EP2170281A1 - Verfahren zur herstellung eines arzneimittels enthaltend tadalafil - Google Patents

Verfahren zur herstellung eines arzneimittels enthaltend tadalafil

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Publication number
EP2170281A1
EP2170281A1 EP08759325A EP08759325A EP2170281A1 EP 2170281 A1 EP2170281 A1 EP 2170281A1 EP 08759325 A EP08759325 A EP 08759325A EP 08759325 A EP08759325 A EP 08759325A EP 2170281 A1 EP2170281 A1 EP 2170281A1
Authority
EP
European Patent Office
Prior art keywords
peg
tadalafil
solid
polyvinylpyrrolidone
molecular weight
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Withdrawn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
EP08759325A
Other languages
German (de)
English (en)
French (fr)
Inventor
Rainer Alles
Julia Schulze Nahrup
Katrin Rimkus
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.)
Ratiopharm GmbH
Original Assignee
Ratiopharm 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 Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of EP2170281A1 publication Critical patent/EP2170281A1/de
Withdrawn legal-status Critical Current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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention relates to a process for the preparation of a medicament containing tadalafil, wherein tadalafil is mixed with suitable excipients and heated to a temperature of about 150 ° C to about 200 ° C.
  • Tadalafil (IUPAC name: (6R, 12aR) - 6 - (1,3-benzodioxol-5-yl) -2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino [2, 1: 6,1] pyrido [3,4-b] indole-1,4-dione) belongs to the group of PDE-V (phosphodiesterase V) inhibitors used as an oral formulation for the treatment of erectile dysfunction (see e.g. WO01 / 08688).
  • the production of tadalafil can be carried out, for example, according to Daugan A. et al. (2003) J. Med. Chem., 46, 4533-4542, wherein it contains as (6R, 12aR) - 2, 3, 6, 7, 12, 12a - hexahydro - 2
  • the sparingly soluble in water tadalafil is soluble according to WO 01/08687 in water only to about 2 ug / ml. In order for oral formulations to have sufficiently high bioavailability despite the poor solubility of the active ingredient, it is necessary to improve the solubility.
  • EP 1 269 994 A2 describes so-called concentration-improving polymers in order to obtain an improvement in the solubility of active ingredients.
  • WO 96/38131 describes a process for preparing a solid dispersion which contains a sparingly soluble active substance.
  • the solubility of the active ingredient should be improved by coprecipitation.
  • attempts to release the active ingredient tadalafil have shown that tablets containing coprecipitates release the active ingredient more slowly than tablets containing pure active ingredient.
  • coprecipitates also contain proportions of tadalafil particles which are not embedded in the solid, but are free. These free particles dissolve faster than the particles embedded in the coprecipitate. This may possibly lead to an undesirable, bimodal release of the Tadalafil.
  • co-precipitates are difficult to reproduce, i. Large-scale production is complex.
  • Another possibility for improving the solubility of poorly soluble active substances is the surface enlargement of the active substance particles by grinding or micronizing, as disclosed in WO 01/08688 or WO 01/08686. From WO01 / 08688 are oral Known formulations with rapid release. The desired solubility or release could be achieved by reducing the Tadalafil particle size to less than 40 microns.
  • the grinding or micronizing of active ingredients can bring disadvantages. Micronized particles tend to agglomerate. This results in difficult-to-define particle sizes with again difficult defiesable solubility. A possible additional electrostatic charge of the drug also has a negative effect on the processability.
  • Another possible disadvantage is the poor flowability of the ground active substance. In particular, when tablets are pressed or capsules are to be filled, further processing steps, for. B. granulation required. Despite small particles, the addition of much surfactant is often necessary to achieve sufficient solubility.
  • soft capsules made of gelatin which are filled with a Tadalafil solution.
  • the solvent used for tadalafil is a mixture of PEG (polyethylene glycol) 400 NF LA and polypropylene glycol.
  • the capsules may be filled with a tadalafil suspension.
  • soft capsules made of gelatin are known, being used as solvent for the active ingredient exclusively PEG 400 NF.
  • Soft gelatin capsules however, have the disadvantage of complex filling. Here are z. As special machines and strictly air-conditioned production rooms needed. In contrast, hard capsules can be relatively easily filled with standard capsule filling machines that are equipped with semi-solid feeds instead of powder feeders. It can be used in addition to gelatin as capsule material on cellulose-based materials.
  • the object of the present invention was therefore to provide a process for the preparation of a medicament containing tadalafil, in which the abovementioned disadvantages and in particular the severe solubility of tadalafil are substantially avoided or circumvented.
  • tadalafil can be processed very well at elevated temperatures as a solid or semi-solid solution and higher active ingredient concentrations or proportions in the formulation could be achieved than was described, for example, in WO 01/08687.
  • the present invention therefore provides a process for the preparation of a medicament containing tadalafil, in which tadalafil with one or more suitable Excipients mixed and heated to a temperature of about 100 ° C to about 200 ° C, preferably about 150 ° C to about 200 0 C, in particular about 200 0 C is heated. In general, this is the minimum temperature above the softening temperature of the corresponding excipient.
  • the term "about” according to the present invention generally means +/- 5% and in particular +/- 2% of the respective physical size.
  • excipient generally includes all common excipients.
  • tadalafil was in the form of solid or semisolid solutions.
  • Fixed solutions are characterized by being transparent and strong.
  • Semisolid solutions are characterized by being transparent and doughy, i. not liquid, are. These are thus viscous or highly viscous (honey-like) solutions.
  • transparent means that the tadalafil usually present as a white powder is dissolved in the appropriate excipient.
  • Thickening takes place in one step, and then subsequently filled into capsules.
  • the mixture is up to about 2 hours, z. B. about 1 hour to about 3 hours, in particular about 1.5 hours to about 2.5 hours, heated above all about 2 hours to achieve a substantially complete melting of the excipients.
  • the heating can be carried out in a common oven.
  • the heating time can also be significantly less than one hour and when using an extruder, the heating time can be about 1 minute to about 5 minutes.
  • auxiliaries or solvents have been found according to the present invention: polyethylene glycol (PEG), copovidone, a Polyoxyethylenglykolmonostearat, glycerol-Polyethylenglykol-ricinoleat, polyvinylpyrrolidone and / or vinylpyrrolidone-vinyl acetate copolymer.
  • PEG is hereby selected above all from PEG 200, PEG 400, PEG 600, PEG 800, PEG 1500, PEG 4000, PEG 6000, PEG 8000, PEG 10000 and / or PEG 2000, preferably from PEG 400, PEG 4000, PEG 6000 and / or PEG 20000 and in particular from PEG 400 and / or PEG 4000.
  • the polyvinylpyrrolidone preferably has a molecular weight of about 40,000 and the vinylpyrrolidone-vinyl acetate copolymer preferably has a molecular weight of about 60,000.
  • other suitable auxiliaries be added.
  • the heating can also be carried out advantageously in an extruder, whereby a homogeneous extrudate of active ingredient and excipient or solvent is obtained.
  • the extrusion according to the invention is preferably carried out at an outlet pressure of about 10 bar to about 100 bar, preferably from about 20 bar to about 100 bar, in particular from about 20 bar to about 50 bar.
  • subsequent temperature gradients are advantageous, in particular if vinylpyrrolidone-vinyl acetate copolymer having a molecular weight of about 60,000 is used as adjuvant: gradient 1: 20-50-100-150-160-160-200 ° C with preferably about 50 bar outlet pressure or in particular gradient 2: 20-50-100- 150-200-200-200 ° C with preferably about 20 bar outlet pressure.
  • auxiliaries or solvents have been found to be particularly advantageous: polyvinylpyrrolidone and / or vinylpyrrolidone-vinyl acetate copolymer, in particular polyvinylpyrrolidone having a molecular weight of about 40,000 and / or vinylpyrrolidone-vinyl acetate copolymer having a molecular weight of about 60,000.
  • the proportion of tadalafil in the solid or semi-solid solution or in the extrudate can therefore, according to the invention, be from about 2% by weight to about 15% by weight, preferably from about 3% by weight to about 10% by weight. %, especially at about 5 wt .-% to about 10 wt .-%, especially at about 7.5 wt .-% to about 10 wt .-% are. According to the present examples, approximately 7.5% by weight of tadalafil could be dissolved in the extrusion process according to the invention, otherwise even 10% by weight of tadalafil.
  • oral drug formulations of tadalafil can be prepared according to the present examples.
  • particularly drug formulations were advantageous as further excipient Ludipress ® or Kollidon ®, Kollidon ® CL, in particular, or mixtures of Avicel ®, Avicel ® PH 102 in particular, and Primojel ®; of Avicel and Kollidon ®, in particular Kollidon ® CL; from Fujicalin ® and Kollidon ®, in particular Kollidon ® CL; contain from L-HPC and LHI l and from Primojel ® and Ac-Di-Sol ®.
  • the pure extrudate of tadalafil and Kollidon ® VA 64 was particularly advantageous because in this case the drug was fastest released.
  • Another object of the present invention is therefore also a medicament containing a solid or semi-solid solution of tadalafil, which can be prepared by the process according to the invention, as described in more detail above.
  • the solid solution of tadalafil is prepared by extrusion.
  • the drug thus contains a solid or semi-solid solution of tadalafil, with preferably 80% of the tadalafil being released in vitro after 8-120 minutes, especially after 20 minutes.
  • the medicine is z. B. as a tablet or in the form of a capsule, advantageously without further excipients before.
  • the capsule is in particular a hard capsule z. On gelatin or HPMC basis.
  • the dose of active substance When administered orally in humans, the dose of active substance generally ranges from about 1 to 20 mg per day.
  • the following examples are intended to illustrate the invention without limiting it.
  • Aerosil ® (Degussa GmbH) highly dispersed, hydrophilic silica Avicel ® (102/200; FMC Corp.) Microcrystalline cellulose
  • Cellactose ® (Dairy Meggle Wasserburg GmbH & Co. KG): spray-dried mixture of 75% alpha-Lacotse monohydrate and 25% cellulose powder
  • Cetiol ® (Cognis GmbH): decyl CMC: carboxymethylcellulose Cremophor ® EL (BASF AG): glycerol polyethyl English ykolricinoleat DEP: diethyl DBS: dibutyl
  • Emdex ® J. Rettenmaier & Söhne GmbH & Co. KG: malto-dextrin with a 93- 99% proportion of dextrose Eudragit ® (Rohm & Haas GmbH): acrylic polymer
  • Fujicalin ® (Fuji Chemical Industry Co., Ltd.): calcium hydrogen phosphate dihydrate
  • Gelucire ® (Gattefosse): semi-synthetic glycerides based on hydrogenated vegetable oils
  • GMS glycerol monostearate
  • HPMC hydroxypropylmethyl cellulose Klucel ® (Hercules Inc.): hydroxypropyl cellulose
  • Kollidon ® Cl (BASF AG): crospovidone (crosslinked polyvinylpyrrolidone)
  • Kollidon ® VA 64 (BASF AG): copovidone (copolymer of vinylpyrrolidone and vinyl acetate; average molecular weight of 60000 +/- 15000)
  • Kollidon ® 30 (BASF AG): polyvinylpyrrolidone with a molecular weight of about 40,000
  • Labrafil ® (Gattefosse): transesterified and polyethoxylated, nonionic triglycerides
  • L-HPC (Shin-Etsu Chemical Co., Ltd.): low-substituted hydroxypropyl Lubritab ® (Penwest Pharmaceuticals Co.): hydrogenated vegetable oil
  • Ludipress ® (BASF AG): composition of lactose Monohydrate (about 93.4%),
  • Kollidon ® 30 polyvinylpyrrolidone having a molecular weight of about 40000, about 3.2%
  • Kollidon ® CL crosslinked polyvinylpyrrolidone, approximately 3.4%) and water ( ⁇ 6%)
  • Lutrol ® (BASF AG): PEG
  • Microcelac ® (Dairy Meggle Wasserburg GmbH & Co. KG): spray-dried composition consisting of microcrystalline cellulose (25%) and alpha-lactose monohydrate (75%)
  • Miglyol ® (SASOL Germany GmbH): caprylic-capric acid triglyceride
  • PEG Polyethylene glycol with the corresponding molecular weight of z. B. 4000, 6000, 8000 and 20000
  • Pharmacoat ® (Shin-Etsu Chemical Co., Ltd.): hydroxypropylmethylcellulose
  • Pluronic ® BASF AG: polyoxyethylene polyoxypropylene block polymer
  • Primojel ® (Avebe BA): explosives based on sodium carboxymethyl cellulose and starch PRUV ® (JRS Pharma GmbH & Co. KG): sodium stearyl PVA: polyvinyl alcohol PVP: polyvinylpyrrolidone
  • PVP-VA copolymer of vinylpyrrolidone and vinyl alcohol
  • SDS sodium dodecylsulfate
  • Solutol ® (BASF AG): diethylene Tagat ® (Goldschmidt AG): polyoxyethylene glycol monostearate TEC: triethyl
  • tadalafil 0.5 g was mixed with 4.5 g of a polymer (homogenized) and heated in an oven at 200 0 C for two hours. It was then cooled to room temperature (1 hour). The active ingredient content was 10% by weight.
  • the extrusion was carried out, depending on the mixture at an outlet temperature of 60-200 0 C and an outlet pressure of 10-100 bar.
  • the extruder had 7 individually heatable cylinders in which two screws convey the material from the entrance to the outlet nozzle. Cylinder 1 is the entrance, where the powder mixture is metered. Cylinder 7 is the output, so the nozzle.
  • the cylinders were preheated for several hours before use.
  • Various temperature gradients were set for the extrusion, of which the following two have been found to be particularly optimal:
  • the extrudate b of Example 3 was stored at 40 ° C for four weeks to study the stability of tadalafil. The experiment showed that essentially no difference was found in the chemical purity and release of tadalafil from the extrudate between the stored extrudate and the non-stored extrudate immediately after extrusion.
  • Extrudate b from Example 3 was ground in a Comil and sieved. The mixture was then mixed with auxiliaries and the mixture was pressed into tablets of 340 mg.
  • ground extrudate was used which was sieved through a 1000 ⁇ m sieve.
  • the milled extrudate was first sieved through a 800 ⁇ m sieve, then through a 500 ⁇ m sieve. Table 1
  • As Kollidon VA64, Kollidon ® 30, another PVP polymer or a polymer instead of PEG or HPMC is ground to an arbitrary, desired particle size and optionally sieved.
  • magnesium stearate, talc and / or colloidal silica are coated.
  • the granules are then in capsules (4), z.
  • a solubility enhancer, eg SDS may be added before or after extrusion.
  • a suitable hard capsule containing 20 mg of tadalafil is composed as follows: TABLE 2
  • a polymer (2), z. As Kollidon ® VA64, Kollidon ® 30, another PVP polymer or a polymer instead of PEG or HPMC is ground to an arbitrary, desired particle size and optionally sieved. Subsequently, the granules with other excipients (3), z.
  • cellulose cellulose derivatives, starches, starch derivatives, PVP, lactose, sugar or sugar alcohols, PEG, calcium sulfate, calcium phosphate, carrageenan, koaline and / or silica, mixed and then with a lubricant, for.
  • HPMC polymethacrylates, PVA, PVP, PEG, CMC and / or copolymers of PVA, PVP and PEG as a coating agent (4), dibutyl sebacate, PEG, propylene glycol, TEC, DBT and / or DEP as plasticizer (5) and stearic acid, Magnesium stearate, stearic acid, hydrogenated vegetable oils, ethylene oxide; Glycerol mono-, di- or tri-stearate, talc and / or SDS as moisture protection against sticking (6).
  • a solubility enhancer eg SDS, may be added before or after extrusion.
  • a suitable hard capsule with an amount of active ingredient of 20 mg tadalafil is composed as follows: TABLE 3
  • the active ingredient is in a heated adjuvant (2), z. B. PEG 600, Tagat ® and / or Cremophor ® EL with heating and optionally ultrasonic treatment dissolved, then with an excipient (3), z.
  • the semi-solid mass is filled in hard capsules by means of a capsule filling machine for semi-solid substances.
  • a solubility enhancer eg SDS, may be added before or after extrusion.
  • a suitable hard capsule with an amount of active ingredient of 20 mg tadalafil is composed as follows: TABLE 4
  • cellulose or HPC can also be used as thickener.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP08759325A 2007-06-22 2008-06-23 Verfahren zur herstellung eines arzneimittels enthaltend tadalafil Withdrawn EP2170281A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007028869A DE102007028869A1 (de) 2007-06-22 2007-06-22 Verfahren zur Herstellung eines Arzneimittels enthaltend Tadalafil
PCT/EP2008/005066 WO2009000493A1 (de) 2007-06-22 2008-06-23 Verfahren zur herstellung eines arzneimittels enthaltend tadalafil

Publications (1)

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EP2170281A1 true EP2170281A1 (de) 2010-04-07

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EP08759325A Withdrawn EP2170281A1 (de) 2007-06-22 2008-06-23 Verfahren zur herstellung eines arzneimittels enthaltend tadalafil

Country Status (14)

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US (2) US9238007B2 (ko)
EP (1) EP2170281A1 (ko)
JP (1) JP5443344B2 (ko)
KR (1) KR101525021B1 (ko)
CN (1) CN101720221A (ko)
AU (1) AU2008267431C1 (ko)
BR (1) BRPI0812807A2 (ko)
CA (1) CA2691667C (ko)
DE (1) DE102007028869A1 (ko)
EA (1) EA022100B1 (ko)
IL (1) IL202783A (ko)
UA (1) UA95374C2 (ko)
WO (1) WO2009000493A1 (ko)
ZA (1) ZA200908965B (ko)

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DE102007028869A1 (de) 2007-06-22 2008-12-24 Ratiopharm Gmbh Verfahren zur Herstellung eines Arzneimittels enthaltend Tadalafil
US20110136815A1 (en) 2009-12-08 2011-06-09 Horst Zerbe Solid oral film dosage forms and methods for making same
US10610528B2 (en) 2009-12-08 2020-04-07 Intelgenx Corp. Solid oral film dosage forms and methods for making same
US20110263606A1 (en) * 2010-04-26 2011-10-27 Horst Zerbe Solid oral dosage forms comprising tadalafil
DE102010017463B4 (de) * 2010-06-18 2014-02-20 Eickhoff Antriebstechnik Gmbh Planetenbolzen, Planetenträger, Planetengetriebe und Verfahren zur drehfesten Befestigung eines Planetenbolzens an einen Planetenträger
WO2012107092A1 (en) 2011-02-10 2012-08-16 Synthon Bv Pharmaceutical composition comprising tadalafil and a cyclodextrin
RU2013141446A (ru) 2011-02-10 2015-03-20 Синтон Бв Фармацевтическая композиция, содержащая тадалафил и циклодекстрин
WO2012107090A1 (en) 2011-02-10 2012-08-16 Synthon Bv Granulated composition comprising tadalafil and a disintegrant
WO2014003677A1 (en) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Pharmaceutical compositions comprising solid dispersion particles containing tadalafil
WO2014003678A1 (en) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Pharmaceutical compositions comprising ambrisentan and solid dispersion particles containing tadalafil
WO2014125352A1 (en) * 2013-02-14 2014-08-21 Aurobindo Pharma Limited Pharmaceutical compositions comprising tadalafil
KR102223105B1 (ko) * 2013-04-11 2021-03-04 주식회사 씨티씨바이오 분산안정화제로 폴리에틸렌글리콜계 고분자 및/또는 비닐피롤리돈계 고분자를 포함하는 타다라필 유리염기 함유 필름 제형
US11116769B2 (en) 2013-04-11 2021-09-14 Ctc Bio, Inc. Tadalafil free base-containing film dosage form containing polyethylene glycol-based polymer and/or vinyl pyrrolidone-based polymer as dispersion stabilizer
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KR101538985B1 (ko) * 2014-09-02 2015-07-24 주식회사 서울제약 타다라필 구강붕해필름 및 이의 제조방법
CN104523644B (zh) * 2015-01-27 2017-06-20 江苏联环药业股份有限公司 一种快速溶出的氯雷他定片剂及其制备工艺
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CN101720221A (zh) 2010-06-02
AU2008267431A1 (en) 2008-12-31
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IL202783A (en) 2017-01-31
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UA95374C2 (ru) 2011-07-25
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CA2691667C (en) 2014-10-28
DE102007028869A1 (de) 2008-12-24
IL202783A0 (en) 2010-06-30
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