EP1545454A1 - Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite - Google Patents

Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite

Info

Publication number
EP1545454A1
EP1545454A1 EP03750616A EP03750616A EP1545454A1 EP 1545454 A1 EP1545454 A1 EP 1545454A1 EP 03750616 A EP03750616 A EP 03750616A EP 03750616 A EP03750616 A EP 03750616A EP 1545454 A1 EP1545454 A1 EP 1545454A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
form according
active ingredient
matrix
nanocapsules
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Withdrawn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
EP03750616A
Other languages
German (de)
English (en)
Inventor
Jörg Mayer
Karsten Cremer
Lutz KRÖHNE
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.)
Capsulution Nanoscience AG
Original Assignee
Capsulution Nanoscience AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Capsulution Nanoscience AG filed Critical Capsulution Nanoscience AG
Publication of EP1545454A1 publication Critical patent/EP1545454A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/0012—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin

Definitions

  • the invention is concerned with solid dosage forms for oral
  • Dosage forms for the administration of systemically active substances are preferably taken orally by most people.
  • a number of dosage forms are available for this, for example conventional tablets with or without film, chewable tablets, lozenges, soft capsules, hard capsules, drops, juices or drinking granules. Tablets and soft or hard capsules for swallowing are particularly common dosage forms. However, children and the elderly who have difficulty swallowing tablets or capsules often receive drops or juices.
  • a second group are the oral lyophilisates, which are produced as highly porous Maurices by freeze-drying a solution or suspension of active ingredient and suitable excipients.
  • the third group is formed by the rapidly disintegrating film-like preparations which have recently become available on the market as oral cosmetics (Listerine PocketPak, Pfizer) and are also propagated for the administration of active pharmaceutical ingredients.
  • These dosage forms which disintegrate very quickly in the mouth, are generally considered to be particularly suitable for the administration of active ingredients for combating acute diseases or conditions such as migraines.
  • this is correct, because after all, the patient can apply the medication as soon as the symptoms appear, unlike in the case of conventional tablets or capsules, for which a suitable situation and the availability of drinking water must first be waited for.
  • the rapid disintegration of the dosage form there is no rapid onset of action.
  • the usually speed-determining step until a medication takes effect is the dissolution of the active substance in gastric juice or saliva or intestinal juice. This can take a long time, especially with poorly soluble active ingredients.
  • the object of the invention is to provide such a dosage form.
  • the problem is solved by a fixed dosage form for oral
  • the matrix contains an active ingredient which is sparingly soluble in a physiological liquid and is in the form of quick-release micro- or nanocapsules.
  • a dosage form means a preparation for
  • a dosage form contains one or more suitable excipients in addition to the active ingredient itself.
  • Dosage forms include tablets, film-coated tablets, sublingual tablets, buccal tablets, oral lyophilisates and oral films, among others.
  • An active ingredient can be, for example, a pharmaceutical or therapeutic active ingredient, an active ingredient mixture, a diagnostic substance, a vitamin, vital substance, nutrient or a mineral substance.
  • the active ingredient is preferably a therapeutic active ingredient or a therapeutic active ingredient mixture. Since the aim of the invention is to achieve a rapid release of the active substance, the dosage form is particularly suitable for those active substances which are used for the treatment of an acute illness or acute symptoms.
  • Examples of such classes of drugs are analgesics, antimigraine agents, antispasmodics, antiemetics, antiallergics, anti-diarrheal agents, antihypertensives, antihypotensives, antinauseants, analeptics, psychotropics, antidotes, withdrawal agents, antiarrhythmic agents, sedatives, hypnotics, antiepileptics, blow killing agents, diagnostic agents or agents for erectile dysfunction.
  • analgesics antimigraine agents, antispasmodics, antiemetics, antiallergics, anti-diarrheal agents, antihypertensives, antihypotensives, antinauseants, analeptics, psychotropics, antidotes, withdrawal agents, antiarrhythmic agents, sedatives, hypnotics, antiepileptics, blow killing agents, diagnostic agents or agents for erectile dysfunction.
  • the dosage form can also contain a second active ingredient, either a poorly soluble or a soluble one. If the second active ingredient is sparingly soluble and, like the first, would benefit from accelerated release after application, it can also be in micro- or nano-encapsulated form. If, on the other hand, it is water-soluble, it will advantageously be in an encapsulated form.
  • a second active ingredient either a poorly soluble or a soluble one. If the second active ingredient is sparingly soluble and, like the first, would benefit from accelerated release after application, it can also be in micro- or nano-encapsulated form. If, on the other hand, it is water-soluble, it will advantageously be in an encapsulated form.
  • the fact that the dosage form is constructed in the form of a coherent matrix means that it is not a disperse form such as a powder or granulate, but rather a solid, shaped "single unit", each one
  • the matrix can optionally be coated with a saliva-soluble film.
  • Matrix-like solid dosage forms with rapid disintegration on contact with aqueous liquids are usually produced either as highly porous tablets by tableting or freeze-drying or as oral films by coating and drying - alternatively by extrusion.
  • a detailed description of these dosage forms, their manufacture and functionality can be found in K. Cremer: Orally Disintegrating Dosage Forms, Berlin 2001, the content of which is expressly referred to here.
  • a proportion of one or more physiologically acceptable excipients is almost always required to build up a matrix.
  • Oral films are primarily water-soluble, film-forming polymers such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like.
  • a binder is generally primarily used, preferably a plastically readily deformable dry binder such as microcrystalline cellulose.
  • Lyophilized moldings can contain a polymer such as gelatin as a matrix former or structuring agent, and often also a sugar alcohol such as mannitol. Additional pharmaceutical excipients can be used as needed, e.g. B.
  • binders thickeners, surfactants, wetting agents, stabilizers, antioxidants, flavors, taste improvers, sweeteners, fillers, absorption improvers, colorants, pigments, plasticizers, lubricants, release agents, flow regulators, etc.
  • the disintegration time of the matrix should be less than 2 minutes.
  • the disintegration time relates to the disintegration time measured in vivo when used
  • Oral cavity which is to be determined without chewing the dosage form, or which is measured according to the method of a recognized pharmacopoeia (e.g. the United States Pharmacopeia 25) under standard conditions in vitro, whereby in the sense no artificial gastric juice, but water or physiological buffer solution with a pH> 5.5 should be used as the decay medium.
  • a matrix is preferred which has a disintegration time of less than 1 minute.
  • a disintegration time of less than 30 seconds is particularly preferred.
  • a disintegration time of less than 20 seconds is preferred.
  • a lyophilized matrix according to the invention has a disintegration time of less than 10 seconds, in particular less than 5 seconds.
  • the matrix contains an active ingredient which is sparingly soluble in a physiological liquid and which is in the form of quick-release micro- or nanocapsules.
  • the poor solubility of an active substance is present when the active substance is in a physiological liquid relevant for the release, ie. H. has a solubility of at most about 1% (w / v) in saliva, artificial saliva, gastric juice, artificial gastric juice, small intestine juice or artificial small intestine juice.
  • a further criterion of poor solubility which is essential in the sense of the use of the invention, can be used, according to which this is the case if the amount of active substance contained in the matrix is not approximately 500 ml of physiological liquid at 37 ° C. solves. In a preferred embodiment, 200 ml of physiological fluid are not sufficient to dissolve the amount of active ingredient contained. Active substances which do not completely dissolve in 100 ml or even 50 ml of physiological liquid are particularly preferred. In the case of such active substances in particular, the dosage form according to the invention is intended to enable rapid release, which cannot be achieved solely by using a rapidly disintegrating matrix as the active substance carrier.
  • the active ingredient is in the form of rapidly releasing micro- or Contain nanocapsules.
  • microcapsules and “nanocapsules” refer to all known types of micro- and nanoparticles with a capsule-like structure, ie they contain a core and a shell that is distinguishable from the core. While the core contains the major part of the poorly soluble active ingredient and, if necessary, also contains one or more pharmaceutical adjuvants, the shell can be constructed from different materials, e.g. B. consist of one or more polymers, a mixture of polymeric and non-polymeric substances, lipids and lipid-like substances, or a combination of lipids and polymers. In this respect, the term micro- or nanocapsules also includes liposomes.
  • microcapsules or nanocapsules are supposed to be quick-release species means that the capsule shells have a high permeability for dissolved molecules of the active substance contained and no significant retarding effect.
  • a high permeability is e.g. B. given when the capsules are able to release the poorly soluble active ingredient contained within 60 minutes at 37 ° C under sink conditions.
  • Preferred capsules are those which release their active ingredient in one of the physiological liquids defined above under the conditions mentioned within less than 30 minutes. Capsules are particularly preferred whose release takes place within 15 minutes, in particular within 10 minutes.
  • release times of less than 5 or less than 2 minutes can even be achieved, namely when the capsule shell is particularly permeable to the active ingredient and the particle size of the capsules is particularly small, as will be explained in the following.
  • the release takes place when at least about 90% by weight of the active ingredient contained in the capsules or in the matrix or else in the dosage form is dissolved in the release medium.
  • the release time from the capsules is best determined using a recognized in vitro release test (e.g., according to United States Pharmacopeia 25), but the equipment and conditions must be selected so that the required sink conditions are met. This can mean that at certain Active ingredients instead of the most commonly used paddle apparatus, a flow cell is to be used. Also preferred are those capsules which release the active ingredient not only in the acidic gastric juice, but also in the more neutral saliva during the specified periods.
  • Nanocapsules are capsules containing active ingredients that primarily serve to mask the taste, which are therefore primarily aimed at not releasing an active ingredient, at least in the saliva, since otherwise there would be no taste masking.
  • Such capsules have already been described as a component of dosage forms that rapidly disintegrate in the oral cavity, see e.g. B. US 5,607,697 and WO 98/14179.
  • Capsules that can be used for this purpose considerably delay the release of the active ingredient in the saliva.
  • these are relatively thick-walled capsules with a rather low permeability in a neutral environment and with a diameter of more than 10 ⁇ m.
  • the capsules according to the invention are rather thin-walled, with typical mean wall thicknesses of less than about 20 nm, in some cases also less than about 10 nm. They typically have an average diameter of at most about 10 ⁇ m, measured as z-average by means of quasi-elastic light scattering or photon correlation spectroscopy. Capsules with an average diameter of approximately 200 nm to 5 ⁇ m are preferred, particularly those with an average diameter of approximately 400 nm to 3 ⁇ m, and very particularly those with an average diameter of approximately 500 nm to 2 ⁇ m. Such small particle sizes mean a particularly large surface area, which can significantly increase the dissolution rate of the poorly soluble active ingredient.
  • an essential advantage of the invention is to have created a possibility for incorporating the active substance into a rapidly disintegrating matrix in a state with a particularly large surface area. Otherwise, the provision of such a large surface area is extremely problematic.
  • poorly soluble active ingredients can often be comminuted to an average particle size of 5 to 10 ⁇ m, but such large ones are created below this range Surface energies that the particles in question tend to agglomerate and are hardly manageable.
  • capsules in the preferred size range can be constructed from different materials with regard to their shell material, e.g. B. consist of one or more polymers, a mixture of polymeric and non-polymeric substances, lipids and lipid-like substances, or a combination of lipids and polymers.
  • shell material e.g. B. consist of one or more polymers, a mixture of polymeric and non-polymeric substances, lipids and lipid-like substances, or a combination of lipids and polymers.
  • hydrophilic, water-soluble or water-swellable materials should be used, whereby water-soluble capsules are more suitable for tableted matrices, while hydrophilic, swellable but insoluble materials should be more suitable for lyophilisates and films.
  • Stable, but highly permeable capsule shells can e.g. B.
  • Suitable capsules can also be produced by complex formation from at least two opposite polyelectrolytes.
  • Usable polycations for the production of polyelectrolyte complex capsules include u. a. Polyvinylamines, polyvinylpyridines, polyallylamines, polyethyleneimines, ammonium salts of polyacrylates, aminated dextrans, aminated celluloses, aminated pectins, chitosan, polylysine, spermine but also corresponding copolymers.
  • Usable polyanions include u. a. Polyacrylic acids, polyvinylsulfonic acids, polyvinylphosphonic acids,
  • Polyphosphoric acids polymaleic acids, polystyrenesulfonic acids, polylactic acids, polyglycolic acids, carboxymethyl celluloses, carboxymethyl dextranes, hyaluronic acid, chitosan sulfates, cellulose sulfates, sulfoethyl celluloses, chondroitin sulfates, dextran sulfates, carageenans, alginic acids, also peptic acids, gum lignin acids, also gum lignin acids, also gum lignin acids, corresponding gum lignin acids, also gum lignin acids, also gum lignin acids, corresponding gum lignins acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic acid acids, also nucleic
  • Polyvalent low molecular weight ions with which poorly soluble salts can be formed with a suitable polyelectrolyte include u. a. Yttrium (III) cations, terbium (III) cations, iron (III) cations.
  • Thin-walled micro- and nanocapsules based on polyelectrolyte complexes or poorly soluble salts of polyelectrolytes can be produce by various known methods, e.g. B. by coacervation, spray drying, common double emulsion processes.
  • a particularly suitable method is the so-called layer-by-layer method (LBL), according to which such capsules can be built up by layer-by-layer adsorption or electrostatic self-assembly of polyelectrolytes on nano- or microdisperse surfaces.
  • LBL layer-by-layer method
  • Capsules made by this method can have a wall thickness of less than 20 nm or even less than about 10 nm. With a suitable selection of the polyelectrolytes, such thin-walled capsules at the same time have such a high permeability for low-molecular substances that their diffusion through the capsule wall takes at most a few minutes, but usually only a few seconds, so that the capsules excellently meet the requirements according to the invention rapid release.
  • a particularly rapid release of a poorly soluble active ingredient from a dosage form according to the invention is particularly given when the
  • the time required for the active ingredient to pass through the capsule shell is significantly less than the time saved by dissolving the active ingredient due to the high degree of dispersity.
  • capsules with envelopes made of lipid layers or lipid bilayers which are also known as liposomes, this term primarily referring to the state of such capsules in liquid dispersion.
  • Lipid layers or lipid bilayers can also stabilize a micro- or nanodisperse, poorly soluble active ingredient without significantly hindering its diffusion out of the capsule.
  • layers based on phospholipids which have a low phase transition temperature and are therefore fluid at body temperature, e.g. B. phospholipids with at least one unsaturated fatty acid residue or those with short to medium chain fatty acid residues such as dipalmitoylphosphatidylcholine.
  • the rapidly disintegrating matrix can be produced in the form of a tablet.
  • the microcapsules or nanocapsules containing the poorly soluble active ingredient are processed with the other auxiliaries which are required for the construction of the matrix and for the formation of the tablet, according to one of the methods known in pharmaceutical technology, to give a powder mixture or granules.
  • a granulate can be produced from auxiliary substances, to which the capsules are subsequently mixed. The granulate or the powder mixture is then pressed to tablets of suitable shape and relatively high porosity with a low to moderate pressing force. Since tablets with high porosity typically have a lower friability than ordinary tablets, not every tablet shape is equally suitable, but shapes with pronounced curvatures and facets are preferred.
  • the matrix is to be shaped like a film so that rapid disintegration is achieved primarily over a large outer surface and not over a large inner surface, as is the case with tablets, one can also proceed according to known formulation and process principles, which can be varied accordingly that the micro- or nanocapsules described above have to be incorporated.
  • the solvent or mixture should be selected so that it is in the capsules contained, hardly soluble active ingredient if possible or only very difficult to dissolve in it. The capsules are now mixed into the mass.
  • the matrix is to be designed as a lyophilized molding, known auxiliaries can also be used to build it up, and known methods can be used.
  • the liquid or viscous mass for the production of the lyophilized molding contains a solvent and a carrier material containing gelatin, into which the nano- or microcapsules described above are to be incorporated.
  • the carrier must be soluble in the chosen solvent and the solvent must be inert to the pharmaceutically active substance.
  • Carrier material means the thickeners added to the dosage form and mentioned above, which provide a solid matrix for supporting the encapsulated active substances after the solvent has been removed by sublimation.
  • the encapsulated pharmaceutically active substances are incorporated into the matrix of the carrier material.
  • gelatins suitable as a carrier material include simple gelatin, partially hydrolyzed gelatin, and succinylated gelatin.
  • the carrier matrix can be supplemented with auxiliary substances from the group of cryoprotectors in order to realize an amorphous freezing of the solvent and a protection of the with frozen nano or micro capsules. If the selected solvent is water, examples of these auxiliaries are mannitol, sucrose, glucose or the like.
  • the preparation of the liquid or viscous mass of the lyophilized dosage form according to the invention is typically prepared in a larger batch and divided into small controlled dosage amounts by pouring the mass into one or more wells of a shaped bowl or the like.
  • the deepening will correspond to the shape and size of the finished dosage form.
  • several of these recesses will be formed in one piece of sheet-like material.
  • This sheet-like material can e.g. B. be made of thermoplastic material, with recesses shaped under the influence of heat.
  • the liquid or viscous mass can be poured into the indentations using known methods. Freezing also happens with a
  • the freezer is operated at a temperature low enough to fully solidify the mixture.
  • the frozen amount of solvent in the mass is then sublimed.
  • the sublimation is preferably carried out in a freeze dryer in which the now frozen mass in the wells is exposed to a reduced pressure.
  • the sublimation can be supported by the controlled supply of heat.
  • the temperature of the shelves on which the frozen mixture is located can be raised in order to accelerate the sublimation process.
  • the freeze dryer is brought back to atmospheric pressure level and the now solid moldings are removed from the freeze dryer.
  • the material containing the solid moldings is then usually sealed with a suitable film, which is applied either by gluing or with heat sealing over the depressions containing the moldings.
  • Gelatin and mannitol used. While gelatin is generally used in excess according to the prior art, it surprisingly proves to be particularly advantageous for lyophilized matrices with polyelectrolyte-coated active ingredient particles if the ratio is significantly shifted in favor of mannitol becomes.
  • the encapsulation of the micronized active ingredient takes place. This is done using LBL technology in accordance with patent applications WO 01/51196 and WO 99/47252.
  • the micronized active ingredient is dispersed in an aqueous sodium dodecyl sulfate solution and then encapsulated in acid with the polyelectrolytes gelatin A and chondroitin sulfate. Gelatin and mannitol are dissolved in water, the pH is adjusted to 3.5 and the ketoprofen suspension is added to this solution and homogenized. 25 mg units are prepared by filling suitable preformed blister cards, 490 mg of the dispersion being introduced into each individual well (12 mm diameter). The product is then frozen at -80 ° C and freeze-dried, e.g. in WO 95/01782.
  • the release in vitro was determined with a release apparatus according to Pharmacopoea Europaea using the paddle method at 50 revolutions per minute in 600 ml 0.1N HCl at 37 ° C. and with UV spectrometric detection and is shown in the following table. All samples were drawn through a 0.45 ⁇ m filter. It should be noted that the work was carried out in an acidic environment under non-sink conditions. If the experiment is carried out under sink conditions according to Pharmacopoea Europaea, it can be expected that this would lead to an accelerated release.
  • the encapsulation of the micronized active ingredient takes place. This is done using LBL technology in accordance with patent applications WO 01/51196 and WO 99/47252.
  • the micronized active ingredient is dispersed in an aqueous sodium dodecyl sulfate solution and then encapsulated with the polyelectrolytes gelatin A and carboxymethyl cellulose. Gelatin and mannitol are dissolved in water and the carbamazepine suspension is added to the solution and homogenized. 25 mg units are prepared by filling suitable preformed blister packs, 500 mg of the dispersion being introduced into each individual well (12 mm diameter). The product is then frozen at -80 ° C and freeze-dried, e.g. in WO 95/01782.
  • Auxiliaries can be added to the formulation, e.g. Aspartame and flavors.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formes d'administration solides en dose unique destinée à une libération accélérée de principes actifs à solubilité réduite. Ces formes d'administration sont basées sur une matrice cohérente qui se décompose rapidement dans des liquides physiologiques. La matrice comporte au moins un principe actif à solubilité réduite qui se présente sous la forme de microcapsules et nanocapsules à libération rapide. Cette forme d'administration est particulièrement adaptée à l'administration de principes actifs à solubilité réduite, pour lesquels on souhaite un effet rapide.
EP03750616A 2002-09-25 2003-09-24 Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite Withdrawn EP1545454A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10244504 2002-09-25
DE10244504A DE10244504A1 (de) 2002-09-25 2002-09-25 Schnellfreisetzende Darreichungsform mit schwerlöslichem Wirkstoff
PCT/EP2003/010630 WO2004030648A1 (fr) 2002-09-25 2003-09-24 Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite

Publications (1)

Publication Number Publication Date
EP1545454A1 true EP1545454A1 (fr) 2005-06-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP03750616A Withdrawn EP1545454A1 (fr) 2002-09-25 2003-09-24 Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite

Country Status (7)

Country Link
US (1) US20060093679A1 (fr)
EP (1) EP1545454A1 (fr)
JP (1) JP2006503855A (fr)
AU (1) AU2003270255A1 (fr)
CA (1) CA2500062A1 (fr)
DE (1) DE10244504A1 (fr)
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JP2006503855A (ja) 2006-02-02
WO2004030648A1 (fr) 2004-04-15
AU2003270255A1 (en) 2004-04-23
CA2500062A1 (fr) 2004-04-15
US20060093679A1 (en) 2006-05-04

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