EP1499298A1 - Forme d'administration orale pour principes actifs basiques difficilement solubles - Google Patents

Forme d'administration orale pour principes actifs basiques difficilement solubles

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Publication number
EP1499298A1
EP1499298A1 EP03722336A EP03722336A EP1499298A1 EP 1499298 A1 EP1499298 A1 EP 1499298A1 EP 03722336 A EP03722336 A EP 03722336A EP 03722336 A EP03722336 A EP 03722336A EP 1499298 A1 EP1499298 A1 EP 1499298A1
Authority
EP
European Patent Office
Prior art keywords
acid
weight
pharmaceutical composition
core material
active ingredient
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Withdrawn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
EP03722336A
Other languages
German (de)
English (en)
Inventor
Ulrich Brauns
Rolf Brickl
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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 Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to EP07108392A priority Critical patent/EP1818047A3/fr
Publication of EP1499298A1 publication Critical patent/EP1499298A1/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Withdrawn legal-status Critical Current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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to an oral administration form for basic active ingredients with a pH-dependent solubility behavior and salts thereof.
  • an “active ingredient” is any pharmacologically active compound which (as such or as one of its pharmaceutically acceptable salts) is a weak base and has a pH-dependent solubility behavior in the range from pH 1 to pH 7.5 (with better Solubility under acidic conditions and poorer solubility under basic conditions) shows that with such active substances the bioavailability when given orally can depend on the pH in the gastrointestinal tract.
  • Active substances within the meaning of this invention preferably exhibit in aqueous solutions low pH values due to single or multiple protonation, relatively high saturation solubilities, while the neutral compounds are practically insoluble at pH values above 5 according to the definition of the European Pharmacopoeia (saturation solubility ⁇ 100 ⁇ g / ml).
  • the oral dosage form according to the invention can, for example, 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl ⁇ -1-methyl! -1H-benzimidazole-5-carbonyl) -pyridine-2- ethyl yl-amino] propionate (WO98 / 37075), BIBU 104 (lefradafiban; (3S, 5S) -5 - [[4H / V-methoxycarbonylamidino) -4-biphenylyl] - oxymethyl] -3 - [(methoxycarbonyl) methyl] -2-pyrrolidinone; EP 0 483 667), (f?) - 2- [4- ( ⁇ / - phenylcarbonylamidino) phenylaminomethyl] -1-methyl-5- [1 - (/?
  • the solubility of a compound can be determined by dispersing an excess of the compound in the respective medium at room temperature and shaking vigorously for a defined period of time (approx. 1 to 24 h) until equilibrium is established. After filtration, the pH is determined in the clear filtrate and the concentration of the dissolved substance is determined by means of spectral photometry or another suitable analytical method.
  • the pH-dependent solubility behavior of the active ingredient can lead to the fact that it can only completely dissolve in the patient's stomach if the liquid present in the stomach has a sufficiently low pH when it is administered orally in a conventional manner. If the pH value in the stomach is increased (this may be due to normal physiological variability, an illness or due to comedication with drugs that increase the stomach pH), the active ingredient can no longer dissolve completely.
  • the influence of the dose of the respective active substance on its bioavailability can be described quantitatively using the concept of the (dimensionless) dose number (Do).
  • Do dose number
  • the active substances contained in the oral dosage form according to the invention have a value of less than 1 for the dose number based on the solubility at pH ⁇ 2 (ie sufficiently acidic stomach) and for the dose number based on the solubility at pH> 5 (ie none or only negligible) Gastric acid) has a value of well over 1, ie Both the extent of the pH dependence of the solubility of the active substance and the amount of the active substance dose are of interest for the oral dosage form according to the invention.
  • the object of the invention is to provide an orally administered pharmaceutical composition for active substances with pH-dependent solubility behavior, which ensures the largely pH-independent bioavailability of the active substance.
  • acids for the purposes of this invention are, for example, tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid including their hydrates and acidic salts.
  • tartaric acid, fumaric acid, succinic acid and citric acid, in particular tartaric acid, fumaric acid and succinic acid are particularly suitable.
  • a further object of the invention is therefore to avoid the undesirable interactions between acid and active ingredient despite the use of an organic acid to improve solubility.
  • Multiparticulate dosage forms in which the individual particles are structured as in FIG. 1 are particularly suitable for the preferred spatial separation of active substance and organic acid.
  • Figure 1 shows the schematic structure of the pharmaceutical composition based on a section through a pellet suitable for the production of the pharmaceutical composition according to the invention.
  • the approximately spherical / spherical core region of this pellet contains / consists of the pharmaceutically acceptable organic acid.
  • This is followed, if necessary, by a layer which separates the acid core from the active substance-containing layer, the so-called insulating layer.
  • the insulating layer in turn, or the core material in the absence of an insulating layer, is surrounded by the active ingredient layer, which is also spherical in shape, which in turn can be enclosed by a coating which increases the abrasion resistance and the storage stability of the pellets.
  • a pharmaceutically acceptable organic acid with a water solubility of> 1 g / 250 ml at 20 ° C e.g. Tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid including their hydrates and acid salts, to which a small proportion of 1 to 10% by weight, preferably 3 to 6% by weight, of a suitable binder is optionally added.
  • a binder is e.g. required if the core material is manufactured in a boiler construction process.
  • other technological auxiliaries are required instead of binders, for example microcrystalline cellulose.
  • a water-soluble, pharmaceutically acceptable polymer for example, gum arabic or a partially or fully synthetic polymer from the group consisting of hydroxypropyl celluloses, hydroxypropyl methyl celluloses, methyl celluloses and hydroxyethyl celluloses. the carboxymethyl celluloses, the polyvinyl pyrrolidones, the copolymers of N-vinyl pyrrolidone and vinyl acetate, or combinations of these polymers. Gum arabic or a hydroxypropylmethyl cellulose is preferably used.
  • the coating with the water-soluble, pharmaceutically acceptable polymer can be carried out with the addition of suitable plasticizers, release agents and pigments, such as, for example, triethyl citrate, tributyl citrate, triacetin, polyethylene glycols (plasticizers), talc, silica (release agent), titanium dioxide or iron oxide pigments (pigments).
  • suitable plasticizers, release agents and pigments such as, for example, triethyl citrate, tributyl citrate, triacetin, polyethylene glycols (plasticizers), talc, silica (release agent), titanium dioxide or iron oxide pigments (pigments).
  • the active substance layer contains the active substance as well as binding agents and optionally release agents.
  • Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, copolymers of olid / -vinyl pyrrolidone and vinyl acetate or combinations of these polymers can be used as binders, for example. Hydroxypropyl cellulose or copolymers of ⁇ / -vinylpyrrolidone and vinyl acetate are preferably used.
  • release agents such as Talc, magnesium stearate or silica serve to prevent the particles from growing together during the process.
  • the preferred active ingredient content is at most 60%, preferably at most 50%, of the pharmaceutical composition.
  • the optional outermost layer which serves to reduce increased abrasion when filling into capsules and / or to increase the storage stability, consists of pharmaceutically customary film formers, plasticizers and optionally pigments.
  • plasticizers include triethyl citrate, tributyl citrate, triacetin and polyethylene glycols.
  • titanium dioxide or iron oxide pigments can be used as pigments.
  • the outer coating preferably consists of hydroxypropylmethyl cellulose and / or methyl cellulose, optionally with the addition of polyethylene glycols as plasticizers.
  • the pellets can be produced by the process described below:
  • the acidic core material consists either of crystals of the organic acid used in each case or, more advantageously, of approximately spherical particles of the desired size with a high content of organic acid, which can be produced by processes which are known and established in pharmaceutical technology , In particular, the construction of the core material in boiler processes, on pelletizing plates, or by means of extrusion / spheronization are possible.
  • the core material thus obtained can then be divided into fractions of the desired diameter by sieving. Suitable core material has an average diameter of 0.4 to 1.5 mm, preferably 0.6 to 0.8 mm.
  • the insulating layer is first applied to this acidic core material. This can be done by conventional methods, e.g. by applying an aqueous dispersion of the water-soluble, pharmaceutically acceptable polymer, optionally with the addition of plasticizers, release agents and / or pigments in the fluidized bed, in coating pans or in conventional film coating systems. If necessary, you can then sieve again.
  • the active ingredient is then applied from a dispersion containing binder and, if appropriate, release agent.
  • the volatile dispersant is removed by drying during and / or after the process.
  • a binder in the dispersion for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, copolymers of ⁇ / -vinyl pyrrolidone and vinyl acetate or combinations of these polymers can be used. Hydroxypropyl cellulose or copolymers of ⁇ / -vinylpyrrolidone and vinyl acetate are preferably used.
  • Suitable separating agents are, for example, talc, magnesium stearate or silica; talc is preferably used.
  • suitable dispersants are water, ethanol, 2-propanol, acetone or mixtures of these solvents with one another.
  • the drug application to the core material can be done in the pharmacy table technology of known and established processes, for example in coating pans, conventional film coating systems or in the fluidized bed. Then a screening process can be carried out again.
  • the system can finally be coated with a layer of pharmaceutically customary film formers, plasticizers and possibly pigments. This can be done with the aid of customary methods, as already mentioned in the description of the application of the insulating layer.
  • pellets containing active substance are obtained by the process described above, which can then be filled into hard capsules, for example.
  • a large number of these units according to the dosage are filled into hard capsules on standard capsule filling machines.
  • Suitable hard capsules are, for example, hard gelatin capsules or hard capsules made of hydroxypropylmethyl cellulose (HPMC).
  • HPMC hydroxypropylmethyl cellulose
  • the preferred active ingredient content of the pharmaceutical composition is at most 60%, preferably at most 50%.
  • the pharmaceutical compositions according to the invention have an improved bioavailability of the active ingredient contained.
  • the pharmaceutical compositions according to Examples 1 and 2 were tested for their bioavailability improvement.
  • the formulation prepared according to Example 1 was clinically tested on a total of 15 test persons with regard to their bioavailability.
  • the extent of absorption was determined by quantitative determination of the urine excretion of the active metabolite 3 - [(2 - ⁇ [4- (amino-imino-methyl) -phenylamino] -methyl ⁇ -1-methyl-1H-benzimidazole-5- carbonyl) pyridin-2-yl-amino] -propionic acid determined.
  • the relative bioavailability after pretreatment with pantoprazole was 94% on average compared to application without previous pretreatment.
  • the bioavailability was improved by a factor of about 5 by using the formulation according to the invention.
  • the formulation prepared according to Example 2 was also clinically tested on a total of 15 subjects with regard to its bioavailability.
  • the subjects received the composition fasted orally without pretreatment.
  • the same test subjects were treated with 40 mg pantoprazole b.i.d. for three days prior to oral application of the composition to increase the gastric pH. pretreated by os; the treatment was continued during the administration of the formulation according to the invention.
  • the extent of the absorption was determined by quantitative determination of the urine excretion of the active metabolite 3 - [(2 - ⁇ [4- (amino-imino-methyl) -phenyl-amino] -methyl ⁇ -1-methyl-1 H-benzimidazole-5 -carbonyl) -pyridin-2-yl-amino] -propionic acid determined.
  • the relative bioavailability after pretreatment with pantoprazole was 76% on average compared to application without previous pretreatment.
  • the bioavailability of the active ingredient was improved by a factor of about 4 compared to conventional formulations.
  • FIG. 2 graphically represents the bioavailability of the formulations according to the invention in comparison with the conventional tablet with or without administration of pantoprazole.
  • the amount of active ingredient per capsule is preferably chosen so that 1 to 2 capsules daily are sufficient to achieve the desired effect.
  • the preferred acid-drug ratio is about 1: 1 to about 20: 1.
  • the theoretical lower limit at which the system can still function is 1 equivalent acid per mole of the active ingredient.
  • the upper limit of approx. 20: 1 is determined by the size of the dosage form at the desired dosages (number of pellets per capsule). In quality control, in vitro releases are measured using USP methods. Here, the dosage form is released in a volume of 900 ml and the pH selected so that "sink conditions" exist, ie the complete dose of active ingredient is soluble in these 900 ml.
  • a dosage form containing the highest dose used in humans is used in a volume of 200 ml (this corresponds to human use) in buffer at a pH with low solubility of the active ingredient in the physiologically sensible range, i.e. released between pH 1-7. Since this method can be used to predict absorbability well even with an acidic gastric pH, it is well suited for the optimization of dosage forms.
  • the maximum release and / or the area under the curve from the time 0 to the end point of the release can be used as relevant parameters.
  • Table 3 shows the in vitro releases and characteristic data AUC and maximum release of an example C5 according to the invention (active ingredient: flibanserin; see Table 11) in comparison to the reference form with a similar active ingredient content in 0.005 mol citrate buffer pH 5.0
  • This value represents the pH value at the end of the release.
  • Table 4 shows the in vitro releases and characteristic data AUC and maximum release of examples C4 to C15 according to the invention (active ingredient: flibanserin; see Table 11) in comparison to reference forms C1 to C3.
  • This value represents the pH value at the end of the release.
  • This value represents the pH value at the end of the release.
  • Table 7 shows the in vitro releases and characteristic data AUC and maximum release of the examples C54 to C59 according to the invention (active ingredient: amelubant; see Table 14) in comparison to the reference form C53. Due to the very low solubility of the active ingredient, a mixture of water / ethanol 2/1 was used as the test medium.
  • Table 8 shows the in vitro releases and characteristic data AUC and maximum release of the examples C60 to C61 according to the invention (active ingredient: telmisartan; see Table 15) in comparison to reference forms C58 and C59.
  • active ingredient telmisartan; see Table 15
  • a 0.0005 M citrate buffer adjusted to pH 5.0 was used as the test medium.
  • Example C58 0 0 1 2 2 2 2 2 20.64 5
  • Example C59 0 0 0 0 0 0 0 0 4.57 5
  • Example C60 0 15 20 25 26 24 26 322.11 2
  • Example C61 0 5 6 7 7 8 8 93, 11 2 *: This value represents the pH value at the end of the release.
  • Figure 1 shows the schematic structure of a pharmaceutical composition according to the invention in the form of a sectional view of a pellet.
  • FIG. 2 shows the bioavailability of the formulations according to the invention in comparison with the conventional tablet with or without administration of pantoprazole.
  • FIG. 3 shows the in vitro releases of an example C5 according to the invention in comparison with the reference formulation C2 with a similar active substance content in 0.005 mol citrate buffer pH 5.0.
  • the following examples are intended to explain the invention in more detail:
  • Gum arabic 1 part by weight tartaric acid 20 parts by weight 1 part by weight of gum arabic is dissolved in 4 parts by weight of purified water at 50 ° C. with stirring. 5 parts by weight of tartaric acid are then dissolved in this solution with stirring.
  • the spherical tartaric acid core material is then dried in a rotating kettle at a supply air temperature of 60 ° - 80 ° C.
  • the core material is fractionated using a tumbler sieve with sieve trays with a nominal mesh size of 0.6 and 0.8 mm.
  • the good fraction between 0.6 and 0.8 mm is used in the further process.
  • composition tartaric acid core material 23 parts by weight gum arabic 1 part by weight talc 2 parts by weight
  • the isolated tartaric core material is then dried in a forced-air drying cabinet at 40 ° C for 8 hours.
  • the dried isolated tartaric core material is sieved with a sieve with a nominal mesh size of 1.0 mm.
  • the good fraction (grain size ⁇ 1 mm) is expanded / developed.
  • Insulated tartaric core material 91 parts by weight
  • Active ingredient (mesylate from BIBR 1048) 25 parts by weight
  • Hydroxypropyl cellulose is dissolved in 168 parts by weight of 2-propanol with stirring and then the active ingredient and talc are dispersed in this solution with stirring.
  • 91 parts by weight of insulated tartaric acid-containing core material are sprayed with the active ingredient-containing dispersion at a supply air temperature of 20 ° -30 ° C using the bed spray method.
  • the active ingredient-containing pellets are then dried in a forced-air drying cabinet at 35 ° C for 8 hours.
  • the active substance-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm.
  • the good fraction (grain size ⁇ 1.25 mm) is processed further.
  • a quantity of active substance-containing pellets, each containing 50 mg of active substance base, is filled into size 1 hard gelatin capsules by means of a capsule filling machine.
  • composition gum arabic 1 part by weight tartaric acid 20 parts by weight
  • the spherical tartaric acid core material is then dried in a rotating kettle at a supply air temperature of 60 ° - 80 ° C.
  • the core material is fractionated using a tumbler sieve with sieve bottoms with a nominal mesh size of 0.6 and 0.8 mm. The good fraction between
  • composition tartaric core material 23 parts by weight
  • Talc 2 parts by weight 1 part by weight of gum arabic is dissolved in a mixture of 6.7 parts by weight of ethanol 96% and 13.5 parts by weight of purified water. Then 2 parts by weight of talc are dispersed in the solution with stirring.
  • the isolated tartaric core material is then dried in a forced-air drying cabinet at 40 ° C for 8 hours.
  • the dried isolated tartaric core material is sieved with a sieve with a nominal mesh size of 1.0 mm.
  • the good fraction (grain size ⁇ 1 mm) is expanded / developed.
  • Insulated tartaric core material 57 parts by weight
  • Active ingredient (mesylate from BIBR 1048) 50 parts by weight
  • Hydroxypropyl cellulose is dissolved in 335 parts by weight of 2-propanol with stirring and then the active ingredient and talc are dispersed in this solution with stirring.
  • a fluidized bed process system 91 parts by weight of insulated tartaric acid-containing core material are sprayed with the active ingredient-containing dispersion at a supply air temperature of 20 ° -30 ° C using the bed spray method.
  • the active ingredient-containing pellets are then dried in a forced-air drying cabinet at 35 ° C for 8 hours.
  • the active substance-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm.
  • the good fraction (grain size ⁇ 1.25 mm) is processed further.
  • a quantity of active substance-containing pellets, each containing 50 mg of active substance base, is filled into size 2 hard gelatin capsules by means of a capsule filling machine.
  • Step b is absolutely necessary if the acid and the active substance layer are incompatible
  • step d is necessary if the mechanical stability of the active substance layer is not sufficient for complete dissolution of the active substance.
  • Example a1 Structure of tartaric acid core material
  • Gum arabic 1 part by weight tartaric acid 20 parts by weight 1 part by weight of gum arabic is dissolved in 4 parts by weight of purified water at 50 ° C. with stirring. 5 parts by weight of tartaric acid are then dissolved in this solution with stirring.
  • the spherical tartaric acid core material is then dried in a rotating kettle at a supply air temperature of 60 ° - 80 ° C.
  • the core material is fractionated using a tumbler sieve with sieve trays with a nominal mesh size of 0.6 and 0.8 mm.
  • the good fraction between 0.6 and 0.8 mm is used in the further process.
  • Example a2 Structure of core material containing fumaric acid
  • 77 parts by weight of fumaric acid, 20 parts by weight of Avicei PH 101 and 3 parts by weight of Kollidon K25 are mixed in a ring mixer for 15 minutes.
  • the powder mixture is then transferred to a twin screw feeder.
  • This mixture is introduced into a Werner & Pfleiderer 37 / 18D twin-screw extruder (or another suitable type of extruder) at a rate of approximately 1 kg / h together with water which is added using a ProMinent metering pump.
  • the water metering is automatically controlled so that a target torque of approx. 19% is generated in the extruder.
  • the extrusion is carried out via a die plate with 8 mm diameter holes.
  • the extrusion strands are rounded to pellets in a WyPro spheromat, with approx. 3 minutes being rounded at approx. 850 RPM.
  • the core material is fractionated using a tumbler screening machine with different screening trays with a nominal mesh size of 0.71 to 1.25 mm.
  • the appropriate good fraction between 0.71 and 0.90 or 0.90 and 1, 12 mm is used in the further processes.
  • Example a3 Structure of core material containing succinic acid
  • composition Kollidon K25 3 parts by weight
  • Example a4 Structure of core material containing citric acid
  • Citric acid 20 parts by weight 1 part by weight of Koilidon K90 is dissolved in 6 parts by weight of isopropanol and 1 part by weight of talc is suspended. 3 parts by weight of citric acid are dissolved in a further 6 parts by weight of isopropanol with stirring.
  • 17 parts by weight of insulated citric acid-containing core material of size 0.5 - 0.6 mm at a supply air temperature of 20 ° - 30 ° C are sprayed with the two active ingredient-containing dispersions / solutions by means of a three-head nozzle in the bed spray process, so that almost spherical particles are formed.
  • the active ingredient-containing pellets are then dried in a forced-air drying cabinet at 35 ° C for 8 hours.
  • the spherical tartaric acid core material is then dried in a rotating kettle at a supply air temperature of 60 ° - 80 ° C.
  • the core material is fractionated using a tumbler sieve with sieve trays with a nominal mesh size of 0.6 and 0.8 mm.
  • the good fraction between 0.6 and 0.8 mm is used in the further process.
  • Acidic core material 23 parts by weight
  • the isolated core material containing tartaric acid is then post-dried in a forced-air drying cabinet at 40 ° C. for 8 hours.
  • the dried isolated tartaric core material is sieved with a sieve with a nominal mesh size of 1.0 mm.
  • the good fraction (grain size ⁇ 1 mm) is processed further.
  • the build-up of the active substance layer is generally carried out in the same way, but the type of active substance and amount, type of binder and quantity, amount of talc and isopropanol or amount of ethanol are varied.
  • the preparation is therefore only described for example C4, the respective compositions are shown in tabular form for each active ingredient.
  • Insulated tartaric core material 74 parts by weight
  • Active ingredient e.g. flibanserin 25 parts by weight
  • Hydroxypropyl cellulose is dissolved in 492 parts by weight of 2-propanol with stirring and then the active ingredient and talc are dispersed in this solution with stirring.
  • 74 parts by weight of insulated tartaric acid-containing core material are sprayed with the active ingredient-containing dispersion at a supply air temperature of 20 ° -30 ° C using the bed spray method.
  • the active ingredient-containing pellets are then dried in a forced-air drying cabinet at 35 ° C for 8 hours.
  • the active substance-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm.
  • the good fraction (grain size ⁇ 1.25 mm) is processed further.
  • Table 11 shows the composition of Examples C1-C 15 (active ingredient flibanserin). Parts by weight are given which correspond to the experimentally determined active substance content, i.e. the spray losses, which can fluctuate somewhat from batch to batch, were compensated for in the invoice in order to obtain really comparable data.
  • Examples C1-C3 contain a commercially available neutral core instead of the acid-containing starter cores according to the invention. These cores serve as reference values for in vitro testing (see above).
  • Table 12 shows the composition of Examples C16 - C 31 (active ingredient pimobendan). Parts by weight are given which correspond to the experimentally determined active substance content, i.e. the spray losses, which can fluctuate somewhat from batch to batch, were compensated for in the invoice in order to obtain really comparable data.
  • Examples C16-C17 contain a commercially available neutral core instead of the acidic starter cores according to the invention. These cores serve as reference values for in vitro testing (see above).
  • Table 13 shows the composition of Examples C32-C 52 (active ingredient lefradafiban, BIBU 104). Parts by weight are given which correspond to the experimentally determined active substance content, ie the spray losses, which can fluctuate somewhat from batch to batch, were each compensated for in the calculation in order to obtain really comparable data.
  • Examples C32-C34 contain a commercially available neutral core instead of the acidic starter cores according to the invention. These cores serve as reference values for in vitro testing (see above).
  • Example C53 contains a commercially available neutral core instead of the acidic starter cores according to the invention. This core serves as reference values for in vitro testing (see above).
  • Table 15 shows the composition of Examples C58-C 61 (active ingredient pimobendan). Parts by weight are given which correspond to the experimentally determined active substance content, i.e. the spray losses, which can fluctuate somewhat from batch to batch, were compensated for in the invoice in order to obtain really comparable data.
  • Examples C58-C59 contain a commercially available neutral core instead of the acid-containing starter cores according to the invention. These cores serve as reference values for in vitro testing (see above). Table 11:
  • Active substance-containing pellets 23 parts by weight
  • the isolated tartaric core material is then dried in a forced-air drying cabinet at 40 ° C for 8 hours.
  • the dried active substance-containing pellets are sieved using a sieve with a nominal mesh size of 1.25 mm.
  • the good fraction (grain size ⁇ 1.25 mm) is expanded / developed.
  • a quantity of active substance-containing pellets corresponding to the desired dosage is filled into hard gelatin capsules of a suitable size by means of a capsule filling machine.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une nouvelle forme d'administration orale pour des principes actifs dont les caractéristiques de solubilité sont dépendantes du pH et pour leurs sels acceptables sur le plan pharmacologique, ladite forme d'administration améliorant la biodisponibilité du principe actif.
EP03722336A 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles Withdrawn EP1499298A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07108392A EP1818047A3 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10209982 2002-03-07
DE10209982A DE10209982A1 (de) 2002-03-07 2002-03-07 Oral zu applizierende Darreichungsform für schwerlösliche basische Wirkstoffe
PCT/EP2003/002184 WO2003074032A1 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles

Related Child Applications (1)

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EP07108392A Division EP1818047A3 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles

Publications (1)

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EP1499298A1 true EP1499298A1 (fr) 2005-01-26

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EP03722336A Withdrawn EP1499298A1 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles
EP07108392A Withdrawn EP1818047A3 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles

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EP07108392A Withdrawn EP1818047A3 (fr) 2002-03-07 2003-03-04 Forme d'administration orale pour principes actifs basiques difficilement solubles

Country Status (10)

Country Link
US (1) US20050095293A1 (fr)
EP (2) EP1499298A1 (fr)
JP (1) JP2005526738A (fr)
AU (1) AU2003229555A1 (fr)
BR (1) BR0308188A (fr)
DE (1) DE10209982A1 (fr)
ME (1) MEP43508A (fr)
NO (1) NO20043998L (fr)
RS (1) RS77904A (fr)
WO (1) WO2003074032A1 (fr)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7183410B2 (en) * 2001-08-02 2007-02-27 Bidachem S.P.A. Stable polymorph of flibanserin
US20030060475A1 (en) * 2001-08-10 2003-03-27 Boehringer Ingelheim Pharma Kg Method of using flibanserin for neuroprotection
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
UA78974C2 (en) 2001-10-20 2007-05-10 Boehringer Ingelheim Pharma Use of flibanserin for treating disorders of sexual desire
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US20040048877A1 (en) * 2002-05-22 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions containing flibanserin
DE10339862A1 (de) * 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel
WO2005046663A1 (fr) * 2003-11-04 2005-05-26 Shire Laboratories, Inc. Composes d'ammonium quaternaire contenant des activateurs de la biodisponibilite
DE102004011512B4 (de) 2004-03-08 2022-01-13 Boehringer Ingelheim Vetmedica Gmbh Pharmazeutische Zubereitung enthaltend Pimobendan
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
EP1579862A1 (fr) 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Utilisation des inhibiteurs de PDE III pour la réduction de la taille du coeur chez des mammifères souffrant d'insufficances cardiaques
JP4572296B2 (ja) * 2004-07-21 2010-11-04 トーアエイヨー株式会社 ピモベンダン経口投与製剤
JP4572293B2 (ja) * 2004-07-21 2010-11-04 トーアエイヨー株式会社 ピモベンダン経口投与製剤
JP2006028130A (ja) * 2004-07-21 2006-02-02 Toa Eiyo Ltd ピモベンダン経口投与製剤
US20060025420A1 (en) * 2004-07-30 2006-02-02 Boehringer Ingelheimn International GmbH Pharmaceutical compositions for the treatment of female sexual disorders
WO2006096439A2 (fr) * 2005-03-04 2006-09-14 Boehringer Ingelheim International Gmbh Compositions pharmaceutiques destinees au traitement et/ou a la prevention de la schizophrenie et de maladies associees
CA2599937A1 (fr) * 2005-03-04 2006-09-14 Boehringer Ingelheim International Gmbh Compositions pharmaceutiques permettant de traiter et/ou de prevenir les troubles de l'anxiete
CA2608363A1 (fr) * 2005-05-19 2006-11-23 Boehringer Ingelheim International Gmbh Procede pour le traitement de dysfonctionnements sexuels d'origine medicamenteuse
JP2009503020A (ja) 2005-08-03 2009-01-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 肥満症の治療におけるフリバンセリンの使用
HU227490B1 (en) * 2005-08-26 2011-07-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Sustained release pharmaceutical preparation containing carvedilol
CA2626134C (fr) 2005-10-29 2013-12-24 Boehringer Ingelheim International Gmbh Derives de benzimidazolone utiles pour le traitement des troubles premenstruels et d'autres troubles sexuels chez la femme
US20070105869A1 (en) * 2005-11-08 2007-05-10 Stephane Pollentier Use of flibanserin for the treatment of pre-menopausal sexual desire disorders
JP4572300B2 (ja) * 2006-01-19 2010-11-04 トーアエイヨー株式会社 ピモベンダン経口投与製剤
RU2428176C2 (ru) † 2006-01-27 2011-09-10 Юранд, Инк. Системы доставки лекарственного средства, содержащие слабоосновные лекарственные средства и органические кислоты
BRPI0712039A2 (pt) * 2006-05-09 2011-12-20 Boehringer Ingelheim Int uso de flibanserina para o tratamento de distúrbios de desejo sexual pós-menopausa
WO2008000760A1 (fr) 2006-06-30 2008-01-03 Boehringer Ingelheim International Gmbh Flibansérine dans le traitement de l'incontinence urinaire et des maladies associées
JP2009543839A (ja) * 2006-07-14 2009-12-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 女性の性的障害を治療するためのフリバンセリンの使用
CL2007002214A1 (es) 2006-08-14 2008-03-07 Boehringer Ingelheim Int Composicion farmaceutica en la forma de comprimido, donde al menos la longitud del comprimido en el estado anterior de la aplicacion es al menos 7/12 del diametro pilorico del paciente y despues de ingerirlo en estado alimentado, la longitud del comp
BRPI0716439B8 (pt) * 2006-08-14 2021-05-25 Boehringer Ingelheim Int sistemas de liberação farmacêutico compreendendo flibanserina, processo para preparação e uso dos mesmos
EA200900270A1 (ru) * 2006-08-25 2009-08-28 Бёрингер Ингельхайм Интернациональ Гмбх Системы регулируемого высвобождения и способ их приготовления
EP1894561A1 (fr) * 2006-08-30 2008-03-05 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques de dipyridamole
EP1920785A1 (fr) 2006-11-07 2008-05-14 Boehringer Ingelheim Vetmedica Gmbh Préparation liquide contenant un complexe du pimobendane et de la cyclodextrine
CA2672957C (fr) 2006-12-20 2015-04-14 Boehringer Ingelheim International Gmbh Derives de benzimidazolone sulfates ayant une affinite mixte au recepteur de la serotonine
HU227881B1 (en) * 2007-02-23 2012-05-29 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Sustained release pharmaceutical preparation containing carvedilol
CA2682015A1 (fr) * 2007-03-28 2008-10-02 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques
TW200914006A (en) * 2007-07-12 2009-04-01 Takeda Pharmaceutical Coated preparation
PE20091188A1 (es) * 2007-09-12 2009-08-31 Boehringer Ingelheim Int Compuesto 1-[2-(4-(3-trifluorometil-fenil)piperazin-1-il)etil]-2,3-dihidro-1h-benzimidazol-2-ona (flibanserina), sus sales de adicion y composiciones farmaceuticas que los contienen
DE102008004893A1 (de) 2008-01-17 2009-07-23 Add Technologies Ltd. Trägerpellets, Verfahren zu deren Herstellung und deren Verwendung
EP2090297A1 (fr) * 2008-02-13 2009-08-19 Boehringer Ingelheim International GmbH Formules de flibanserine
FR2934156B1 (fr) * 2008-07-23 2010-09-24 Virbac Medicament appetissant a administration orale sous forme solide
WO2010055119A2 (fr) * 2008-11-17 2010-05-20 Novartis Ag Composition pharmaceutique comprenant du pimobendane
EP2482803B1 (fr) * 2009-09-30 2021-12-22 Merck Sharp & Dohme (UK) Limited Formulations pour des inhibiteurs de la kinase c met
US20120039999A1 (en) * 2010-08-11 2012-02-16 Ashish Chatterji Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists
US20120040008A1 (en) * 2010-08-11 2012-02-16 Ashish Chatterji Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists
EA201400737A1 (ru) * 2011-12-22 2014-12-30 Бёрингер Ингельхайм Интернациональ Гмбх Система доставки на основе множества пеллет с немедленным высвобождением активного вещества
WO2013135852A1 (fr) 2012-03-15 2013-09-19 Boehringer Ingelheim Vetmedica Gmbh Formulation pharmaceutique de comprimé pour le secteur médical vétérinaire, son procédé de production et utilisation
WO2013150545A2 (fr) * 2012-04-02 2013-10-10 Msn Laboratories Limited Procédés de préparation de dérivés de benzimidazole et de sels de ceux-ci
US20130345262A1 (en) 2012-06-25 2013-12-26 Boehringer Ingelheim International Gmbh Method for prevention of stroke
DK2898886T3 (en) 2012-09-19 2017-03-27 Taiho Pharmaceutical Co Ltd PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION WITH IMPROVED ELUTION AND / OR ABSORPTION
WO2015007760A1 (fr) 2013-07-19 2015-01-22 Boehringer Ingelheim Vetmedica Gmbh Composition pharmaceutique aqueuse liquide contenant des dérivés de cyclodextrine éthérifiés conservés
PL3106150T3 (pl) 2013-12-04 2022-01-03 Boehringer Ingelheim Vetmedica Gmbh Ulepszone kompozycje farmaceutyczne pimobendanu
US20170042806A1 (en) 2015-04-29 2017-02-16 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2470599A1 (fr) * 1979-12-07 1981-06-12 Panoz Donald Perfectionnements apportes aux procedes de preparation de formes galeniques a action retard et a liberation programmee et formes galeniques de medicaments ainsi obtenus
DE3126703A1 (de) * 1981-07-07 1983-01-27 Dr. Karl Thomae Gmbh, 7950 Biberach Bromhexin-retardform und verfahren zu ihrer herstellung
JPS58134033A (ja) * 1982-02-02 1983-08-10 Fujisawa Pharmaceut Co Ltd 医薬組成物
DK151608C (da) * 1982-08-13 1988-06-20 Benzon As Alfred Fremgangsmaade til fremstilling af et farmaceutisk peroralt polydepotpraeparat med kontrolleret afgivelse
DE3627423A1 (de) * 1986-08-13 1988-02-18 Thomae Gmbh Dr K Arzneimittel enthaltend dipyridamol oder mopidamol und o-acetylsalicylsaeure bzw. deren physiologisch vertraegliche salze, verfahren zu ihrer herstellung und ihre verwendung zur bekaempfung der thrombusbildung
IE66933B1 (en) * 1990-01-15 1996-02-07 Elan Corp Plc Controlled absorption naproxen formulation for once-daily administration
US5286736A (en) * 1990-11-22 1994-02-15 Dr. Karl Thomae Gmbh Pyridyl compounds and pharmaceutical compositions containing these compounds
DE4216364A1 (de) * 1991-12-14 1993-11-25 Thomae Gmbh Dr K Neue Pyridylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19539361A1 (de) * 1995-10-23 1997-04-24 Basf Ag Verfahren zur Herstellung von mehrschichtigen, festen Arzneiformen zur oralen oder rektalen Verabreichung
JP3404648B2 (ja) * 1998-07-28 2003-05-12 武田薬品工業株式会社 速崩壊性固形製剤
DE10149674A1 (de) * 2001-10-09 2003-04-24 Apogepha Arzneimittel Gmbh Orale Darreichungsformen für Propiverin oder seinen pharmazeutisch annehmbaren Salzen mit verlängerter Wirkstoffreisetzung

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO03074032A1 *

Also Published As

Publication number Publication date
MEP43508A (en) 2011-02-10
AU2003229555A1 (en) 2003-09-16
NO20043998L (no) 2004-10-05
US20050095293A1 (en) 2005-05-05
WO2003074032A1 (fr) 2003-09-12
BR0308188A (pt) 2004-12-21
EP1818047A2 (fr) 2007-08-15
RS77904A (en) 2006-10-27
JP2005526738A (ja) 2005-09-08
DE10209982A1 (de) 2003-09-25
EP1818047A3 (fr) 2008-08-06

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