EP1879555A2 - Forme galenique a liberation amelioree du cefuroxime axetil - Google Patents

Forme galenique a liberation amelioree du cefuroxime axetil

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Publication number
EP1879555A2
EP1879555A2 EP06724559A EP06724559A EP1879555A2 EP 1879555 A2 EP1879555 A2 EP 1879555A2 EP 06724559 A EP06724559 A EP 06724559A EP 06724559 A EP06724559 A EP 06724559A EP 1879555 A2 EP1879555 A2 EP 1879555A2
Authority
EP
European Patent Office
Prior art keywords
carrageenan
cefuroximaxetil
pellets
dosage form
modification
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Withdrawn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
EP06724559A
Other languages
German (de)
English (en)
Inventor
Iris Ziegler
Andreas Fischer
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 EP1879555A2 publication Critical patent/EP1879555A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system

Definitions

  • the invention relates to a pharmaceutical composition which contains cefuroximaxetil and ensures an improved release of the active ingredient from dosage forms. Furthermore, the invention relates to a stable crystalline modification of cefuroximaxetil.
  • Cefuroxime axetil (ATC code J01DA45) is a broad-spectrum antibiotic of the cephalosporin class, which is usually administered orally. Administration of cefuroximaxetil is indicated for respiratory, urogenital, and ear, nose and throat infections. Soft tissue infections and bone and joint infections may also be used (see LJ, Scott et al., Drugs 2001, 61, 1455-1500).
  • Cefuroximaxetil is the 1-acetoxyethyl ester of cefuroxime, i. of (6R, 7R) -3-carbomolyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] ceph-3-em-4-carboxylic acid (see US 3,974,153 and US 4,267,320; ATC Code J01 DA06).
  • cefuroximaxetil is usually a mixture of two diastereomers. In the prior art, methods for isolating the individual diastereomers are described (cf DE-OS-27 06 413 and US 5,063,224).
  • cefuroximaxetil is preferably the pharmaceutically usable mixture of diastereomers, as defined, for example, in USP 23, pages 315/316.
  • the two diastereomers are present in a ratio of about 1: 1.
  • a sample of the mixture of diastereomers is chromatographed.
  • the A isomer then corresponds to a peak r A
  • the B isomer a peak r B.
  • the ratio of diastereomers is then determined according to USP 23, page 315, right column, determined by the formula r A / (r A + r B ). This ratio must be between 0.48 and 0.55.
  • cefuroximaxetil A significant problem, which is directly attributable to the properties of the active substance as such, is the low solubility of cefuroximaxetil in an aqueous medium. It is particularly unfavorable that this low solubility is not only present in gastric juice, but also at pH values which correspond to the physiological pH values of the small intestinal milieu. In principle, cefuroximaxetil should be available as quickly as possible, especially in the small intestine, as its absorption mainly takes place there.
  • the bioavailability of cefuroximaxetil is i.a. a function of its solubility.
  • USP 23, page 316 describes a test for determining the bioavailability of cefuroximaxetil.
  • the solubility of the active ingredient is determined from a standardized tablet formulation in methanol. Approved are those products in which at least 60% of the active ingredient is dissolved in 15 minutes and at least 75% of the active ingredient is dissolved within 45 minutes.
  • cefuroxime axetil Various solid modifications of cefuroxime axetil are known in the art, including but not limited to: characterized by a different solubility.
  • the amorphous form of cefuroxime axetil is usually used (compare DE-OS 34 27 828, EP-A 107 276 and US Pat. No. 4,562,181).
  • the use of the amorphous form presents difficulties.
  • amorphous cefuroximaxetil forms a poorly soluble gel layer at 37 ° C on the outer surface of the particles when in contact with water, which significantly slows down drug release.
  • various crystalline modifications of cefuroxime axetii are known. It has been reported that these crystalline modifications are less prone to gel than the amorphous form. In comparison to the amorphous form, however, the previously known crystalline modifications have a lower solubility and thus also a reduced bioavailability.
  • GB-A-15 71 683 discloses a modification which is referred to hereinafter as " ⁇ -modification”.
  • An IR spectrum is disclosed in GB-A-2145409.
  • the ⁇ modification does not show sufficient bioavailability for use as a drug; it does not reach the prescribed minimum solubility in the test according to USP 23 by far.
  • EP-A-757 991 discloses a modification hereinafter referred to as " ⁇ -modification”.
  • the solubility of the active ingredient determined according to the standard method according to USP 23 page 316 reaches only slightly more than 40% after 45 minutes.
  • EP-A-937 727 discloses a modification which "M ⁇ - ° ification" is hereinafter referred to as.
  • EP-A-937 727 discloses a hemihydrate which is about 95% of the R isomer.
  • cefuroxime axetil plays a role in the formulation of oral dosage forms.
  • cefuroxime axetil is usually in the form of film-coated tablets marketed (Elobact ® and Zinnat ®), which according to the manufacturer are not to be crushed or chewed because of the bitter taste of cefuroxime axetil. For children under 5 years other forms of administration are recommended.
  • cefuroxime axetil is also marketed as a dry juice wherein the active ingredient is provided as dry granules. Shortly before the first ingestion, a suspension is prepared therefrom by addition of water, which is stable in the refrigerator (+ 2 ° C. to + 8 ° C.) for 10 days.
  • the currently marketed dry juices contain granules of amorphous cefuroxime axetil which is coated with stearic acid to mask the bitter taste of the active ingredient (see DE-OS-38 16 464). Because of her despite the coating still However, this formulation does not always meet with unrestricted acceptance in children with unpleasant, bitter tastes. The taste even deteriorates during storage of the suspension as the coating softens over time. In addition, the bioavailability of cefuroximaxetil from this dosage form is about 30% lower than in comparable drug forms with uncoated particles.
  • the dosage form e.g. a coated film tablet
  • the dosage form quasi spontaneously disintegrates upon contact with the intestinal juice, so that the active substance particles contained therein can disperse and release the active ingredient quickly, without resulting in any appreciable gelation.
  • particles with a small diameter and a large specific surface area are usually used for producing the film-coated tablets.
  • cefuroximaxetil necessitates a comparatively high loading of the dosage forms.
  • high drug loading is possible, in particular with extrusion pellets, which moreover have the desired smooth, preferably spherical shape.
  • a disadvantage of these dosage forms is that they usually have a very compact structure, for which especially auxiliaries such as microcrystalline cellulose (MCC) are responsible. As a result of their compact structure, these dosage forms do not disintegrate in an aqueous medium or at most only very slowly, which can lead to an undesired, strongly retarded release of cefuroxime axetil.
  • MCC microcrystalline cellulose
  • cefuroximaxetil complicates the fact that, when the amorphous form of the active ingredient is used, the release is made more difficult by the gelation and, when the known crystalline modifications are used, the release is reduced as a result of the lower solubility.
  • the bioavailability of the active ingredient from such pellets is unsatisfactory; For example, pellets are known which release the active ingredient after 60 minutes to only 20-30%.
  • cefuroximaxetil which has advantages over the prior art compositions.
  • the pharmaceutical composition should be well processable into pharmaceutical dosage forms, especially extrusion pellets.
  • the release of cefuroxime axetil from the administration forms in an aqueous medium with a pH value should be as fast as possible according to the physiological pH values of the small intestine in order to ensure a high bioavailability within the so-called absorption window.
  • this object can be achieved by a pharmaceutical composition
  • a pharmaceutical composition comprising cefuroximaxetil and at least one carrageenan selected from the group consisting of ⁇ -carrageenan, ⁇ -carrageenan and ⁇ -carrageenan and, preferably ⁇ -carrageenan.
  • Carrageenans are sulfated polysaccharides that occur as structural components in the cell walls of certain red algae genera. Kappa carrageenan can be obtained, for example, from Kappaphycus alverezii, Chondrus crispus and Sarcothalia crispata.
  • ⁇ -carrageenan, ⁇ -carrageenan and ⁇ -carrageenan are polysaccharides, which differ in particular in number and position of sulfate ester groups.
  • the term "carrageenan” as used herein means at least one carrageenan selected from the group consisting of ⁇ -carrageenan, ⁇ -carrageenan and ⁇ -carrageenan.
  • a lead structure of / c-carrageenan can preferably also be denoted by "- (1 ⁇ 3) - ⁇ -D-galactopyranose-4-sulphate (1 ⁇ 4) -3,6-anhydro- ⁇ -D-galactopyranose- (1-> 3) - ", the lead structure of ⁇ -carrageenan with" - (1-> 3) - ⁇ -D-galactopyranose-4-sulphate (1-> 4) -3,6-anhydro- ⁇ - D-galactopyranose-2-sulfate- (1 ⁇ 3) - "and the lead structure of ⁇ -carrageenan with" - (1 ⁇ 3) - ⁇ -D-galactopyranose-2-sulfate (1-> 4) - ⁇ - D-galactopyranose-2,6-disulfate (1 ⁇ 3) - ".
  • ⁇ -carrageenan preferably comprises sulfated polygalactoside substructures derived from D-galactose and 3,6-anhydro-D-galactose. Examples of such substructures are:
  • carrageenans are known in the prior art, for example ⁇ -carrageenan, ⁇ -carrageenan, ⁇ -carrageenan and ⁇ -carrageenan.
  • composition according to the invention preferably contains a carrageenan which has on average per unit of pyranose less than 1.5 sulphate equivalents, more preferably less than 1.0 sulphate equivalents and in particular 0.6 ⁇ 0.1 sulphate equivalents.
  • composition according to the invention preferably contains ⁇ -carrageenan, preferably as sodium, potassium or calcium salt.
  • ⁇ -carrageenan and its salts are commercially available, for example under the name Gelcarin ®.
  • the composition according to the invention contains at least 5.5% by weight, more preferably at least 6.0% by weight, even more preferably at least 6.5% by weight, most preferably at least 7.0% by weight and in particular at least 7.5% by weight of carrageenan, preferably ⁇ -carrageenan.
  • the composition according to the invention particularly preferably contains 7.5 to 50% by weight, more preferably 10 to 40% by weight and in particular 20 to 30% by weight of carrageenan, preferably ⁇ -carrageenan, based on the total weight of the composition.
  • the weight ratio of cefuroxime axetil to carrageenan is in the range of 0.5: 1 to 5.0: 1, more preferably 1: 0: 1 to 4.0: 1, even more preferably 1: 5: 1 to 3.5: 1, most preferably 2.0: 1 to 3.0: 1, and more preferably 2.2: 1 to 2.6: 1.
  • the composition according to the invention contains tricalcium phosphate and / or at least one sucrose ester. In a particularly preferred embodiment, the composition according to the invention contains both tricalcium phosphate and at least one sucrose ester.
  • Preferred sucrose esters have a hydrophilic-lipohilic balance (HLB) value of 10 to 17, more preferably 11 to 16, especially 13 to 15.
  • HLB hydrophilic-lipohilic balance
  • the composition according to the invention contains the sucrose ester in an amount of 1, 0 to 10 wt .-%, more preferably 2.0 to 8.0 wt .-% and in particular 4.0 to 6.0 wt .-%, based on the Total weight of the composition.
  • the sucrose ester is preferably sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate or mixtures thereof.
  • sucrose palmitate which has an HLB of about 15 and is commercially available, for example, under the type designation "S-1570" from Mitsubishi.
  • composition according to the invention contains tricalcium phosphate and carrageenan
  • the weight ratio of tricalcium phosphate to carrageenan is preferably 1: 1 to 1:10, in particular 1: 2 to 1: 6.
  • the tricalcium phosphate used is preferably a finely divided powder having a mean particle size ⁇ 50 ⁇ m.
  • composition of the invention may contain conventional auxiliaries, such as fillers, binders, lubricants, antioxidants, dyes or preservatives.
  • auxiliaries such as fillers, binders, lubricants, antioxidants, dyes or preservatives.
  • Such adjuvants are known to the person skilled in the art. In this context, for example, can be fully referenced to HP Fiedler, Lexicon of adjuvants for pharmacy, cosmetics and related fields, 2 vols, Editio Cantor, Aulendorff, 2002; DE BUGAY, Pharmaceutical Excipients (Drugs and the Pharmaceutical Sciences, V. 94) (hardcover), CRC, 1998.
  • the composition according to the invention contains no microcrystalline cellulose or other spheronization auxiliaries, such as, for example, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, powdered cellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone, if it has not yet been coated as a dosage form.
  • microcrystalline cellulose or other spheronization auxiliaries such as, for example, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, powdered cellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone, if it has not yet been coated as a dosage form.
  • composition according to the invention can be further processed into a multiparticulate, pharmaceutical dosage form, preferably in the form of extrusion pellets, which release the cefuroxime axetil at a pH of 6 to 7 within 30 minutes, preferably at least 85%, after initially dissolving an optionally present coating Has.
  • the rate of dissolution and thus virtually unrestrained release of the active ingredient is preferably determined according to the method described in the Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on a Biopharmaceutics Classification System. 3/7, Publisher US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 1 August 2000, BP ".
  • Such a high dissolution rate is not achieved even with the aid of extrusion pellets known from the state of the art using microcrystalline cellulose, even if the gastric juice is rendered resistant and / or tasteless. Namely, after dissolution of the film coating, such dosage forms continue to show a delayed disintegration, thereby delaying the release in the small intestine - as with corresponding, uncoated pellets - and thereby impairing their bioavailability.
  • the dosage forms prepared from the compositions according to the invention even if they are coated with a gastric juice-resistant coating, for example for taste neutralization, at a physiological pH of the small intestine of 6 to 7 Dissolution of such a coating, a rapid dissolution and thus within 30 minutes to release of preferably at least 85% Cefuraxirnaxeti! to lead. Particularly preferably, a release of at least 85% is already achieved within 15 minutes ⁇ rapid release).
  • a gastric juice-resistant coating for example for taste neutralization
  • composition of the invention can therefore be used in particular for the production of extrudates, which can then be converted by spheronization into rounded pellets. Therefore, multiparticulate dosage forms obtained by extrusion containing cefuroximaxetil, carrageenan, optionally tricalcium phosphate and optionally at least one sucrose ester, because of the possible high drug loading, the lower requirements for taste neutralization and the rapid dissolution rate at a pH from 6 to 7 particularly suitable for the administration of cefuroximaxetil.
  • Another aspect of the invention relates to a process for producing pellets from a pharmaceutical composition as described above comprising the steps
  • Cefuroximaxetil preferably a mixture of amorphous cefuroximaxetil and crystalline cefuroximaxetil, preferably the ⁇ -modification, at least one carrageenan selected from the group consisting of ⁇ -carrageenan, ⁇ -carrageenan and ⁇ -carrageenan, and
  • optionally further ingredients preferably tricalcium phosphate and / or at least one sucrose ester;
  • step (b) granulating the mixture obtained in step (a);
  • step (c) extruding the granules obtained in step (b), and preferably subsequently dicing the extrudate thus obtained;
  • step (d) optionally spheronizing the extrudate obtained in step (c), and preferably then classifying the pellets thus obtained;
  • step (e) optionally coating the pellets obtained in step (d) with a gastric juice-resistant and / or saliva-resistant coating.
  • Preferred embodiments of the process according to the invention, such as preferred proportions of the components used, are described above in connection with the pharmaceutical composition according to the invention.
  • the process according to the invention comprises all steps (a) to (e) so that extrusion pellets coated by the process are obtained.
  • These pellets may be provided with the usual gastric juice resistant and / or saliva resistant coatings.
  • Cefuroximaxetil which has a solubility of approximately 0.5 mg / ml, which is largely independent of the pH, is preferably protected with gastric juice-resistant coatings.
  • the pellets are not coated with a lipid or a mixture of several lipids which are insoluble in water but dissolve upon contact with the gastrointestinal fluid.
  • the pellets of the invention are preferably e.g. not coated with stearic acid.
  • the components can be added simultaneously or in succession to the mixture.
  • the mixture can be carried out in a known mixer or granulator, so that optionally the mixture, the granulation and extrusion can take place simultaneously.
  • step (b) is carried out as wet granulation.
  • the wet granulation may preferably be carried out with water or aqueous solvent.
  • the spheronization, extrusion and coating can each take place in the apparatuses known to the person skilled in the art.
  • a fluidized bed apparatus may preferably be used.
  • the crystalline cefuroximaxetil is the ⁇ -modification.
  • the relative weight ratio of cefuroxime axetil is in amorphous form Cefuroximaxetil in crystalline form is preferably in the range of 10:90 to 90:10, more preferably 20:80 to 80:20, even more preferably 30:70 to 70:30, and most preferably 40:60 to 60:40. Most preferably, the relative weight ratio is 50:50.
  • the aspect of the invention relates to such a mixture comprising amorphous cefuroximaxetil and cefuroxime axetil in the ⁇ -modification, preferably in one of the abovementioned relative weight ratios.
  • pellets preferably extrusion pellets, which are obtainable by the method described above.
  • the pellets of the invention are characterized by excellent disintegration properties in an aqueous medium. In addition, they allow a relatively high drug loading.
  • the release and, concomitantly, the bioavailability of cefuroxime axetil from dosage forms containing the pellets according to the invention is markedly improved in comparison with the dosage forms of the prior art.
  • a release of at least 85% can be achieved after only 30 minutes, after first having dissolved any coating that may be present.
  • a further aspect of the invention relates to a solid pharmaceutical dosage form containing cefuroxime axetil which releases the cefuroxime axetil under physiological conditions at a pH of 6 to 7 within 30 minutes in an amount of at least 75%, preferably at least 85% first an optional coating has dissolved.
  • the dosage form is multiparticulate. The determination of the release is preferably carried out as described in connection with the examples.
  • a further aspect of the invention relates to a multiparticulate pharmaceutical dosage form comprising a pharmaceutical composition described above, preferably pellets described above.
  • Preferred embodiments of the dosage form according to the invention such as preferred proportions of the components used, are mentioned above Connection with the pharmaceutical composition according to the invention or the pellets according to the invention described.
  • the dosage form according to the invention is preferably intended for oral administration. It is preferably multiparticulate. It preferably comprises granules, pellets, preferably extrusion pellets, microgranules or micropellets.
  • the administration form according to the invention is particularly preferably in the form of extrusion pellets, preferably in spherical form. These can optionally be filled into gelatine capsules.
  • the particles of the multiparticulate dosage form according to the invention preferably have an average diameter (size) ⁇ 1000 ⁇ m, more preferably ⁇ 900 ⁇ m, even more preferably ⁇ 800 ⁇ m, most preferably ⁇ 700 ⁇ m and in particular between 250 and 700 ⁇ m.
  • the dosage form according to the invention is present as a tablet, in particular as a film tablet.
  • the tablets are particularly preferably obtainable by tableting the pellets according to the invention, preferably extrusion pellets, with the addition of the customary tabletting aids.
  • the dosage form according to the invention has a gastric juice-resistant and / or saliva-resistant coating.
  • a protective coating is additionally applied before the application of this coating, which isolates the core.
  • these coatings are preferably applied in an amount of from 1.0 to 50% by weight, more preferably from 2.0 to 25% by weight, based on the total weight of the administration forms.
  • Suitable materials for a gastric juice-resistant coating are preferably methacrylic acid / alkyl methacrylate copolymers, preferably copolymers of methacrylic acid / methyl methacrylate with a molar ratio of monomers of 1: 1 to 1: 2, such as Eudragit L ® , Eudragit S ® or Eudragit L30D-55 ® , or ethyl methacrylate, which dissolve rapidly at a pH of> pH 6.
  • coatings which are resistant to gastric juice can be applied to those based on celluloses which are known to the person skilled in the art. The application of the coatings can be carried out with appropriate solutions or dispersions in organic or aqueous medium, with an aqueous medium being preferred.
  • Saliva resistant coatings are coatings based on Eudragit E, 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 to 2.0) known to the person skilled in the art the release in small intestinal juice similar preparations at pH values of 6 to 7, preferably pH 6.4 to 6.8 understood.
  • the dosage forms according to the invention are characterized in that they have a high dissolution rate and the cefuroximaxetil is preferably released within 30 minutes to at least 85%, after initially an optionally present coating has dissolved.
  • the pH-dependent dissolution time of such a coating can be determined by simple preliminary experiments in appropriate standard buffer solutions.
  • the active ingredient content of the dosage form according to the invention is preferably adapted to a once or twice daily administration to an adult or a pediatric patient.
  • the daily dose is usually in the range of 250 to 1000 mg per day, in children depending on age and weight, usually in the range of 80 to 500 mg per day.
  • the dosage form according to the invention comprises, per dosage unit, an equivalent amount based on 125, 250 or 500 mg cefuroxime.
  • the dosage form according to the invention has an improved release profile of Cefuroximaxetil on.
  • the dosage form of the invention cefuroximaxetil, after an optionally present coating has first dissolved, at a pH of 8 to 7 within 30 minutes in an amount of at least 75%, preferably at least 80%, more preferably at least 85% , most preferably at least 90% and in particular at least 95% free, determined according to the method described in the Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on a Biopharmaceutics Classification System., p -3 / 7, Publisher US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000, BP ".
  • the multiparticulate dosage form is in the form of spherical extrusion pellets. These may preferably be present as a single dose in accordance with a delivery system comprising a drinking straw with a preferably movable blocking device, as described in WO 03/079957, WO 2004/000202, WO2004 / 000264.
  • the blocking device is preferably a plug whose cross section is preferably adapted to the cross section of the drinking straw. The plug can be moved between two stops. The stops narrow the straw, with the constrictions designed to hold back the plug, but not the multiparticulate dosage form.
  • administration to the patient is with a transport fluid.
  • Another object of the present invention is a delivery system comprising a dosage form according to the invention, preferably as a single dose, arranged in a drinking straw with at least one preferably movable locking device for administration by means of a transport fluid to a human patient.
  • Suitable transport liquids are particle-free drinks, preferably aqueous liquids, such as. As water, tea, fruit juices, Coca-Cola, lemonades, Transportfiüsstechniken with an acidic pH when using gastric juice resistant equipped, ie coated, multiparticulate dosage forms such. B. extrusion pellets, are preferred.
  • Another aspect of the invention relates to a novel crystalline modification of cefuroxime axetil (" ⁇ -modification").
  • a new crystalline modification results.
  • Virtually complete conversion of the employed forms / modifications to the novel crystalline modification can be observed when the amorphous form of cefuroxime axetil and crystalline cefuroxime axetil of the 50:50 weight ratio in the presence of K-carrageenan are formulated into extrusion pellets by the process of this invention.
  • the granulation is carried out as wet granulation in an aqueous medium, comparatively large amounts of water are required, the presence of the crystalline ⁇ -modification, in addition to the amorphous form, simplifying the handling of the composition during pellet production.
  • the new crystalline modification is hereinafter also referred to as " ⁇ -modification".
  • the novel crystalline modification is preferably formed when a mixture of amorphous cefuroximaxetil and crystalline cefuroximaxetil, preferably the ⁇ -modification, together with carrageenan, preferably ⁇ -carrageenan, is processed to pellets, preferably to extrusion pellets.
  • step (a) powder diffractograms of the starting mixture (step (a)), the granules (step (b)), the extrudate (step (c)) and the pellets (step (d)) were recorded.
  • the ⁇ -modification of cefuroximaxetil according to the invention can also be prepared by suspending the ⁇ -modification or a 1: 1 mixture of the ⁇ -modification and the amorphous form in water and at room temperature for a period of several hours , Preferably several days, preferably at room temperature or slightly elevated temperature, for example at 40 0 C.
  • the ⁇ -modification of cefuroximaxetil according to the invention can also be prepared by precipitation from a solution of the ⁇ -modification in acetone by addition of water.
  • a filtered solution of the ⁇ -modification in acetone can be introduced and the precipitation of the ⁇ -modification by slow addition of water induced.
  • the amount of water used is preferably at least the simple, more preferred at least one and a half times and more preferably at least twice the amount of acetone used.
  • one aspect of the invention also relates to a crystalline modification of cefuroxime axetil obtainable by the above-mentioned methods.
  • FIG. 1 An X-ray diffractogram of the novel crystalline modification of cefuroxime axetil ( ⁇ -modification) is shown in FIG.
  • the modification according to the invention is characterized in particular by an X-ray diffraction spectrum comprising one or more reflections selected from 8.3, 10.4, 13.0, 16.4, and 25.5 ( ⁇ 2 ⁇ ⁇ 0.2).
  • a corresponding X-ray diffractogram additionally has the following x-ray reflections (° 2 ⁇ ⁇ 0.2): 7.3, 14.5, 18.3, 21, 1, 21, 8 and / or 29.0.
  • FIG. 1 An FT Raman spectrum of the novel crystalline modification of cefuroxime axetil ( ⁇ -modification) is shown in FIG.
  • the modification according to the invention is in particular characterized by an FT Raman spectrum comprising one or more peaks selected from 1676, 1646, 1629 and 1593 ( ⁇ 3 cm -1 ), Preferably a corresponding FT Raman spectrum additionally has the following peaks: 2948, 1781, 1485 , 1398, 1076, 881 and / or 767 ( ⁇ 3 cm 1 ).
  • cefuroximaxetil has advantages over the previously known crystalline modifications of cefuroxime axetil.
  • the specific physical properties of the modification may be of interest during processing and storage (thermodynamic stability, shape, color, density, bulk density, melting point, solubility properties, hygroscopicity, tack, hardness, deformability, etc.).
  • the crystalline modification may also have improved chemical properties. For example, it is known that a lower hygroscopy to a improved chemical stability and longer shelf life of chemical compounds can result.
  • pellets which can be prepared by the process according to the invention or contain the inventive crystalline modification of cefuroximaxetil, an almost complete drug release after as little as 20 to 30 minutes, largely independent of modification and particle size of the cefuroxime axetil, which was used to prepare the pellets ,
  • the rapid release of the drug is also maintained when the pellets are coated and the release after dissolution of the coating is measured.
  • the inventive crystalline modification of cefuroximaxetil is storage stable. After storage at elevated temperature, no significant change in the composition can be observed, neither in chemical terms (decomposition products) nor in physical terms (solubility, X-ray diffractogram). The content of the comparatively easily formed ⁇ 3 -Abbau.s is even after storage for 2 months at 40 0 C at 75% rel. Humidity still below 1, 0 wt .-%, which indicates excellent stability of the modification according to the invention.
  • the stability of the modification is a very important aspect of the polymorphism. Namely, by using the stable modification in the drug, it can be ensured that no polymorphic conversion takes place during storage in the formulation. This is of particular importance in that otherwise due to a conversion from a less stable Modification in a more stable modification can change the properties of the drug.
  • Cefuroximaxetil Due to the fact that three further crystalline modifications are already known for cefuroximaxetil in addition to the amorphous modification, including the crystalline ⁇ modification according to the invention ( ⁇ -, ⁇ - and ⁇ -), this aspect additionally gains importance.
  • Cefuroxime axetil appears to have a pronounced tendency to polymorphism, which is not the case with any drug.
  • polymorphic transformation becomes more likely during storage. In such cases, therefore, there is a particular need to provide the most stable polymorphic modification possible.
  • cefuroximaxetil The rate of release of cefuroximaxetil was determined according to the method described in the Guidance for Industry, Waiver of ln vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on a Biopharmaceutics Classification System., Pages 1-3 / 7, publ. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000, BP ".
  • a release apparatus with blade stirrer according to US Pharmacopeia was used and the release at a temperature of 37 ° C and a rotational speed of 150 min "1 in 1000 ml of artificial intestinal juice (sodium phosphate buffer, pH 6.8) and 0.3% SDS or in 1000 ml of artificial gastric juice (pH 1, 2) and 0.5% Tween 80 as the release medium in the time indicated in the examples, each released at a time Amount of the active ingredient was determined by HPLC. The detection was carried out with the aid of a UV detector at 282 nm. The mean value over 6 measurements was formed.
  • Extrusion pellets of the following composition were prepared:
  • the release was determined both in artificial gastric juice + Tween, and in artificial intestinal juice + SDS with about 253 mg unpainted pellets (total content of cefuroximaxetil about 150 mg, equivalent equivalent amount of 125 mg cefuroxime, dose unit for children).
  • Example 2 The pellets from Example 1 were coated with a film of the following composition:
  • Solids content 12.58% by weight
  • the coating was carried out by aqueous coating in the fluidized bed at a production temperature of 30 ° C.
  • the coating dissolved completely after 5 minutes.
  • Example 8 The pellets from Example 8 were coated with a film of the following composition:
  • Solids content 15% by weight
  • the coating was carried out in the fluidized bed at a production temperature of 30 ° C in an amount such that the coating constituted 15% by weight of the coated pellets (15% w / w).
  • the crystalline modification of cefuroximaxetil according to the invention was characterized by X-ray diffractometry.
  • XRPD X-ray powder diffractogram
  • cefuroximaxetil is characterized by one or more of the following X-ray reflections (° 2 ⁇ ⁇ 0.2) which are measured at a powder absorption at room temperature and Cu K ⁇ radiation: 8.3, 10.4, 13.0, and 25.5.
  • a corresponding X-ray diffractogram additionally has the following X-ray reflections (° 2 ⁇ ⁇ 0.2): 7.3, 14.5, 18.3, 21, 1, 21, 8 and 29.0.
  • the X-ray diffractograms were recorded as powder images with a STOE Stadi P powder diffractometer.
  • the instrument was equipped with a curved germanium monochromator and a linear position-selective detector. The samples were prepared as flat samples.
  • the diffraction reflections were measured in an angle range of 2 ° to 50 °.
  • the step size was 0.05 °. The measurement was carried out at 23 ⁇ 1 ° C.

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Abstract

L'invention concerne une composition pharmaceutique comprenant du céfuroxime axétil et au moins un carraghénane sélectionné dans le groupe comprenant ?-carraghénane, ?-carraghénane et ?-carraghénane. L'invention concerne également des pastilles, une forme galénique pharmaceutique multiparticulaire, ainsi qu'une nouvelle modification cristalline du céfuroxime axétil.
EP06724559A 2005-04-25 2006-04-25 Forme galenique a liberation amelioree du cefuroxime axetil Withdrawn EP1879555A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005019458A DE102005019458A1 (de) 2005-04-25 2005-04-25 Darreichungsform mit verbesserter Freisetzung von Cefuroximaxetil
PCT/EP2006/003814 WO2006114277A2 (fr) 2005-04-25 2006-04-25 Forme galenique a liberation amelioree du cefuroxime axetil

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EP (1) EP1879555A2 (fr)
DE (1) DE102005019458A1 (fr)
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DE102006059510A1 (de) 2006-12-14 2008-06-19 Grünenthal GmbH Beschichtete Pellets
WO2013038323A1 (fr) * 2011-09-13 2013-03-21 Unimark Remedies Ltd. Compositions pharmaceutiques de céfuroxime axétil à goût masqué
US20130273209A1 (en) * 2012-04-13 2013-10-17 Frito-Lay North America, Inc. Bi-Colored Random Collets and Methods for Making Same
US9510617B2 (en) 2012-04-13 2016-12-06 Frito-Lay North America, Inc. Micropellets of fine particle nutrients and methods of incorporating same into snack food products
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US9669574B2 (en) 2014-11-11 2017-06-06 Frito-Lay North America, Inc. Twin screw rotary head extruder, method of extrusion and random extruded products
EP3692805A1 (fr) * 2019-01-18 2020-08-12 GNT Group B.V. Aliments liquides colorés ayant un faible ph

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DE102005019458A1 (de) 2006-10-26
WO2006114277A3 (fr) 2007-05-24
WO2006114277A2 (fr) 2006-11-02
US8747900B2 (en) 2014-06-10
US20080187594A1 (en) 2008-08-07

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