EP1986529A2 - Forme d'administration par voie orale stable au stockage d'amoxicilline et d'acide clavulanique - Google Patents

Forme d'administration par voie orale stable au stockage d'amoxicilline et d'acide clavulanique

Info

Publication number
EP1986529A2
EP1986529A2 EP07722835A EP07722835A EP1986529A2 EP 1986529 A2 EP1986529 A2 EP 1986529A2 EP 07722835 A EP07722835 A EP 07722835A EP 07722835 A EP07722835 A EP 07722835A EP 1986529 A2 EP1986529 A2 EP 1986529A2
Authority
EP
European Patent Office
Prior art keywords
packaged system
desiccant
air
drinking straw
tightly packaged
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Withdrawn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
EP07722835A
Other languages
German (de)
English (en)
Inventor
Dieter Schateikis
Elke Sternberger
Iris Ziegler
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.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
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 Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1986529A2 publication Critical patent/EP1986529A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47G—HOUSEHOLD OR TABLE EQUIPMENT
    • A47G21/00—Table-ware
    • A47G21/18—Drinking straws or the like
    • A47G21/183—Drinking straws or the like with means for changing the flavour of the liquid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0038—Straws
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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

Definitions

  • the present invention relates to an airtight packaged system comprising
  • a combination of two independently prepared, multiparticulate pharmaceutical dosage forms consisting of an aqueous formulated dosage form containing amoxicillin trihydrate as a pharmaceutical active ingredient and from a separately prepared, preferably formulated, drug form containing potassium clavulanate as a pharmaceutical active substance, wherein the active ingredients in the combination in a nominal weight ratio of amoxicillin to clavulanic acid of 20: 1 to 1: 1, and
  • a preparation comprising at least one desiccant in such amounts that at storage of the packaged system under stress conditions of 40 ° C / 75% relative humidity up to 3 months amoxicillin trihydrate dimerized at most up to 1, 5 wt.% And the clavulanic acid be reduced to at most 10 wt.%.
  • Formulations comprising the antibiotic amoxicillin, as amoxycillin trihydrate, and potassium clavulanate as the ⁇ -lactamase inhibitor are known oral drugs for the treatment of bacterial infections such as otitis media, sinusitis, and upper and lower respiratory, urinary or skin infections in both children as well as in adults.
  • the pharmaceutical composition comprising amoxicillin trihydrate and potassium clavulanate can be compressed with conventional excipients as a powder mixture into tablets or can only be made available as a dry powder mixture, which is dispersed in water or aqueous liquids before the first intake. This dispersion is less suitable for continued therapy, especially for children and patients with dysphagia, as it is very difficult for such groups of patients to take pills.
  • the market-driven pharmaceutical formulations are formulations containing the two active ingredients, amoxicillin trihydrate and potassium clavulanate, in a nominal weight ratio of 4: 1, 6: 1, 7: 1 and 8: 1 in terms of amoxicillin and clavulanic acid.
  • Amoxicillin can be taken daily in amounts of 15 to 80 mg / kg / day with a corresponding pro rata amount of clavulanic acid.
  • the corresponding pharmaceutical formulations comprising the two active ingredients as dry powder-active substance mixtures, are preferably present in airtight containers, to which a drying agent can be added in order to exclude the decomposition of the potassium clavulanate by atmospheric water vapor.
  • a drying agent can be added in order to exclude the decomposition of the potassium clavulanate by atmospheric water vapor.
  • potassium clavulanate is very sensitive to water and decomposes under the action of moisture, such as. As water vapor. Accordingly, the preparation of potassium clavulanate and its formulation with amoxicillin trihydrate at the lowest possible humidity and the lowest possible temperatures, preferably below 20 0 C and a relative humidity of not more than 20%.
  • the dry powder-active substance mixtures are preferably distributed in airtight containers, from which the respective dose is taken after dispersion in an aqueous liquid. This can lead to inaccuracies in the dosage during subsequent therapy.
  • Object of the present invention was therefore, storage-stable, preferably multiparticulate dosage forms of amoxicillin trihydrate and potassium clavulanate, which are not powder mixtures of the active ingredients, preferably as a single dose to provide that do not have the disadvantages mentioned and therefore of children happy and of patients with Dysphagia can be well taken.
  • a combination of two independently prepared, multiparticulate pharmaceutical dosage forms consisting of a aqueous formulated dosage form comprising amoxicillin trihydrate as pharmaceutical active ingredient and from a separately formulated, preferably formulated, drug form containing potassium clavulanate as a pharmaceutical active substance, wherein the active ingredients in the combination in a nominal weight ratio of amoxicillin to clavulanic acid of 20: 1 to 1: 1 , and
  • a preparation comprising at least one desiccant in such amounts that at storage of the packaged system under stress conditions of 40 ° C / 75% relative humidity up to 3 months amoxicillin trihydrate dimerized at most up to 1, 5 wt.% And the clavulanic acid be reduced to at most 10 wt.%
  • the inventive system is characterized in that the two active ingredients, amoxicillin trihydrate and potassium clavulanate, not present as a powder mixture, but each prepared separately, preferably formulated into a multiparticulate dosage form such that the desired high drug loading of the individual particles with the respective Active ingredient is achieved and the mass or the volume of the individual particles is not increased so that it comes in particular in the aforementioned patient groups to an incomplete intake.
  • This is achieved, inter alia, by selecting the most favorable formulation variant for each of the two active ingredients without having to consider the second active ingredient of the combination and then combining the two formulations, preferably formulations, in the desired ratio.
  • the formulation of the amoxicillin trihydrate is aqueous, e.g. B.
  • the potassium clavulanate may preferably undiluted, ie as crystals or formulated with a high drug loading - provided that at temperatures below 25 ° C, preferably below 20 0 C, and a low relative humidity takes place - without through the 2.Wirkstoff Amoxicillin Traces of water that cause the decomposition of the Potassium clavulanate lead, be introduced.
  • effective protection of the dosage form comprising both dosage forms against exposure to atmospheric water vapor is necessary only when combining and then storing both dosage forms at a combined dose.
  • a desiccant preparation is added in such amounts that during storage of the airtight packaged system under stress conditions at 40 ° C / 75% relative humidity up to 3 months
  • Amoxicillin trihydrate at most up to 1, 5 wt.% Preferably up to 1, 0 wt.%, Particularly preferably up to 0.5 wt %, is dimerized after the protective water of hydration has also been completely or partially removed, and the clavulanic acid is degraded to not more than 10% by weight, preferably up to 5% by weight.
  • a desiccant formulation comprising a desiccant containing at least 25 mg water / g desiccant, preferably at least 27 mg water / g desiccant both at 40 ° C / 75% relative humidity and at 22 ° C / 80% relative humidity in each case within the first 24 hours of storage of an airtight packaged system according to the invention under the said conditions and at least 40 mg water / g desiccant, preferably at least 50 mg water / g desiccant in a subsequent storage up to a total of 7 days each at the absorbs the water absorption of the desiccant within the first 24 hours or after a total of 7 days each case when changing the storage condition of 22 ° C / 80% relative humidity to 40 ° C / 75% relative humidity at most doubles.
  • An amorphous silica preferably a precipitated silica or a silica gel or a fumed silica, is preferably suitable as the desiccant.
  • Silica gel is very particularly suitable as amorphous silica.
  • the amorphous silicic acid products are available on the market and are u. a. sold under the name "Syloide®” (from Grace Davidson, USA) or "Aerosile®” (from Degussa AG, Germany).
  • the respective active compounds are preferably formulated into granules, which are optionally subjected to further processing to the dosage form used.
  • These dosage forms may also be pellets or microtablets made from the respective granules by compression.
  • Such granules offer over powder mixtures the advantage of a smaller surface, a better flowability and easier swallowing, which also leads to a reduced taste perception. This allows ingestion without the addition of flavoring agents. Since the ingestion of the clavulanic acid component does not lead to taste impairment, this active ingredient may also be present in crystal form, i. H. be used as active ingredient crystals.
  • the Granules containing potassium clavulanate are prepared by melt granulation, if possible with the exclusion of atmospheric water vapor at a relative atmospheric humidity of ⁇ 30%, preferably ⁇ 20%.
  • auxiliaries as anhydrous auxiliaries are to be used, which are optionally again dried immediately before use and, if it is the binder, melt at temperatures below 65 ° C.
  • a mixture of at least 2 of said mono-, di-, tri- or polyesters of sucrose is used.
  • sucrose fatty acid esters of stearic acid and / or palmitic acid are particularly preference.
  • Sucrose fatty acid esters having an HLB value less than or equal to 3, preferably less than or equal to 2, more preferably about 1 are particularly suitable.
  • other physiological adjuvants may optionally also be selected from the group comprising lactose, microcrystalline cellulose, silica, CaHPO 4 , kaolin, talc, titanium dioxide, mannitol, pH regulators, preferably citric acid, Na 2 HPO 4 or ascorbic acid, preferably kaolin and / or CaHPO4 be used.
  • fillers which additionally facilitate the granulation can also be used for the production of the granules.
  • the binder is optionally melted with the optional excipients present and preferably granulated in a closed system with the potassium clavulanate in a suitable granulator, preferably at high revolution or chopper speeds.
  • the high chopper speeds are therefore sought in order to obtain as uniform and as possible particles with a particle size below 1000 ⁇ .
  • the granules thus obtained may optionally be rounded to pellets before they are cooled and classified by the sieving method.
  • the combined sieve fractions of 250 to 800 microns are used.
  • the potassium clavulanate is undiluted, i. H. used without the addition of desiccant.
  • aqueous, preferably multiparticulate, oral dosage form of amoxicillin, as Amoxicillin- trihydrate is in the desired, high-dose dosage forms, preferably in the form of granules or microplates produced therefrom by compression, particularly preferably in the form of pellets , preferably in a smooth, spherical shape to ensure that such dosage forms ensure sufficient bioavailability.
  • This is achieved in particular by the fact that the active substance-containing particles disintegrate rapidly, preferably within 30 minutes, at a pH in the upper part of the small intestine, where predominantly the resorption of the active substance takes place and releases the active substance.
  • the multiparticulate dosage form preferably granules or pellets, very particularly preferably extrusion pellets, carrageenan, preferably kappa carragenan, particularly preferably in an amount of 5 to 30 wt.%, Based on the total weight of the dosage form, is used, Not only is the granulation optionally possible with a subsequent extrusion and spheronization, but also ensures despite high drug loading of the necessary rapid disintegration of the multiparticulate drug form at pH levels that correspond to those in the upper small intestine area.
  • the multiparticulate drug form also contains tricalcium phosphate.
  • the weight ratio of tricalcium phosphate to carrageenan in the multiparticulate dosage forms should be 1: 1 to 1:10, more preferably 1: 2 to 1: 6. This allows a complete release of the drug within 15 minutes.
  • the multiparticulate dosage form of the amoxicillin trihydrate may also contain fillers, binders, lubricants, dyes and / or preservatives as adjuvant.
  • the multiparticulate dosage forms are preferably prepared because of an undesirable effect on the rate of disintegration and thus the release of amoxicillin trihydrate without the use of microcrystalline cellulose or other spheronization excipients such as low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, powder cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone.
  • These adjuvants can but in a coating, for. B. in a coating for taste neutralization and / or enteric coating of appropriate multiparticulate drug forms of amoxicillin trihydrate present.
  • the multiparticulate dosage forms preferably the granules or pellets of amoxicillin trihydrate, with at least a coating, particularly preferably provided with a taste-neutralized and / or enteric coating.
  • the coatings may be applied in an amount of from 1 to 50% by weight, based on the total weight of the dosage form, depending on the nature and function of the coating, preferably for taste-neutralized equipment in an amount of 1 to 5% by weight, preferably 1 to 3% by weight, based on the total weight of the dosage form.
  • materials for enteric coatings or taste masking coating are preferably methacrylic acid / alkyl (meth) acrylate copolymers, more preferably copolymers of methacrylic acid / methyl methacrylate with monomers of 1: 1 to 1: 2, such as Eudragit L ® or Eudragit S ®, especially preferably copolymers of methacrylic acid / ethyl acrylate 1: 1 as Eudragit L55 ® , Eudragit L30D-55 ® , which dissolve rapidly at a pH of> 5.5.
  • coatings based on celluloses or based on shellac which are known in the art, can be applied.
  • Saliva resistant coatings are preferably coatings based on Eudragit E or Eudragit EPO.
  • gastric juice is understood as meaning both the natural composition of the gastric juice and the artificial gastric juice-like preparations (pH 1.2-2) known to the person skilled in the art.
  • Release in the small intestine likewise includes release in the natural small intestinal juice as well as release in small intestinal juice-like preparations at pH values of 6-7, preferably pH 6.4-6.8, as defined in relevant pharmacopoeias understood.
  • the dosage forms prepared with the use of carrageenan and optionally tricalcium phosphate are characterized by the fact that they have a high Decay rate, whereby the antibiotic, amoxicillin, is released within at least 85% within 30 minutes after any coating that has been present has previously dissolved.
  • this high rate of disintegration occurs at pH values of 6.4 to 6.8.
  • the dosage forms containing amoxicillin trihydrate are prepared by mixing and granulating the starting materials.
  • the granulation is carried out as wet granulation, wherein water or aqueous solvents are used as Granulierillonkeiten.
  • the person skilled in the art is familiar with suitable solvents.
  • the advantage of wet granulation using water or aqueous solvent is u a. in that no organic solvent or only easily removable, organic solvents are used in the preparation of the dosage forms.
  • the granules may be extruded, the extrudates separated and optionally shaped, preferably spheronised, or the dried granules pressed into microtablets.
  • the multiparticulate dosage form can also be classified, preferably by means of the sieving method, the particles of the sieve fractions 250 ⁇ m to 710 ⁇ m being used as the drug form according to the invention.
  • the multiparticulate amoxicillin dosage form may preferably be protected with a coating, especially if this also the taste masking when taking the dosage form with other beverages than water, such as. As Coca-Cola or fruit juices, optimally supported.
  • the components of the amoxicillin-trihydrate-containing dosage form can be mixed simultaneously or successively.
  • the preparation of the mixture can be carried out in known mixers or granulators, so that optionally mixing, granulation and optionally extrusion can take place simultaneously.
  • the optionally carried out extrusion and / or spheronization of the granules and their coating with enteric and / or Taste-coating coatings can be carried out in each case in the apparatuses known to the person skilled in the art.
  • a fluidized bed apparatus can preferably be used.
  • Preferred amoxicillin-trihydrate-containing dosage forms, preferably granules or pellets, and processes for their preparation are disclosed in German patent application 10 2005 042 875. The corresponding disclosure is hereby incorporated by reference and is considered part of the present disclosure.
  • the two independently produced multiparticulate, but not present as active ingredient powder separately formulated pharmaceutical forms containing respectively amoxicillin trihydrate or potassium clavulanate, preferably only immediately before the airtight packaging of the system with each other in a nominal weight ratio of amoxicillin Clavulanic acid of 20: 1 to 1: 1, preferably in a nominal weight ratio of 4: 1, 6: 1, 7: 1 and 8: 1, respectively, and before the airtight packaging with a preparation comprising at least one desiccant of the type described above equipped.
  • the multiparticulate, formulated, particularly preferably granulated, drug-containing dosage forms can be combined as a single dose in a sachet, the dry medium preparation as equipment of the sachet, z. B. as a desiccant strip, or as a physiologically acceptable additive the two drug-containing dosage forms can also be added multiparticulate.
  • These disposable cans packed in sachets are packed airtight immediately after filling the sachets for storage.
  • each separately prepared, preferably formulated drug-containing dosage forms may also preferably be filled to the airtight packaged system according to the invention initially as a single dose in the weight ratios mentioned above in a drinking straw.
  • Correspondingly designed delivery systems are described in the publications WO 03/079957, WO 2004/000202, WO 2004/000264. The description of these delivery systems in the cited publications is hereby incorporated by reference and forms part of the present disclosure.
  • the two separately prepared, preferably separately formulated, not present in powder form, pharmaceutical, multiparticulate dosage forms more preferably in each case as granules or pellets as preferably a mixture in the drinking straw before. Possibly.
  • the clavulanic acid-containing component may also be present only as crystals of the active ingredient.
  • the preferably multiparticulate dosage forms have a particle size of 250 to 800 .mu.m and are preferably spheronized into pellets. This also allows patients with dysphagia to absorb such a single dose by sucking the transport liquid through the straw completely in the necessary dose amount.
  • the drinking straw is equipped with a retention agent for the pharmaceutical combination of dosage forms.
  • This retaining means is preferably movably arranged in the drinking straw, so that not only the dosage forms, but also the retention means, preferably in the form of a plug, preferably up to the mouth opening, can be aspirated with the aspiration of the transport liquid, whereby a complete administration of the dosage can be easily controlled can.
  • the retaining means for the transport liquid and air is permeable, for the drug forms, however, not.
  • the combination of dosage forms is arranged between the preferably movable retaining means and the opening of the drinking straw, which serves as a mouth opening.
  • both the movable retaining means and the drug forms are arranged in the leg of the drinking straw, which has the mouth opening and is connected via the curvature to the second leg of the drinking straw.
  • these embodiments of the system according to the invention also have, in addition to the drinking straw with the pharmaceutical combination, a preparation which includes the desiccant.
  • the drying agent as a physiologically acceptable component, preferably as an edible component, optionally multiparticulate the combination of the two preferably granulated, more preferably pelletized, drug-containing dosage forms are preferably added as a further component, or by the retention agent separately from the combination, preferably the mixture of drug forms present in the drinking straw.
  • the desiccant may also be processed as a constituent of the drinking straw material together with the preferably thermoplastic, physiologically acceptable polymer and given further constituents by thermoforming to the drinking straw.
  • the desiccant can also be a component of a drinking straw equipment, such.
  • the desiccant is present in a further drinking straw equipment, namely a closure device of the mouth opening of the drinking straw.
  • This closure device may take the form of a closure membrane or closure cap which is removable, preferably a closure cap.
  • a closure device preferably a cap of the drinking straw, comprises the desiccant as a component of the thermoformed composition.
  • This composition comprises the desiccant, at least one water-insoluble, thermoplastic polymer and a compatibilizer incompatible with this polymer, which is so much more hydrophilic than the polymer, that the difference in hydrophilicity causes these two components to be so intolerant, that they separate from each other.
  • a compound of the group comprising polyglycol, ethylene / vinyl alcohol copolymer, glycerin, polyvinyl alcohol, pentaerythritol, polyvinylpyrrolidone, a saccharinate, a polyhydric alcohol or an ethylene / vinyl acetate copolymer having preferably 4 to 40 mol% of vinyl acetate units.
  • the composition preferably comprises 1 to 10% by weight, preferably 3 to 7% by weight, more preferably 4 to 5% by weight of the channeling agent.
  • the use of an ethylene / vinyl acetate copolymer is preferred because it also positively affects the mechanical properties, such as flexibility.
  • thermoplastic preferably hydrophobic polymer
  • a physiologically acceptable polymer preferably a polyolefin, most preferably a polyethylene or polypropylene.
  • a desiccant preferably amorphous silica, more preferably precipitated silica, such as silica gel in such amounts that in the storage of the airtight packaged Systems under stress conditions of 40 ° C / 75% relative humidity up to 3 months at most 1, 5 wt.% Of the amoxicillin trihydrate dimerized and degraded at most 10 wt.% Of clavulanic acid.
  • the water holding capacity of the desiccant irrespective of which component of the drinking straw or straw equipment is present, must be at least 25 mg water / g desiccant at both 40 ° C C / 75% relative humidity and at 22 ° C / 80% relative humidity in each case within the first 24 hours of storage under the said conditions and at least 40 mg of water / g of desiccant in a subsequent storage up to a total of 7 days in each of the above Conditions, wherein the water absorption of the desiccant within the first 24 hours or after a total of 7 days each doubled when changing the storage condition of 22 ° C / 80% relative humidity to 40 ° C / 75% relative humidity at most.
  • thermoplastically processable composition for producing the closure device in particular the cap of the drinking straw
  • can for Coloring pigments such as. Example, titanium dioxide and / or calcium carbonate in the usual amounts of pigment, preferably up to 2 wt.%, Based on the total weight of the thermoplastically deformable composition having.
  • the chemical affinity of the desiccant to the channeling agent is greater than that of the thermoplastic matrix polymer, so that when the thermoplastic thermosetting polymer is melted, which also melts the channeling agent, the desiccant preferably aggregates with this agent and precipitates Thermoforming on cooling in the thermoplastic polymer, preferably the polyolefin, of which the thermoformable composition consists of more than 50% by weight, separated and thus forms channels in the matrix polymer.
  • the retaining means which is preferably designed like a plug, can be produced in this way.
  • a desiccant preparation from said desiccants with the listed water absorption capacity in the necessary amounts preferably in the form of desiccant-containing strips, which include suitable carrier to attach.
  • the preferred embodiment of the invention is an airtight packaging dosage form in the form of a drinking straw with a closure device equipped with desiccant, preferably with a closure cap.
  • This cap may also have lateral openings, preferably in the form of slots for better handling and safety precautions in case of accidental ingestion.
  • FIG. 1 shows an oral dosage form comprising a drinking straw (1) in which a mixture of the pharmaceutical formulations containing on the one hand amoxicillin trihydrate and on the other hand potassium clavulanate in the form of pellets (3) is present.
  • This formulation is arranged above a movable retaining means in the form of a plug (2).
  • the mouth opening, to which the mixture of the pharmaceutical preparations, preferably formulations can pass unhindered, is provided with a closure cap (4).
  • This closure cap was made from a thermoplastic composition comprising a desiccant, as discussed above, by thermoforming.
  • the mixture of pharmaceutical preparations preferably formulations by suction of a transport liquid, which does not pass through the mouth opening (5), but the other opening (6) of the drinking straw in the drinking straw, preferably with the entrainment of the movable restraint means as a so-called controller be taken by the patient.
  • the closure device Before the suction of the transport liquid is of course the closure device to be removed from the mouth of the drinking straw.
  • the preparation of the desiccant-containing drinking straw equipment may preferably be by injection molding in that the thermoplastic matrix polymer is preferably a water-soluble polymer, preferably a polyolefin such as polyethylene or polypropylene, preferably after having been previously melted, with the other components, namely the channel-forming agent and the Desiccant, preferably in multiparticulate form, is mixed.
  • the mixture is carried out in known mixing equipment with sufficient stirring.
  • the molten mixture can be brought into the desired shape by means of an injection molding machine.
  • the molded article, preferably the cap, for the drinking straw is cooled, during which cooling the channel-forming agent separates and aggregates with it due to its greater affinity for the desiccant.
  • the channel-forming agent separates and aggregates with it due to its greater affinity for the desiccant.
  • channels are formed which have an open connection to the surface of the injection molded article and have an enrichment of the desiccant. This allows the desiccant to absorb the moisture from the environment, so that a storage-stable system of airtight packaged, oral dosage form is achieved.
  • the retaining means arranged in the drinking straw can also be produced with respect to the production of moldings of thermoplastic polymers containing such desiccant-containing channels or corresponding compositions for producing such shaped bodies are disclosed in WO 97/32663 and WO, respectively Referenced 99/61856.
  • the description of the moldings or the methods for producing such moldings in the cited publications is hereby incorporated by reference and is considered part of the present disclosure.
  • Suitable packaging materials preferably multilayer films with a water vapor barrier layer, preferably of aluminum, for the airtight packaging of the system according to the invention are known to the person skilled in the art.
  • the water content is determined according to Karl Fischer according to the publication in the European Pharmacopeia under No. 2.5.32 or 2.5.12 depending on the water content.
  • the active ingredient content and the amount of degradation products of potassium clavulanate is determined by means of HPLC.
  • the method for determining dimer formation of amoxicillin trihydrate is based on HPLC.
  • the active ingredient content of both active ingredients is determined at a certain point in time by HPLC.
  • the release of active ingredient is determined in accordance with European Pharmacopeia at a temperature of 37 ° C. of the release medium and a rotational speed of the blade stirrer of the release apparatus of 100 min -1 in the time and the release medium indicated in the example each released amount of the active ingredient at a given time was determined by HPLC.
  • the pellets were coated with the aqueous coating dispersion with 15 wt.% Solids in a fluidized bed system with hot air at a product temperature of 30 0 C to a weight gain of 2 wt.% With a coating and under reduced hot air supply until reaching product temperature of 40 0 C and a residual moisture of ⁇ 10% using the IR method dried.
  • Pellets were prepared with the following composition in a room with less than 20% humidity and a room temperature below 25 0 C:
  • sucrose stearate (Di, - Tri, - Polyester
  • the pellets having the above composition were prepared in which a 41-Diosna mixer was preheated to 60 0 C and was then mixed sucrose and kaolin at 650 revolutions per minute mixing power and 1000 rpm chopper speed for as long was melted until the mixture , The mixture was cooled to RT (25 ° C) and added to the heated to about 60 0 C mixture of K-clavulanate and granulated at ⁇ 65 ° C, 500-700 revolutions per minute mixing power and 1000 revolutions per minute chopper speed and rounded , The finished pellets were rapidly cooled by introducing liquid N 2 within ⁇ 3 min at 30 0 C and occasionally mixed without chopper.
  • the pellets thus obtained showed a narrow size distribution after classification by the sieving method. All sieve fractions from 250 to 800 microns were stored in airtight containers equipped with desiccant.
  • a transparent drinking straw which has in its interior a movable, porous controller, above the controller amoxicillin trihydrate-containing pellets, which were prepared according to A, and potassium clavulanate-containing pellets, which were prepared according to B, at temperatures below 20 0 C and at a relative humidity ⁇ 20% filled so that the ratio of amoxicillin to clavulanic acid 8: 1 and the absolute dose of 500 mg amoxicillin and 62.5 mg clavulanic acid as a single dose.
  • This cap was produced by means of an injection molding machine and a corresponding cap shape of the following composition: Per cap
  • the caps were stored at a relative humidity ⁇ 20% or tightly sealed in an aluminum bag.
  • the airtight packaged inventive systems were stored for up to 3 months at 40 0 C and 75% relative humidity and at the times indicated in Table 2 each time the content of amoxicillin trihydrate by HPLC and formed as a result of dehydration Dimers as degradation products determined by HPLC.
  • the content of clavulanic acid and the breakdown products of clavulanic acid formed on decomposition were determined by HPLC and reported in Table 2.
  • Comparative Example 1 stored at 40 0 C / 75% RH after
  • a corresponding dosage form was provided in a drinking straw.
  • the cap of the drinking straw contains no desiccant.
  • Example 1D Prior to packaging the drinking straw in a packaging material as described in Example 1D, at temperatures below 25 ° C and a relative humidity of 15%, an 8 cm longer, 33 mm wider and 0, was placed in the packaging just prior to packing the drinking straw. 3 mm high (volume 792 mm 3 ) silica gel strips whose water absorption capacity after 7 days storage at 22 ° C / 80% relative humidity was 129 mg. The sealed packages were subjected to the tests as indicated in Example 1. The corresponding values are given in Table 3. Table 3
  • Example 2 a dosage form was prepared and contained in a package containing a corresponding desiccant strip 8 cm long, 24.5 mm wide and 0.4 mm high (volume 784 mm 3 ) containing as a desiccant a molecular sieve (Grade 4 A) , Siliporite NK 10® from Ceca Arkema Groups), packed by sealing.
  • a desiccant strip 8 cm long, 24.5 mm wide and 0.4 mm high volume 784 mm 3
  • a molecular sieve Molecular sieve
  • Siliporite NK 10® Siliporite NK 10® from Ceca Arkema Groups

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Abstract

La présente invention concerne un système conditionné pour être étanche à l'air, comprenant : 1. une combinaison de deux formes pharmaceutiques qui sont préparées séparément et se composent d'une forme pharmaceutique à formulation aqueuse contenant du trihydrate d'amoxicilline comme principe actif pharmaceutique, et d'une forme pharmaceutique préparée séparément et contenant du clavulanate de potassium comme principe actif pharmaceutique, les principes actifs de la combinaison des deux formes pharmaceutiques étant présents en des proportions pondérales nominales de l'amoxicilline par rapport à l'acide clavulanique de 20:1 à 1 :1; et 2. une préparation comprenant au moins un agent déshydratant en des quantités telles que lors du stockage du système conditionné dans des conditions défavorables de l'ordre de 40°C/75% d'humidité relative de l'air pendant une période allant jusqu'à 3 mois, le trihydrate d'amoxicilline subit une dimérisation au maximum de 1,5 % en poids, et l'acide clavulanique subit une dégradation au maximum de 10 % en poids.
EP07722835A 2006-02-17 2007-02-15 Forme d'administration par voie orale stable au stockage d'amoxicilline et d'acide clavulanique Withdrawn EP1986529A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006007830A DE102006007830A1 (de) 2006-02-17 2006-02-17 Lagerstabile orale Darreichungsform von Amoxicillin und Clavulansäure
PCT/EP2007/001335 WO2007093425A2 (fr) 2006-02-17 2007-02-15 Forme d'administration par voie orale stable au stockage d'amoxicilline et d'acide clavulanique

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EP1986529A2 true EP1986529A2 (fr) 2008-11-05

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EP (1) EP1986529A2 (fr)
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US6426342B2 (en) * 1999-08-16 2002-07-30 Revaax Pharmaceuticals, Llc Use of β-lactamase inhibitors as neuroprotectants
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FR2920308B1 (fr) * 2007-09-05 2011-02-25 Unither Dev Forme pharmaceutique pour l'administration par voie orale de principes actifs.
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KR20120012823A (ko) * 2009-04-29 2012-02-10 렉산 파마슈티컬스, 인코포레이티드 신경보호 및 퇴행성 신경 질환 치료용 클라블라네이트 제제
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US20080300569A1 (en) 2008-12-04
WO2007093425A3 (fr) 2007-10-18
DE102006007830A1 (de) 2007-08-30

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