EP0305464A1 - New pharmaceutical compositions for the buccal tract, and process for their preparation - Google Patents

New pharmaceutical compositions for the buccal tract, and process for their preparation

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Publication number
EP0305464A1
EP0305464A1 EP88902497A EP88902497A EP0305464A1 EP 0305464 A1 EP0305464 A1 EP 0305464A1 EP 88902497 A EP88902497 A EP 88902497A EP 88902497 A EP88902497 A EP 88902497A EP 0305464 A1 EP0305464 A1 EP 0305464A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical compositions
lysine acetylsalicylate
composition according
diluents
pharmaceutical composition
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
EP88902497A
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German (de)
French (fr)
Inventor
Jérôme CORBIERE
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Individual
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Individual
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Publication of EP0305464A1 publication Critical patent/EP0305464A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums

Definitions

  • the present invention relates to novel pharmaceutical compositions for suppressing pain and hyperthermia and a method for preparing them.
  • analgesic and antipyretic pharmaceutical compositions intended to be sucked or to be chewed and the disintegration of which is prolonged.
  • compositions intended for the oral route in the form of tablets or sucking tablets or chewing gums, characterized in that they contain, as active ingredient, lysine etylsalicylate in combination or in mixture with one or more excipients or diluents suitable for producing a pharmaceutical form capable of being sucked or chewed.
  • the pharmaceutical compositions according to the invention are in the form of tablets or tablets, the disintegration of which in the oral cavity is progressive and prolonged.
  • buffering agents such as for example urea or glycine, non-reactive flavoring and bulking agents such as mannitol or sorbitol, adhesion agents with low dissolution rate such as alkylcelluloses, for example methyl cellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose, or copolymers of acrylic acid or methacrylic acid, binding agents such as polyvinyl-pyrrolidone, gum arabic, guar, adraganth or karaya, inert diluents such as lactose, calcium carbonate, phosphate magnesium or calcium sulfate, skim milk powder, sodium caseinate, sweetening agents such as calcium saccharinate, ammonium cyclamate, ammonium glycyrrhizinate or aspartame, lubricating agents such as magnesium stea
  • the active ingredient is lysine acetylsalicylate. It can be DL-lysine acetylsalicylate or L-lysine or D-lysine acetylsalicylate. Preferably, the product used is DL-lysine or L-lysine acetylsalicylate.
  • Lysine acetylsalicylate is presented as a fine white, hygroscopic crystalline powder, easily soluble in water, very slightly soluble in alcohol and in ether.
  • DL-lysine acetylsalicylate melts at around 199 ° C (instant melting).
  • lysine mono-acetylsalicylate described in French patent 1,295,304 has a melting point determined in the Maquenne block of 154-166 °. It is a fairly unstable active principle which combines in its olecule a weak acid easily hydrolyzed and a basic amino acid capable of causing undesirable chemical reactions.
  • compositions of a buffering agent such as glycine which is able to avoid hydrolysis reactions of the acetyl group. It has actually been found that compression of lysine acetylsalicylate tablets without a buffering agent leads to the formation of -N-acetyllysine, of -N-acetyllysine and -diacetyllysine. This reaction is of the autocatalytic type. The presence of a buffering agent is likely to avoid or to stop this reaction.
  • a buffering agent such as glycine
  • lysine carries the risk of a Maillard reaction with sugars present in the formulation leading to strongly colored products, most often brown. It is therefore necessary to carry out the formulation without the addition of reducing sugars such as glucose, capable of reacting with lysine and of replacing them either with non-reducing sugars, that is to say, having no free aldehyde function. , or by glucitols such as inositol, mannit ⁇ l, sorbitol or dulatol which are not liable to react with the amino function of lysine.
  • the pharmaceutical compositions according to the invention are intended to produce a form which gradually releases this active principle in the oral cavity where it is almost completely absorbed. A more effective antipyretic and analgesic pharmaceutical form is thus produced, since it ensures higher measured salicylic acid blood levels than by the usual compositions.
  • the pharmaceutical compositions according to the invention contain a quantity of lysine acetylsali cylate calculated as acetylsalicylic acid varying from 200 to 600 mg per unit dose, ie from 360 to 1080 mg of lysine acetylsalicylate.
  • the dose of lysine acetylsalicylate calculated as acetylsalicylic acid varies from 250 to 500 mg, or 630 mg to 810 mg of lysine acetylsalicylate.
  • the invention also relates to a process for preparing the pharmaceutical compositions according to the invention in which the active principle is mixed or combined with one or more diluents, excipients, adhesion agents, buffering agents, bulking agents, lubricating agents and / or flavoring agents for producing a pharmaceutical form capable of being chewed, such as tablets, tablets or gums.
  • This preparation is carried out according to the usual methods of pharmacotechnology.
  • sorbitol for direct compression marketed under the name NEOSORB 60 .. 660 g
  • Palatinite is the trademark to designate an equi mixture of isomers of -D-glucopyranosi to 1,6 mannitol and -D-glucopyranosi to 1,6-glucitol crystallized with 2 molecules of ea.
  • EXAMPLE II SUGAR TABLETS
  • polyvinylpyrrolidone of PM greater than 30,000 ........ briefly 20 g
  • hydroxypropylcellulose having a determined viscosity at 20 ° C.
  • a 2% aqueous solution of 2,080 centipoises and a particle diameter of less than 0.25 mm 15 g of a copolymer of acrylic acid sold on the market under the brand Carbopol 934 (product essentially consisting of a copolymer of acrylic acid and allylsaccharose), 110 g of tricalcium phosphate, 140 g of palatinite and 725 g of acetylsali cylys lysine.
  • 5 g of magnesium stearate and 15 g of talc and mint essence are added.
  • the powder is sieved and then compressed by direct compression into tablets having a diameter of 10 mm, a thickness of 1.1 mm, a weight of approximately 1,100 mg and a hardness of 5.6 kg.
  • the amount of lysine acetylsalicylate increases with contact time in a quasi-linear fashion.
  • Salicylemia is determined on a batch of healthy volunteers absorbing a solution prepared with 900 mg of commercial lysine acetylsalicylate dissolved in 90 ml of water. Each subject maintains the solution for 4 minutes in his oral cavity. The dosage of lasalicylemia is practiced ten minutes later. It shows a rate of 4 mg / l. This rate is therefore very low.
  • the determination of salicylemia is practiced after ingestion of the tablets according to the invention. Subjects keep the tablets in the mouth for 4 minutes. Salicylemia is determined ten minutes and then 30 minutes after administration. The values obtained are more than ten times higher than those obtained after injection of the lysine acetylsalicylate solution.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention se rapporte au domaine de la chimie pharmaceutique et plus précisément au domaine de la pharmacie galénique. Elle a pour objet de nouvelles compositions pharmaceutiques destinées à la voie buccale dont le principe actif est l'acétylsalicylate de lysine, en association ou en mélange avec un ou plusieurs excipients et/ou diluants adaptés pour réaliser une forme pharmaceutique apte à être sucée ou mâchée. L'invention concerne également un procédé de préparation des compositions pharmaceutiques selon l'invention.The invention relates to the field of pharmaceutical chemistry and more specifically to the field of galenic pharmacy. It relates to new pharmaceutical compositions intended for the oral route, the active principle of which is lysine acetylsalicylate, in association or in admixture with one or more excipients and / or diluents suitable for producing a pharmaceutical form suitable for being sucked or chewed. . The invention also relates to a process for preparing the pharmaceutical compositions according to the invention.

Description

NOUVELLES COMPOSITIONS PHARMACEUTIQUES POUR LA VOIE BUCCALE ET LEUR PROCEDE DE PREPARATION NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE AND THEIR PREPARATION METHOD
La présente invention concerne de nouvelles compositions pharmaceutiques destinées à supprimer la douleur et l'hyperthermie ainsi qu'un procédé pour les préparer.The present invention relates to novel pharmaceutical compositions for suppressing pain and hyperthermia and a method for preparing them.
Elle a plus particulièrement pour objet, des compositions pharmaceutiques antalgiques et antipyrétiques destinées à être sucées ou à être mâchées et dont le délitement est prolongé.More particularly, it relates to analgesic and antipyretic pharmaceutical compositions intended to be sucked or to be chewed and the disintegration of which is prolonged.
Elle a spécifiquement pour objet des compositions pharmaceutiques destinées à la voie buccale, sous forme de comprimés ou de tablettes à sucer ou de gommes à mâcher, caractérisées en ce qu'elles renferment à titre de principe actif de l'a'étylsalicylate de lysine en association ou en mélange avec un ou plusieurs excipients ou diluants adaptés pour réaliser une forme pharmaceutique apte à être sucée ou mâchée.It specifically relates to pharmaceutical compositions intended for the oral route, in the form of tablets or sucking tablets or chewing gums, characterized in that they contain, as active ingredient, lysine etylsalicylate in combination or in mixture with one or more excipients or diluents suitable for producing a pharmaceutical form capable of being sucked or chewed.
D'une manière préférée, les compositions pharmaceutiques selon l'invention se présentent sous forme de comprimés ou de tablettes dont le délitement dans la cavité buccale est progressif et prolongé.Preferably, the pharmaceutical compositions according to the invention are in the form of tablets or tablets, the disintegration of which in the oral cavity is progressive and prolonged.
Parmi les excipients ou diluants appropriés, on citera particulièrement des agents tampons comme par exemple l'urée ou la glycine, des agents de sapidité et de charge non réactifs comme le mannitol ou le sorbitol, des agents d'adhésion à faible vitesse de dissolution comme les alcoyl-celluloses par exemple la méthyl-cellulose l'éthylcellulose, l'hydroxy propylcellulose, l'hydroxypropyl méthylcellulose ou la carboxyméthyl cellulose, ou les copolymères d'acide acrylique ou d'acide méthacryli que, des agents liants comme la polyvinyl-pyrrolidone, les gommes arabique, guar, adraganth ou karaya, des diluants inertes comme le lactose, le carbonate de calcium, le phosphate de magnésium ou le sulfat de calcium, la poudre de lait écrémé, le caséinate de sodium, des agents édulcorants comme le saccharinate de calcium, le cyclamate d'ammonium, le glycyrrhizinate d'ammonium ou l'aspartam, des agents de lubrification tels que stéarate de magnésium, ou des agents aromatisants comme le furanéol, le maltol, l'isomaltol, la vanilline, 1 'éthylvanilline ou des arômes naturels sur un support inerte tel que silice, lactose ou gomme arabique, des agents colorants comme le jaune naphtol ou l'érythrσsine.Among the suitable excipients or diluents, particular mention will be made of buffering agents such as for example urea or glycine, non-reactive flavoring and bulking agents such as mannitol or sorbitol, adhesion agents with low dissolution rate such as alkylcelluloses, for example methyl cellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose, or copolymers of acrylic acid or methacrylic acid, binding agents such as polyvinyl-pyrrolidone, gum arabic, guar, adraganth or karaya, inert diluents such as lactose, calcium carbonate, phosphate magnesium or calcium sulfate, skim milk powder, sodium caseinate, sweetening agents such as calcium saccharinate, ammonium cyclamate, ammonium glycyrrhizinate or aspartame, lubricating agents such as magnesium stearate, or flavoring agents such as furaneol, maltol, isomaltol, vanillin, ethylvanillin or natural flavors on an inert support such as silica, lactose or gum arabic, coloring agents such as naphthol yellow or erythrσsine.
Le principe actif est l'acétylsalicylate de lysine. Il peut s'agir de l'acétylsalicylate de DL-lysine ou de l'acétylsalîcylate de L-lysine ou de D-lysine. De préférence, le produit utilisé est l'acétylsalicylate de DL-lysine ou de L-lysine.The active ingredient is lysine acetylsalicylate. It can be DL-lysine acetylsalicylate or L-lysine or D-lysine acetylsalicylate. Preferably, the product used is DL-lysine or L-lysine acetylsalicylate.
C'est un principe actif connu, déjà utilisé sous forme de sachets, de poudres, aisément soluble dans l'eau et pratiquement dénué de saveur à l'état dilué.It is a known active ingredient, already used in the form of sachets, powders, easily soluble in water and practically devoid of flavor in a diluted state.
L'acétylsalicylate de lysine se présente comme une fine poudre cristalline blanche, hygroscopique, facilement soluble dans l'eau, très peu soluble dans l'alcool et dans l'éther.Lysine acetylsalicylate is presented as a fine white, hygroscopic crystalline powder, easily soluble in water, very slightly soluble in alcohol and in ether.
L'acétylsalicylate de DL-lysine fond vers 199°C (fusion instantanée).DL-lysine acetylsalicylate melts at around 199 ° C (instant melting).
Au contraire, le produit dénommé mono-acétylsalicylate de lysine décrit dans le brevet français 1.295.304 possède un point de fusion déterminé au bloc Maquenne de 154-166°. C'est un principe actif assez instable qui associe dans sa olécule un acide faible facilement hydrolyse et un aminno- acide basique susceptible d'amener des réactions chimiques indésirâbles.On the contrary, the product called lysine mono-acetylsalicylate described in French patent 1,295,304 has a melting point determined in the Maquenne block of 154-166 °. It is a fairly unstable active principle which combines in its olecule a weak acid easily hydrolyzed and a basic amino acid capable of causing undesirable chemical reactions.
En particulier, il est nécessaire d'additionner les compositions d'un agent tampon comme la glycine qui est à même d'éviter les réactions d'hydrolyse du groupe acétyle. Il a été effectivement constaté que la compression de comprimés d'acétylsalicylate de lysine sans agent tampon conduit à la formation de -N-acétyllysine, d' -N-acétyllysine et de -diacetyllysine. Cette réaction est du type autocatalytique. La présence d'un agent tampon est de nature à éviter ou à arrêter cette réaction.In particular, it is necessary to add the compositions of a buffering agent such as glycine which is able to avoid hydrolysis reactions of the acetyl group. It has actually been found that compression of lysine acetylsalicylate tablets without a buffering agent leads to the formation of -N-acetyllysine, of -N-acetyllysine and -diacetyllysine. This reaction is of the autocatalytic type. The presence of a buffering agent is likely to avoid or to stop this reaction.
En outre, la présence de lysine comporte le risque de réa tion de Maillard avec des sucres présents dans' la formulation conduisant à des produits fortement colorés le plus souvent bruns. Il est donc nécessaire de réaliser la formulation sans adjonction de sucres réducteurs tels que glucose, susceptibles de réagir avec la lysine et de les remplacer soit par des sucres non réducteurs, c'est-à-dire, n'ayant pas de fonction aldéhyde libre, soit par des glucitols tels que l'inositol, le mannitαl, le sorbitol ou le dulatol qui ne sont pas susceptibles de réagir avec la fonction aminée de la lysine.In addition, the presence of lysine carries the risk of a Maillard reaction with sugars present in the formulation leading to strongly colored products, most often brown. It is therefore necessary to carry out the formulation without the addition of reducing sugars such as glucose, capable of reacting with lysine and of replacing them either with non-reducing sugars, that is to say, having no free aldehyde function. , or by glucitols such as inositol, mannitαl, sorbitol or dulatol which are not liable to react with the amino function of lysine.
Les compositions pharmaceutiques selon l'invention sont destinées à réaliser une forme libérant progressivement ce principe actif dans la cavité buccale où il est presque totalement résorbé. On réalise ainsi une forme pharmaceutiq antipyrétique et antalgique plus efficace, car assurant des taux sanguins mesurés en acide salicylique plus élevés que par les compositions usuelles. Les compositions pharmaceutiques selon l'invention renferment une quantité d'acétylsali cylate de lysine calculée en acide acétylsalicylique variant de 200 à 600 mg par prise unitaire, soit de 360 à 1 080 mg d'acétylsalicylate de lysine. D'une manière préférée, la dose d'acétylsalicylate de lysine calculée en acide acétylsalicylique varie de 250 à 500 mg, soit 630 mg à 810 mg d'acétylsalicylate de lysine.The pharmaceutical compositions according to the invention are intended to produce a form which gradually releases this active principle in the oral cavity where it is almost completely absorbed. A more effective antipyretic and analgesic pharmaceutical form is thus produced, since it ensures higher measured salicylic acid blood levels than by the usual compositions. The pharmaceutical compositions according to the invention contain a quantity of lysine acetylsali cylate calculated as acetylsalicylic acid varying from 200 to 600 mg per unit dose, ie from 360 to 1080 mg of lysine acetylsalicylate. Preferably, the dose of lysine acetylsalicylate calculated as acetylsalicylic acid varies from 250 to 500 mg, or 630 mg to 810 mg of lysine acetylsalicylate.
L'invention concerne également un procédé de préparation des compositions pharmaceutiques selon l'invention dans lequel on mélange ou associe le principe actif à un ou plusieurs diluants, excipients, agents d'adhésion, agents tampons, agents de charge, agents de lubrification et/ou agents d'aromatisation pour réaliser une forme pharmaceutique apte à être sucée au mâchée telle que comprimés, tablettes ou gommes. Cette préparation est effectuée selon les méthodes usuelles de la pharmacotechnie.The invention also relates to a process for preparing the pharmaceutical compositions according to the invention in which the active principle is mixed or combined with one or more diluents, excipients, adhesion agents, buffering agents, bulking agents, lubricating agents and / or flavoring agents for producing a pharmaceutical form capable of being chewed, such as tablets, tablets or gums. This preparation is carried out according to the usual methods of pharmacotechnology.
Les exemples suivants illustrent l'invention sans toutefois la limiter.The following examples illustrate the invention without, however, limiting it.
EXEMPLE IEXAMPLE I
COMPRIMES A SUCERSUGAR TABLETS
. acétylsalicylate de DL-lysine .... 720 g. DL-lysine acetylsalicylate .... 720 g
. glycine .......................... 80 g. wisteria .......................... 80 g
. sorbitol pour compression directe commercialisé sous la dénomination NEOSORB 60 .. 660 g. sorbitol for direct compression marketed under the name NEOSORB 60 .. 660 g
. palatinite ....................... 259 g. palatinite ....................... 259 g
. stéarate de magnésium ............ 45 g. magnesium stearate ............ 45 g
. aspartam ......................... 42 g. aspartame ......................... 42 g
pour 1.000 comprimés terminés au poids moyen .de 2,80 g.for 1,000 finished tablets at an average weight of 2.80 g.
Palatinite est la marque déposée pour désigner un mélang equi mαléculai re d'isomère de -D-glucopyranosi to 1,6 mannitol et de -D-glucopyranosi to 1,6-glucitol cristallis avec 2 molécules d ' ea . EXEMPLE II COMPRIMES A SUCERPalatinite is the trademark to designate an equi mixture of isomers of -D-glucopyranosi to 1,6 mannitol and -D-glucopyranosi to 1,6-glucitol crystallized with 2 molecules of ea. EXAMPLE II SUGAR TABLETS
. acétylsalicylate de DL-lysine ... 810 g. DL-lysine acetylsalicylate ... 810 g
. glycine ..................... .... 36 g. wisteria ..................... .... 36 g
. éthylcellulose 145 g. ethylcellulose 145 g
. phosphate de magnésium pour compress i on directe ......................... 2.050 g. magnesium phosphate for direct compression ......................... 2.050 g
. polyvinylpyrrolidone de PM supérieure à 30.000 ........................ 20 g. polyvinylpyrrolidone of PM greater than 30,000 ........................ 20 g
. stéarate de magnésium ........... 25 g. magnesium stearate ........... 25 g
. talc ............................ 25 g. talc ............................ 25 g
. saccharinate de calcium ......... 1 g. calcium saccharinate ......... 1 g
. arôme orange .................... q.s. orange flavor .................... q.s
pour 1.000 comprimés terminés au poids moyen de 3„10 g.per 1,000 finished tablets at an average weight of 3 „10 g.
EXEMPLE III GOMME A MACHEREXAMPLE III CHEWING GUM
On mélange soigneusement 85 g d'hydroxypropylcellulose, ayant une viscosité déterminée à 20°C sur une solution aqueuse à 2% de 2.080 centipoises et un diamètre de particules inférieur à 0,25 mm, 15 g d'un copolymère d'acide acrylique commercialisé sous la marque Carbopol 934 (produit constitué essentiellement d'un copolymère d'acide acrylique et d'allylsaccharose), 110 g de phosphate tricalcique, 140 g de palatinite et 725 g d'acétylsali cylate de lysine. Une fois le mélange parfait ment homogène, on ajoute 5 g de stéarate de magnésium et 15 g de talc et de l'essence de menthe. La poudre est tamisée puis comprimée par compression directe en comprimés ayant un diamètre de 10 mm, une épaisseur de 1,1 mm, un poids de 1.100 mg environ et une dureté de 5,6 kg.85 g of hydroxypropylcellulose, having a determined viscosity at 20 ° C., are carefully mixed with a 2% aqueous solution of 2,080 centipoises and a particle diameter of less than 0.25 mm, 15 g of a copolymer of acrylic acid sold on the market under the brand Carbopol 934 (product essentially consisting of a copolymer of acrylic acid and allylsaccharose), 110 g of tricalcium phosphate, 140 g of palatinite and 725 g of acetylsali cylys lysine. Once the mixture is perfectly homogeneous, 5 g of magnesium stearate and 15 g of talc and mint essence are added. The powder is sieved and then compressed by direct compression into tablets having a diameter of 10 mm, a thickness of 1.1 mm, a weight of approximately 1,100 mg and a hardness of 5.6 kg.
Ces comprimés présentent une bonne stabilité géométrique. Ils gonflent en prenant une forme expansée pratiquement semblable à celle du comprimé de départ. Ils libèrent progressivement et complètement le principe actif par contact avec la salive.These tablets have good geometric stability. They swell to a virtually similar expanded form to that of the starting tablet. They gradually and completely release the active ingredient by contact with saliva.
La quantité d'acétylsalicylate de lysine augmente avec le temps de contact d'une manière quasi-linéaire.The amount of lysine acetylsalicylate increases with contact time in a quasi-linear fashion.
EXEMPLE IVEXAMPLE IV
DETERMINATION DE LA BIODISPONIBILITE DES COMPOSITIONS SELONDETERMINATION OF THE BIOAVAILABILITY OF THE COMPOSITIONS ACCORDING TO
L'INVENTIONTHE INVENTION
On détermine la salicylémie sur un lot de sujets sains volontaires absorbant une solution préparée avec 900 mg d'acétylsalicylate de lysine du commerce dissous dans 90 ml d'eau. Chaque sujet maintient pendant 4 minutes, dans sa cavité buccale, la solution. Le dosage de lasalicylémie est pratiqué dix minutes plus tard. Il montre un taux de 4 mg/l. Ce taux est donc très faible.Salicylemia is determined on a batch of healthy volunteers absorbing a solution prepared with 900 mg of commercial lysine acetylsalicylate dissolved in 90 ml of water. Each subject maintains the solution for 4 minutes in his oral cavity. The dosage of lasalicylemia is practiced ten minutes later. It shows a rate of 4 mg / l. This rate is therefore very low.
Sur les mêmes sujets, on pratique la détermination de la salicylémie après ingestion des comprimés selon l'invention. Les sujets gardent les comprimés en bouche pendant 4 minutes. La salicylémie est déterminée dix minutes puis 30 minute après administration. Les valeurs obtenues sont plus de dix fois supérieures à celles obtenues après injection de la solution d'acétylsalicylate de lysine. On the same subjects, the determination of salicylemia is practiced after ingestion of the tablets according to the invention. Subjects keep the tablets in the mouth for 4 minutes. Salicylemia is determined ten minutes and then 30 minutes after administration. The values obtained are more than ten times higher than those obtained after injection of the lysine acetylsalicylate solution.

Claims

R E V E N D I C A T I O N SL'invention a pour objet : CLAIMS The object of the invention is:
1. Des compositions pharmaceutiques destinées à la voie buccale, caractérisées en ce qu'elles renferment à titre de principe actif de l'acétylsalicylate de lysine en association ou en mélange avec un ou plusieurs excipients ou diluants adaptés à la réalisation d'une forme pharmaceutique apte à être sucée ou mâchée.1. Pharmaceutical compositions intended for the oral route, characterized in that they contain, as active principle, lysine acetylsalicylate in association or in mixture with one or more excipients or diluents suitable for the production of a pharmaceutical form suitable for sucking or chewing.
2. Une composition pharmaceutique selon la revendication dans laquelle le principe actif est l'acétylsalicylate DL-lysine.2. A pharmaceutical composition according to claim in which the active ingredient is DL-lysine acetylsalicylate.
3. Une composition pharmaceutique selon la revendication 1, dans laquelle les excipients ou les diluants sont de ceux qui conviennent pour la réalisation de tablettes ou de comprimés à sucer.3. A pharmaceutical composition according to claim 1, in which the excipients or diluents are those which are suitable for the production of lozenges or lozenges.
4. Une composition pharmaceutique selon la revendication 1, dans laquelle les excipients ou les diluants sont de ce qui conviennent pour la réalisation de gommes à mâcher.4. A pharmaceutical composition according to claim 1, wherein the excipients or diluents are of what are suitable for the production of chewing gum.
5. Une composition pharmaceutique selon la revendication 1 , dans laquelle les diluants sont formés d'un ou plusieurs agents tampons et d'un ou plusieurs agents de sapidité non réactifs.5. A pharmaceutical composition according to claim 1, wherein the diluents are formed of one or more buffering agents and one or more non-reactive flavoring agents.
6. Une composition pharmaceutique selon l'une des revendic tions 1 à 4, dans laquelle la teneur en principe act varie de 360 mg à 1.080 mg, exprimée en acétylsalicylate de lysine. 6. A pharmaceutical composition according to one of claims 1 to 4, in which the content of act principle varies from 360 mg to 1,080 mg, expressed as lysine acetylsalicylate.
7. Une composition pharmaceutique selon l'une des revendications 1 à 5, dans laquelle la teneur en principe actif varie de 630 à 81G mg, exprimée en acétylsalicylate de lysine par prise unitaire.7. A pharmaceutical composition according to one of claims 1 to 5, in which the content of active principle varies from 630 to 81G mg, expressed as lysine acetylsalicylate per unit dose.
8. Un procédé d'obtention de compositions pharmaceutiques destinées à la voie buccale selon l'une des revendications 1 à 6, caractérisé en ce qu'on mélange ou associe de l'acétylsalicylate de lysine avec un ou plusieurs agents tampons, des agents d'adhésion, des agents liants, des diluants inertes et/ou des agents d'aromatisatiαn.8. A process for obtaining pharmaceutical compositions intended for the oral route according to one of claims 1 to 6, characterized in that one mixes or associates lysine acetylsalicylate with one or more buffering agents, adhesion, binding agents, inert diluents and / or flavoring agents.
9. Utilisation de l'acétylsalicylate de lysine en vue de la réalisation d'un médicament des phénomènes algiques ou de l'hyperthermie, administré sous forme de compositions pharmaceutiques destinées à être sucées ou mâchées. 9. Use of lysine acetylsalicylate for the production of a medicament for algal phenomena or hyperthermia, administered in the form of pharmaceutical compositions intended to be sucked or chewed.
EP88902497A 1987-03-04 1988-03-04 New pharmaceutical compositions for the buccal tract, and process for their preparation Ceased EP0305464A1 (en)

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FR8702939A FR2611501B1 (en) 1987-03-04 1987-03-04 NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE BASED ON LYSINE ACETYLSALIELYLATE AND PROCESS FOR OBTAINING SAME
FR8702939 1987-03-04

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EP88902497A Ceased EP0305464A1 (en) 1987-03-04 1988-03-04 New pharmaceutical compositions for the buccal tract, and process for their preparation

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US (1) US4988683A (en)
EP (1) EP0305464A1 (en)
FR (1) FR2611501B1 (en)
WO (1) WO1988006449A1 (en)
ZA (1) ZA881571B (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671953A (en) * 1985-05-01 1987-06-09 University Of Utah Research Foundation Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics
US5288497A (en) * 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
FR2611501B1 (en) * 1987-03-04 1991-12-06 Corbiere Jerome NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE BASED ON LYSINE ACETYLSALIELYLATE AND PROCESS FOR OBTAINING SAME
US4971798A (en) * 1989-11-30 1990-11-20 Miles Inc. Hard confections containing hydrogenated isomaltulose and medicinally active ingredient
DE4102629A1 (en) * 1991-01-30 1992-08-06 Bayer Ag PHARMACEUTICAL RUBBER WITH ACETYL SALICYLIC ACID
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
ATE220327T1 (en) * 1992-09-29 2002-07-15 Inhale Therapeutic Syst PULMONARY RELEASE OF ACTIVE FRAGMENTS OF THE PARATHORMONE
US20030113273A1 (en) * 1996-06-17 2003-06-19 Patton John S. Methods and compositions for pulmonary delivery of insulin
KR100419037B1 (en) * 1994-03-07 2004-06-12 넥타르 테라퓨틱스 Methods of delivery of insulin through the lungs and their composition
CA2190502A1 (en) * 1994-05-18 1995-11-23 Robert M. Platz Methods and compositions for the dry powder formulation of interferons
US6290991B1 (en) 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US6565885B1 (en) * 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US8404217B2 (en) * 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
EP1280520B2 (en) 2000-05-10 2018-03-21 Novartis AG Phospholipid-based powders for drug delivery
AU2001280934A1 (en) * 2000-07-28 2002-02-13 Alliance Pharmaceutical Corp. Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds
TWI324518B (en) 2001-12-19 2010-05-11 Nektar Therapeutics Pulmonary delivery of aminoglycosides
DE10202019A1 (en) * 2002-01-18 2003-07-24 Bayer Ag Pharmaceutical composition, useful in oral formulations for the treatment of e.g. rheumatism, neuralgia, migraine or myocardial infarction, comprises a free-flowing salt of acetylsalicylic acid and a basic amino acid
US20070031342A1 (en) * 2005-06-22 2007-02-08 Nektar Therapeutics Sustained release microparticles for pulmonary delivery
PT2280687T (en) * 2008-03-26 2019-06-04 Stichting Sanammad Chewing gum compositions comprising cannabinoids
CA3044137C (en) 2016-12-23 2021-06-15 Ventaleon Gmbh Improved synthesis of lysine acetylsalicylate · glycine particles

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2243684B1 (en) * 1973-09-19 1977-01-28 Semb
CA1080024A (en) * 1975-12-24 1980-06-24 Leonard Spooner Confection containing xylitol
FR2390954A1 (en) * 1976-10-13 1978-12-15 Choay Sa NEW GUANYLHYDRAZONES, THEIR METHODS OF PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM
GB1583871A (en) * 1976-10-19 1981-02-04 Ucb Sa Anti-aggregants
US4123544A (en) * 1977-03-02 1978-10-31 Merrell Toraude S. A. Acetylsalicylic acid derivatives
JPS5524105A (en) * 1978-08-09 1980-02-21 Teijin Ltd Method and agent for control of calcium metabolism of warm-blooded animal
US4206209A (en) * 1978-11-02 1980-06-03 Kracauer Paul Sublingual aspirin tablet
JPS5610110A (en) * 1979-07-06 1981-02-02 Green Cross Corp:The Acetyl salicylate salt preparation for injection
DE3171774D1 (en) * 1980-03-31 1985-09-19 Teijin Ltd Pharmaceutical composition for intrarectal administration, and suppository prepared therefrom
FR2589358B1 (en) * 1985-07-30 1987-12-04 Synthelabo PHARMACEUTICAL COMPOSITIONS BASED ON DILTIAZEM AND ASPIRIN
GB8522453D0 (en) * 1985-09-11 1985-10-16 Lilly Industries Ltd Chewable capsules
FR2608597B1 (en) * 1986-12-22 1989-05-12 Synthelabo PHARMACEUTICAL COMPOSITIONS CONTAINING LYSINE ACETYLSALICYLATE
FR2611501B1 (en) * 1987-03-04 1991-12-06 Corbiere Jerome NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ROUTE BASED ON LYSINE ACETYLSALIELYLATE AND PROCESS FOR OBTAINING SAME
US4885287A (en) * 1988-08-09 1989-12-05 University Of Kentucky Research Foundation Novel method of administering aspirin and dosage forms containing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8806449A1 *

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US4988683A (en) 1991-01-29
ZA881571B (en) 1988-08-29
FR2611501B1 (en) 1991-12-06
FR2611501A1 (en) 1988-09-09
WO1988006449A1 (en) 1988-09-07

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