problem (between 80 and 300N for 10R10 mm tablets, for example) . Obtained, according to the methods to be described in more detail in the examples, mono tablets, or at least two phases having a shape that allows easy administration and swallowing.
Selon la quantité de substance active qui est véhiculée, chaque phase du comprimé peut avoir une épaisseur différente allant de 1 à 8 mm, mais de préférence de 2 mm à 6 mm. Ces dimensions peuvent varier en fonction du format de compression.Depending on the amount of active substance that is conveyed, each phase of the tablet may have a different thickness ranging from 1 to 8 mm, but preferably from 2 mm to 6 mm. These dimensions may vary depending on the compression format.
A la préparation pharmaceutique on peut en outre appliquer un enrobage en matériaux polymériques ayant pour but une simple protection ou bien une modulation de la cinétique de libération du principe actif à partir de la matrice polymérique, selon des techniques biens connues de l'homme du métier. Les exemples qui suivent ont pour but d'illustrer l'invention.In addition to the pharmaceutical preparation, it is also possible to apply a coating of polymeric materials for the purpose of a simple protection or a modulation of the kinetics of release of the active principle from the polymeric matrix, according to techniques well known to those skilled in the art. . The following examples are intended to illustrate the invention.
Exemple 1 : Préparation d'un comprimé monocouche comprenant 10 mg de chlorhydrate d'alfuzosineExample 1 Preparation of a monolayer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication- Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une machine à comprimer alternative Forgerais OA.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression machine.
Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur Turbula®. Le mélange s'écoule librement et facilite le remplissage de la chambre de compression.Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® mixer. The mixture flows freely and facilitates the filling of the compression chamber.
Caractéristiques mélange et comprimésCharacteristics mixture and tablets
Ecoulement du mélange : < 10 secondes pour 100g de mélange. Dureté des comprimés : 100 Newtons. Masse des comprimés : 300 mg. Format des comprimés : 10R10 mm. Le taux de gonflement des comprimés est déterminé par mesure de l'épaisseur et du diamètre du comprimé sec et du comprimé resté quinze minutes en immersion dans du liquide gastrique à 37°C (0,01 M HCI + 0,1 M NaCI), et ce à l'aide d'un instrument de mesure adapté. Dans l'exemple décrit, le taux gonflement est de 80 % en épaisseur et 25 % en diamètre, soit environ 200% en volume.Flow of the mixture: <10 seconds per 100g of mixture. Hardness of the tablets: 100 Newtons. Mass of the tablets: 300 mg. Tablet size: 10R10 mm. The rate of swelling of the tablets is determined by measuring the thickness and the diameter of the dry tablet and the tablet which has been left for 15 minutes immersed in gastric liquid at 37 ° C. (0.01 M HCl + 0.1 M NaCl), and this using a suitable measuring instrument. In the example described, the swelling ratio is 80% by thickness and 25% by diameter, ie about 200% by volume.
Le profil de libération un principe actif dans le milieu gastrique (pH2 + 0,1 M NaCI) obtenu avec cette formulation est un profils d'ordre 0 soit : - 10 à 20% libérés en 1 heure.The release profile an active ingredient in the gastric medium (pH2 + 0.1 M NaCl) obtained with this formulation is a profile of order 0 is: - 10 to 20% released in 1 hour.
- 40 à 55% libérés en 6 heures.- 40 to 55% released in 6 hours.
- 65 à 85% en 12 heures.- 65 to 85% in 12 hours.
- 85 à 100% libérés en 20 heures.- 85 to 100% released in 20 hours.
Exemple 2 : Préparation d'un comprimé bi-couche comprenant 10 mg de chlorhydrate d'alfuzosineExample 2 Preparation of a two-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication- Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une machine à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur Turbula®. Le mélange s'écoule librement et facilite le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression machine. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® mixer. The mixture flows freely and facilitates the filling of the compression chamber.
Caractéristiques mélange et comprimésCharacteristics mixture and tablets
Ecoulement du mélange : < 10 secondes pour 100g de mélange. Dureté des comprimés : 125 Newtons. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of the mixture: <10 seconds per 100g of mixture. Hardness of the tablets: 125 Newtons. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 80 % en épaisseur et 30 % en diamètre, soit environ 300% en volume.The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 80% in thickness and 30% in diameter, ie about 300% by volume.
Le profil de libération un principe actif dans le milieu gastrique (pH2 + 0,1 M NaCI) obtenu avec cette formulation est un profils d'ordre 0 soit : - 10 à 20% libérés en 1 heure.The release profile an active ingredient in the gastric medium (pH2 + 0.1 M NaCl) obtained with this formulation is a profile of order 0 is: - 10 to 20% released in 1 hour.
- 40 à 55% libérés en 6 heures. - 65 à 85% en 12 heures.- 40 to 55% released in 6 hours. - 65 to 85% in 12 hours.
- 85 à 100% libérés en 20 heures. Exemple 3 : Préparation d'un comprimé bï-couche comprenant 10 mg de chlorhydrate d'alfuzosine- 85 to 100% released in 20 hours. Example 3 Preparation of a bi-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 130 N Masse des comprimés : 500 mg.Flow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 130 N Mass of the tablets: 500 mg.
Format des comprimés : 12R12 mm.Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 300% en volume. The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
Exemple 4 : Préparation d'un comprimé bi-couche de 500 mg comprenant 10 mg de chlorhydrate d'alfuzosineEXAMPLE 4 Preparation of a 500 mg two-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula ® inverting mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
Caractéristiques mélange et comprimésCharacteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 150N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 150N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment dans l'exemple 1. Dans cet exemple, le gonflement est 350 % en volume. The swelling rate of the tablets is determined by the method described above in Example 1. In this example, the swelling is 350% by volume.
Exemple 5 : Préparation d'un comprimé bi-couche de 500 mg comprenant 10 mg de chlorhydrate d'alfuzosineExample 5: Preparation of a 500 mg two-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement du mélange : < 10 secondes pour 100g de mélange. Dureté des comprimés : 150N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm. Le taux de gonflement des comprimés est déterminé par Ia méthode décrite précédemment. Dans cet exemple, le gonflement est de 360 % en volume. Flow of the mixture: <10 seconds per 100g of mixture. Hardness of the tablets: 150N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm. The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 360% by volume.
Exemple 6 : Préparation d'un comprimé bi-couche de 500 mg comprenant 10 mg de chlorhydrate d'alfuzosineExample 6 Preparation of a 500 mg two-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 140 N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 140 N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple,.. le_ gonflement- est de. 2Z0._% en volume. The swelling rate of the tablets is determined by the method described above. In this example, the swelling is. 2Z0 ._% by volume.
Exemple 7 : Préparation d'un comprimé bï-couche comprenant 10 mg de chlorhydrate d'alfuzosineExample 7 Preparation of a bi-layer tablet comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 150 N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 150 N. Weight of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 300 % en volume. The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
Exemple 8 : Préparation d'un comprimé bî-couche de 500 mg comprenant 10 mg de chlorhydrate d'alfuzosineEXAMPLE 8 Preparation of a 500 mg tablet with a layer comprising 10 mg of alfuzosin hydrochloride
- Procédé de fabrication - Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press.
- Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.- Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 150 N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 150 N. Weight of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 300 % en volume.The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 300% by volume.
Les exemples 9 et 10 suivants présentent des compositions de comprimés monocouches placebos. Ces compositions peuvent être utilisées comme couche placebo gonflante dans le cadre de la fabrication de comprimés multicouches. Il est possible aussi d'incorporer le principe actif dans ces compositions, par exemple à hauteur 10mg, afin d'obtenir une composition pharmaceutique selon l'invention. Exemple 9 : Préparation d'un comprimé mono-couche placebo de 500 mg.Examples 9 and 10 below show single-layer monosaccharide tablet compositions. These compositions can be used as a swelling placebo layer in the manufacture of multilayer tablets. It is also possible to incorporate the active ingredient in these compositions, for example at a height of 10 mg, in order to obtain a pharmaceutical composition according to the invention. Example 9: Preparation of a 500 mg monolayer placebo tablet.
- Procédé de fabrication- Manufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press.
Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.Beforehand, all the excipients are sieved (1 mm grid) then mixed using a Turbula® inverting mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement du mélange : < 10 secondes pour 100g de mélange. Dureté des comprimés : 140 N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of the mixture: <10 seconds per 100g of mixture. Hardness of the tablets: 140 N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 340 % en volume.The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 340% by volume.
Exemple 10 : Préparation d'un comprimé mono-couche placebo de 500 mg.Example 10: Preparation of a 500 mg monolayer placebo tablet.
Procédé de fabricationManufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
Caractéristiques mélange et comprimésCharacteristics mixture and tablets
Ecoulement du mélange : < 10 secondes pour 100g de mélange. Dureté des comprimés : 140 N. Masse des comprimés : 500 mg. Format des comprimés : 12R12 mm.Flow of the mixture: <10 seconds per 100g of mixture. Hardness of the tablets: 140 N. Mass of the tablets: 500 mg. Tablet size: 12R12 mm.
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 470 % en volume.The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 470% by volume.
Exemple 11 : Préparation d'un comprimé tri-couche de 700 mg contenant 10 mg de chlorhydrate d'alfuzosine.Example 11: Preparation of a tri-layer tablet of 700 mg containing 10 mg of alfuzosin hydrochloride.
Procédé de fabricationManufacturing process
Les comprimés décrits dans cet exemple sont obtenus par compression directe à l'aide d'une presse à comprimer alternative Forgerais OA. - Préalablement, tous les excipients sont tamisés (grille de 1 mm) puis mélangés à l'aide d'un mélangeur par retournement Turbula®. Le mélange s'écoule librement facilitant ainsi le remplissage de la chambre de compression.The tablets described in this example are obtained by direct compression using a Forgerais OA alternative compression press. - Beforehand, all the excipients are sieved (1 mm grid) and then mixed using a Turbula® inversion mixer. The mixture flows freely, thus facilitating the filling of the compression chamber.
- Caractéristiques mélange et comprimés- Characteristics mixture and tablets
Ecoulement des mélanges : < 10 secondes pour 100g de chaque mélange. Dureté des comprimés : 200 N. Masse des comprimés : 700 mg. Format des comprimés : 18*9R7 mmFlow of mixtures: <10 seconds per 100g of each mixture. Hardness of the tablets: 200 N. Weight of the tablets: 700 mg. Tablet size: 18 * 9R7 mm
Le taux de gonflement des comprimés est déterminé par la méthode décrite précédemment. Dans cet exemple, le gonflement est de 104% en épaisseur, 41% en largeur et 36% en longueur. The swelling rate of the tablets is determined by the method described above. In this example, the swelling is 104% in thickness, 41% in width and 36% in length.

Claims

REVENDICATIONS
1. Composition pharmaceutique sous forme d'un comprimé matriciel à résidence gastrique, comprenant un principe actif, caractérisée en ce qu'au contact avec un milieu représentatif du fluide gastrique , elle augmente en volume, après quinze minutes, d'un taux de gonflement d'au moins 200%.1. Pharmaceutical composition in the form of a gastric-residence matrix tablet, comprising an active ingredient, characterized in that in contact with a medium representative of the gastric fluid, it increases in volume, after fifteen minutes, of a swelling rate at least 200%.
2. Composition pharmaceutique sous forme d'un comprimé matriciel à résidence gastrique selon la revendication 1 comprenant une ou plusieurs phases.A pharmaceutical composition in the form of a gastric residence matrix tablet according to claim 1 comprising one or more phases.
3. Composition pharmaceutique sous forme d'un comprimé matriciel à résidence gastrique, selon la revendication 2, caractérisée en ce qu'au moins une des phases contient, au moins, en tant qu'excipients:3. Pharmaceutical composition in the form of a gastric residence matrix tablet according to claim 2, characterized in that at least one of the phases contains, at least, as excipients:
- a) de la povidone et/ ou acétate de polyvinyle dans des proportions allant de 30 à 80% en poids de la phase,a) povidone and / or polyvinyl acetate in proportions ranging from 30 to 80% by weight of the phase,
- b) de la crospovidone dans des proportions allant de 5 à 25% en poids de la phase et - c) du carbomer dans des proportions allant de 5 à 40% en poids de la phase.- b) crospovidone in proportions ranging from 5 to 25% by weight of the phase and - c) carbomer in proportions ranging from 5 to 40% by weight of the phase.
4. Composition pharmaceutique sous forme d'un comprimé matriciel, selon là revendication 3 caractérisée en ce que la povidone et/ou acétate de polyvinyle se trouve dans des proportions allant de 30 à 65% en poids de la composition pharmaceutique.4. Pharmaceutical composition in the form of a matrix tablet, according to claim 3 characterized in that the povidone and / or polyvinyl acetate is in proportions ranging from 30 to 65% by weight of the pharmaceutical composition.
5. Composition pharmaceutique sous forme d'un comprimé matriciel comprenant un principe actif, selon la revendication 3 ou 4 caractérisée en ce que la crospovidone se trouve dans des proportions allant de 10 à 25% en poids de la composition pharmaceutique. 5. Pharmaceutical composition in the form of a matrix tablet comprising an active ingredient, according to claim 3 or 4 characterized in that the crospovidone is in proportions ranging from 10 to 25% by weight of the pharmaceutical composition.
6. Composition pharmaceutique sous forme d'un comprimé matriciel, selon la revendication 3, 4 ou 5 caractérisée en ce que le carbomer se trouve dans des proportions allant de 10 à 35% en poids de la composition pharmaceutique.6. Pharmaceutical composition in the form of a matrix tablet according to claim 3, 4 or 5 characterized in that the carbomer is in proportions ranging from 10 to 35% by weight of the pharmaceutical composition.
7. Composition pharmaceutique sous forme d'un comprimé matriciel, selon la revendication 3 ou 5 caractérisée en que ce que la crospovidone est remplacée ou associée à d'autres superdésintégrants choisis parmi l'hydroxypropylcellulose faiblement substitué (L-HPC), le carboxyméthyl amidon sodique et/ou la croscarmellose sodique.7. Pharmaceutical composition in the form of a matrix tablet, according to claim 3 or 5 characterized in that crospovidone is replaced or combined with other super-disintegrants selected from low-substituted hydroxypropylcellulose (L-HPC), carboxymethyl starch sodium and / or croscarmellose sodium.
8. Composition pharmaceutique sous forme d'un comprimé matriciel, selon l'une quelconque des revendications 1 à 7 caractérisée en ce qu'elle contient un diluant en une quantité de 5 à 30%.8. Pharmaceutical composition in the form of a tablet according to any one of claims 1 to 7, characterized in that it contains a diluent in an amount of 5 to 30%.
9. Composition pharmaceutique sous forme d'un comprimé matriciel, selon l'une quelconque des revendications 1 à 8 caractérisée en ce que le principe actif peut être choisi parmi les benzamides, les α1 -antagonistes, le captopril, le furosémide, l'acide ursodesoxycholique, l'amoxicilline, le (+)-α-aminomethyl-2- methoxysulfonamidobenzèneméthanol et le 3'-(2-amino1-hydroxyethyl)-4'- fluoromethanesulfonanilide.9. Pharmaceutical composition in the form of a matrix tablet, according to any one of claims 1 to 8 characterized in that the active ingredient can be selected from benzamides, α1-antagonists, captopril, furosemide, acid ursodesoxycholic, amoxicillin, (+) - α-aminomethyl-2-methoxysulfonamidobenzenemethanol and 3 '- (2-amino-hydroxyethyl) -4'-fluoromethanesulfonanilide.
10. Composition pharmaceutique sous forme d'un comprimé matriciel, selon la revendication 9 caractérisée en ce que le principe actif est le chlorhydrate d'alfuzosine.10. Pharmaceutical composition in the form of a matrix tablet according to claim 9, characterized in that the active ingredient is alfuzosin hydrochloride.
11. Composition pharmaceutique sous forme d'un comprimé matriciel, selon la revendication 9 ou 10 caractérisée en ce que le principe actif se trouve en une quantité allant de 0,1 mg à 200mg.11. Pharmaceutical composition in the form of a matrix tablet according to claim 9 or 10 characterized in that the active ingredient is in an amount ranging from 0.1 mg to 200 mg.
12. Composition pharmaceutique sous forme d'un comprimé matriciel, selon l'une quelconque des revendications 1 à 11 caractérisée en ce que le comprimé matriciel se présente sous forme d'un comprimé matriciel bi-couche comprenant deux phases.12. Pharmaceutical composition in the form of a matrix tablet according to any one of Claims 1 to 11, characterized in that the matrix tablet is in the form of a two-layer matrix tablet. comprising two phases.
13. Composition pharmaceutique sous forme d'un comprimé matriciel, selon l'une quelconque des revendications 1 à 11 caractérisée en ce que Ia composition centésimale est la suivante:13. Pharmaceutical composition in the form of a matrix tablet, according to any one of claims 1 to 11, characterized in that the percentage composition is as follows:
14. Composition pharmaceutique sous forme d'un comprimé matriciel, selon la revendication 12 caractérisée en ce que la composition centésimale est la suivante:14. Pharmaceutical composition in the form of a matrix tablet, according to claim 12, characterized in that the percentage composition is as follows:
Et And
15. Composition pharmaceutique sous forme d'un comprimé matriciel, selon l'une quelconque des revendications 1 à 11 caractérisée en ce que la composition centésimale est la suivante:15. Pharmaceutical composition in the form of a matrix tablet, according to any one of claims 1 to 11, characterized in that the percentage composition is as follows:
Et And
etand
EP05798249A 2004-08-19 2005-08-17 Pharmaceutical composition in the form of a gastric-resident tablet containing an active principle Withdrawn EP1781295A1 (en)

Applications Claiming Priority (2)

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FR0408986A FR2874325B1 (en) 2004-08-19 2004-08-19 PHARMACEUTICAL COMPOSITION IN THE FORM OF A GASTRIC RESISTANCE COMPRESSOR CONTAINING ALFUZOSIN
PCT/FR2005/002092 WO2006021692A1 (en) 2004-08-19 2005-08-17 Pharmaceutical composition in the form of a gastric-resident tablet containing an active principle

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IL181150A0 (en) 2007-07-04
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AU2005276307B2 (en) 2011-02-24
CN101022808B (en) 2013-05-29
JP5048492B2 (en) 2012-10-17
WO2006021692A8 (en) 2007-04-12
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US20070190140A1 (en) 2007-08-16
AU2005276307A1 (en) 2006-03-02
MX2007001957A (en) 2007-04-25
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WO2006021692A1 (en) 2006-03-02
HK1112575A1 (en) 2008-09-12
MA28862B1 (en) 2007-09-03
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