WO2011163469A1 - Forme hydratée du roflumilast-n-oxyde anti-inflammatoire - Google Patents

Forme hydratée du roflumilast-n-oxyde anti-inflammatoire Download PDF

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Publication number
WO2011163469A1
WO2011163469A1 PCT/US2011/041619 US2011041619W WO2011163469A1 WO 2011163469 A1 WO2011163469 A1 WO 2011163469A1 US 2011041619 W US2011041619 W US 2011041619W WO 2011163469 A1 WO2011163469 A1 WO 2011163469A1
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roflumilast
oxide
theta
oxide according
crystalline form
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PCT/US2011/041619
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English (en)
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Wolfgang Albrecht
Jochen Christ
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceutical Usa, Inc.
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Publication of WO2011163469A1 publication Critical patent/WO2011163469A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to new crystalline forms of Roflumilast N- oxide, processes for preparation thereof, as well as formulations thereof.
  • DAXAS ® is purportedly a potent and selective phosphodiesterase 4 (PDE4) inhibitor, and is marketed by Nycomed Pharma under the trade name DAXAS ® .
  • PDE4 potent and selective phosphodiesterase 4
  • DAXAS ® is approved for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD), and is available as a tablet containing 250 or 500 ⁇ g of Roflumilast.
  • Roflumilast requires enzymatic activation by cytochrome P450 3A4
  • CYP3A4 and CYP1 A2 so that the active N-oxidized metabolite is produced.
  • This N- oxidation can even be disturbed by enzyme interaction with other compounds.
  • Ordinary grapefruit juice for example, is an inhibitor of the cytochrome P450 CYP3A4 enzyme, which can impair the metabolism of Roflumilast, thus decreasing its bioavailability.
  • the Roflumilast-N-oxide does not require further activation by an enzyme.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule like Roflumilast-N- oxide, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., as measured by thermo- gravimetric analysis - "TGA”, or differential scanning calorimetry - "DSC"), x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermo- gravimetric analysis -
  • DSC differential scanning calorimetry -
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, it was the objective of the present invention to provide additional polymorphs of Rofiumilast-N-oxide.
  • the present invention provides crystalline forms of Roflumilast N-oxxde, processes for preparation thereof, as well as formulations thereof.
  • the present invention provides the above described solid state forms of Roflumilast N-oxide for use in the preparation of formulation, preferably for the treatment of COPD.
  • the present invention provides a pharmaceutical composition comprising the above described solid state forms of Roflumilast N-oxide and at least one pharmaceutically acceptable excipient.
  • the present invention provides any of the above described crystalline forms of Roflumilast N-oxide for use in the preparation of Roflumilast.
  • Figure 1 provides an X-ray powder diffractogram of crystalline Roflumilast N-oxide Form A, according to Synthesis Example 4.
  • Figure 2 provides an X-ray powder diffractogram of crystalline Roflumilast N-oxide Form A, according to Synthesis Example 3.
  • Figure 3 provides an X-ray powder diffractogram of crystalline Roflumilast N-oxide Form H-l, according to Example 2.
  • Figure 4 provides an X-ray powder diffractogram of crystalline Roflumilast N-oxide Form H-2, according to Example 3.
  • Figure 5 provides a DSC thermogram of Roflumilast-N-oxide, Form A, according to Synthesis Example 4
  • Figure 7 provides a DSC thermogram of Roflumilast-N-oxide, Form H-l , according to Example 2.
  • Figure 8 provides a DSC thermogram of Roflumilast-N-oxide, Form H-2, according to Example 3.
  • the present invention provides solid state forms of Roflumilast N-oxide; the preparation thereof; their use for the preparation of Roflumilast and pharmaceutical compositions thereof.
  • room temperature refers to a temperature from about 20°C to about 30°C. Usually, room temperature ranges from about 20°C to about 25°C.
  • the term “overnight” or “ON” refers to a period of from about 15 to about 20 hours, typically from about 16 to about 20 hours.
  • the units [wt%] are used to refer to the mass of the water molecules in the crystals in relation to the overall crystal mass.
  • the water content can be determined by any suitable technique, for example, by Karl-Fischer titration (e.g., as described in Ph. Eur. 6th edition, 2008, section 2.5.12) or by the "loss-on-drying" analysis (LOD).
  • LOD Loss-on-drying
  • the Karl Fischer method as described in Ph. Eur. 6th edition, 2008, section 2.5.12, may be used.
  • a sample of 300 mg Roflumilast-N-oxide is typically analyzed.
  • a crystal form may be referred to herein as being characterized by graphical data substantially "as depicted in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.
  • a characteristic peak in a DSC thermogram can be referred to herein as being every clearly identifiable amplitude, which rises and falls or vice versa from a baseline within about 30°C, e.g., within 10°C.
  • the integral under this peak can be higher than 50 m J when measured under standard conditions (20 mW).
  • a clearly identifiable amplitude can be one for which the full width half maximum cannot be more than 30°C, e.g., cannot be more than 10°C.
  • the DSC peaks can represent the different groups of more or less loosely bound solvent molecules and/or recrystalliza- tion processes or other solid state transformations.
  • the peak heights and integrals can represent the energy necessary to remove the bound water from within the crystal structure.
  • the new forms of Roflumilast N-oxide, described herein, may have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability ⁇ such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • the present invention provides hydrated
  • Roflumilast-N-oxide The hydrated Roflumilast-N-oxide has an increased solubility and therefore a superior bioavailability and lower inter-individual variability.
  • Hydrated Roflumilast-N-oxide has a water content of about 0.1 to about 30 wt%, or of about 0.5 to about 20 wt%, or of about 1 to about 15 wt%, e.g., of about 2 to about 10 wt%.
  • the hemihydrate form of Roflumilast-N-oxide can have for examples a water content of about 2.15 wt%; the monohydrate form of
  • Roflumilast-N-oxide can have for example a water content of about 4.30 wt%; the sesquihydrate form of Roflumilast-N-oxide, can have for example a water content of about 6.45 w%; and the dihydrate form of Roflumilast-N-oxide, can have for example a water content of about 8.59 wt%.
  • the present invention provides, hydrated Roflumilast-N-oxide that exhibit a characteristic X-ray powder diffraction pattern having at least one characteristic peak at an angle expressed in degrees 2-theta of between 5.0 to 5.4 2- degrees 2-theta and/or between 10.0 and 11.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • hydrated Roflumilast-N-oxide exhibits a
  • characteristic X-ray powder diffraction pattern having at least one characteristic peak at an angle expressed in degrees 2-theta of between 5.0 to 5.4 degrees 2-theta and/or between 10.0 and 11.0 degrees 2-theta ⁇ 0.5 degrees 2-theta.
  • the hydrate Roflumilast-N-oxide can be further characterised by at least one characteristic peak in a DSC thermogram at between about 70°C and about 120°C, or at between about 90°C to about 115°C, for example, at least two or three peaks in the DSC thermogram in the range of 50°C to 130°C.
  • Roflumilast-N-oxide Due to the oxidation of the nitrogen and the overall charge of the structure, Roflumilast-N-oxide is very sensitive to the presence of water. In addition, the anhydrous form of Roflumilast-N-oxide disintegrates relatively quickly when exposed to moisture.
  • the inventors have now found that in comparison to the anhydrous Roflumilast-N-oxide, the hydrate Roflumilast-N-oxide is much easier to handle in the production of medicaments. Often, active ingredients must be protected from air exposure. However, the inventors have observed that the hydrate Roflumilast-N-oxide of the present invention has good storage stability when exposed to air. This stability is ah advantage for the production, storage and processing of pharmaceuticals comprising Roflumilast-N-oxide. In addition, less adhesion to tableting machines and tablet presses has been observed. Furthermore, the flowability is increased and electrostatic charging is reduced.
  • the hydrate Roflumilast-N-oxide provided herein combines the advantages of being an active PDE4-inhibitor with a good overall processability.
  • the invention therefore also includes a pharmaceutical composition comprising a PDE4-inhibitor for parenteral administration.
  • a pharmaceutical composition comprising a PDE4-inhibitor for parenteral administration.
  • the use of hydrated Roflumilast-N-oxide provided herein also has an advantage in that the respective compounds can be given in a very low dose with a good processability.
  • Roflumilast itself can be delivered in once-daily doses of 250 or 500 ⁇ g. Due to the increased bioavailability of the N-oxide, the dosage of the Roflumilast-N- oxide can be even further decreased, thus reducing possible adverse effects.
  • the present invention provides a crystalline form of Roflumilast-N-oxide j designated herein as Form H-l.
  • Roflumilast N-oxide Form H-l can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 5.2, 10.3, 23.6, 25.7, 27.9 and 32.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; an X- ray powder diffraction pattern having peaks at 5.2, 10.3, 20.5, 23.6, 25.7, 27.9 and 32.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 3; and combinations thereof.
  • Form H-l can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 5.2, 10.3, 23.6, 25.7, 27.9 and 32.6 degrees 2-theta ⁇ 0.5 degrees 2-theta.
  • Roflumilast N-oxide Form H- 1 can be further characterized by a data selected from: a DSC thermogram having a characteristic peak at 114°C ⁇ 2°C; a DSC thermogram as depicted in Figure 7 and combination thereof.
  • Roflumilast N-oxide Form H-l can also be characterized by a DSC thermogram having three characteristic peaks; at 92°C, 105°C and 114°C ⁇ 2°C.
  • Form H-l can be a hydrated form of Roflumilast N-oxide.
  • Form H-l can have a water content of about 3.5 to about 6 wt%, e.g., about 4 to about 4.5 wt%.
  • Roflumilast N-oxide Form H- 1 can have a molecular ratio of
  • Form H-l can have an average water content of about 1 water molecule per Roflumilast -N-oxide molecule.
  • Roflumilast N-oxide Form H-l shows a stable crystal structure.
  • the water molecules in the crystal structure of Form H-l may form hydrogen bridges.
  • Such hydrogen bridges could serve to stabilize the crystal structure and may also serve to increase the water solubility of the resulting crystals.
  • the storage stability of Form H-l is improved in comparison with the anhydrous Form. A greater resistance to oxidative decomposition exists, and Form H-l has less of a tendency to acquire electrostatic charge. The Form H-l crystals remain stable, even in air.
  • Form H-l demonstrates good processability which can further provide an excellent dosing conformity.
  • Applications of Form H-l afford a better distribution and faster pharmacokinetic response of the active ingredient.
  • the present invention provides a crystalline form of Roflumilast-N-oxide, designated herein as Form H-2.
  • Roflumilast-N-oxide Form H- 2 can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 5.3, 10.7, 26.8, 27.0, and 32.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 4; and combinations thereof.
  • Roflumilast-N-oxide Form H-2 can be further characterized by a data selected from: a DSC thermogram having a characteristic peak at 110°C ⁇ 2°C; a DSC thermogram as depicted in Figure 8 and combinations thereof.
  • Form H-2 can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 5.3, 10.7, 26.8, 27.0 and 32.0 degrees 2-theta ⁇ 0.5 degrees 2-theta.
  • Roflumilast N-oxide Form H-2 can be further characterized by a DSC thermogram having two characteristic peaks present at 97°C and 110°C ⁇ 2°C.
  • Form H-2 can be a hydrated form of Roflumilast N-oxide.
  • Form H-2 can have a water content of about 2.5 to about 4 wt%, e.g., about 1 to about 1.5 wt%.
  • Roflumilast-N-oxide Form H-2 can have a molecular ratio of Roflumilast-N-oxide to water of from 1:0.1 to 1:0.7 in the crystal structure, respectively.
  • Form H-2 typically can have an average water content of less than one water molecule per Roflumilast-N-oxide molecule.
  • Form H-2 forms a stable crystal structure. Due to the reduced amount of water, this form comprises a structure that is more densely packed. However Form H-2 still demonstrates better water solubility than anhydrous Roflumilast-N-oxide. Form H-2 has been observed to have a better flowability and processabilty than the H-l form. Without being bound by theory, this observation may relate to the presence of fewer hydrogen bridges in the structure of Form H-2.
  • Hygroscopicity is the capacity of a compound or a product to react to the moisture content of the air by absorbing water vapour.
  • Forms H-l and H-2 of the invention have a reduced hygroscopicity.
  • the form H-l has a very low hygroscopicity.
  • the present invention provides a method for the preparation of the hydrated form of Roflumilast-N-oxide, comprising:
  • Alcohols suitable for the above process include a water miscible alcohol, e.g., a lower alkyl alcohol, such as methanol, ethanol, propanol, or isopropanol.
  • a water miscible alcohol e.g., a lower alkyl alcohol, such as methanol, ethanol, propanol, or isopropanol.
  • the ratio of the alcohol to the water can be from about 0.5:2 to about 2:0.5, e.g., the ratio can be 1:1.
  • the choice of solvent mixture can be essential for achieving the hydrated forms according to the invention.
  • Step b) of the above process can be conducted under reflux conditions.
  • Step c) of the above process can be performed by cooling in order to provide a slow and defect-free crystal growth.
  • Other recrystallization techniques are not excluded, but may reduce the crystal quality.
  • Step d) can be done by any suitable technique, for example, by filtration.
  • the above process provides the hydrated form of Roflumilast-N-oxide in an excellent yield and purity without unwanted further components within the crystal structure. This process also generally affords a very high yield of the recrystallization product of Roflumilast-N-oxide.
  • the above method provides Roflumilast-N-oxide Form H-l.
  • the above method can further include an additional step e), of drying of the obtained crystal at higher than room temperature and under vacuum.
  • Step (e) can be performed after step d). Drying can be done at a temperature of about 23 °C to about 80°C, or at a temperature of about 30 °C to about 50 °C, e.g., at a temperature of about 40 °C.
  • the drying step can also be carried out under vacuum conditions, for example, at about 1 mbar to about 1 bar, or at about 10 mbar to about 100 mbar, e.g., at about 30 mbar.
  • the above method provides Roflumilast-N-oxide Form H-2.
  • the present invention provides the hydrated form of Roflumilast-N-oxide as obtained by any of the above mentioned methods.
  • the present invention provides a method for preparing anhydrous Roflumilast-N-oxide comprising the following steps:
  • reaction mixture after the oxidation with one or more suitable solvent(s), e.g., 25% aqueous ammonium acetate, water, brine and diethylether, for example, water or diethylether,
  • suitable solvent(s) e.g., 25% aqueous ammonium acetate, water, brine and diethylether, for example, water or diethylether,
  • drying the organic phase with a suitable drying agent, e.g., sodium sulphate or magnesium sulphate,
  • reaction mixture of step a) can be obtained, e.g., according to the procedure disclosed in WO 01/90076 example 1.
  • the yield of the obtained anhydrous Roflumilast-N-oxide can be improved by optimizing the oxidation method.
  • Roflumilast-N-oxide may be prepared by a process comprising the following steps:
  • a halogenated solvent e.g., dichloromethane
  • the present invention provides a pharmaceutical composition comprising the hydrated forms of Roflumilast-N-oxide, in particular forms HI and H2.
  • compositions with the hydrated forms, in particular forms HI and H2 display improved mixing properties with regard to additional adjuvants in the composition. De-mixing and local accretions are generally avoided. These applied dosages dissolve quickly and uniformly when water is added.
  • the conversion of these forms to an anhydrous form of Roflumilast-N- Oxide can be done, for example, by removing the water by any suitable drying method known to a person skilled in the art.
  • the conversion of these forms to Roflumiiast can be done by reduction of the N-oxide moiety, for example, by any suitable reducing agent known to a person skilled in the art.
  • Anhydrous Roflumilast-N-Oxide designated herein as Form A, can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 5.9, 6.9, 14.0, 17.7 and 27.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; an X-ray powder diffraction pattern substantially as depicted in Figure 2; and combinations thereof.
  • Roflumilast-N ⁇ Oxide, Form A can be further characterized by data selected from: an X-ray powder diffraction pattern, having peaks at 13.4, 21.6, 23.1, 24.4 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; a DSC thermogram as depicted in Figure 5; a DSC thermogram as depicted in Figure 6 and combinations thereof.
  • the present invention further provides 1) a pharmaceutical composition comprising hydrate Roflumiiast N-oxide, in particular any one of the forms H-1 and H-2 or combination thereof, and at least one pharmaceutically acceptable excipient; 2) the use of hydrate Roflumilast N-oxide, in particular any one of the forms H-l and H-2 or combination thereof, in the manufacture of a pharmaceutical composition, and 3) a method of treating COPD using the described formulation.
  • the pharmaceutical composition can be useful for preparing a medicament.
  • the present invention also provides solid state forms as described above for use as a medicament.
  • the present invention provides a pharmaceutical composition comprising any one or combination of solid state forms, as described above, and at least one pharmaceutically acceptable excipient, for the treatment of chronic inflammatory diseases.
  • compositions of the invention are specifically advantageous for the treatment of chronic inflammatory diseases in mammals, including humans.
  • These inflammatory diseases include acute and chronic airway diseases such as asthma or COPD, but also other autoimmune diseases, such as rheumatoid arthritis or inflammatory bowel disease.
  • compositions of the invention are particularly suitable for parenteral administration to groups of patients who suffer from the above- mentioned diseases and have problems in taking pharmaceutical compositions in oral dosage form.
  • the group includes patients with swallowing difficulties, children, patients in intensive medical care or dementia patients.
  • Parenteral administration means that the administration dosage does not involve the digestive tract.
  • the PDE4-inhibitor is any hydrated form of Roflumilast-N-oxide according to the invention.
  • Administration may be by subcutaneous and/or intramuscular injection.
  • the injection takes place with microparticles or microcrystals, which can erode and/or dissolve in the tissue within the desired time.
  • This process is surprisingly advantageous, because the microparticles can erode and/or dissolve in a constant manner, keeping the pharmaceutical dosage of the active ingredient at a steady level.
  • the parenterally administered PDE4-inhibitor of the present invention is preferably Roflumilast or any of its derivatives or salts, and more preferably is
  • the PDE4-inhibitor is a hydrated form of the Roflumilast-N-oxide. This is specifically advantageous, because the Roflumilast- N-oxide is the active metabolite and does not require enzymatic activation.
  • the solubility of the Roflumilast-N-oxide is increased in comparison to Roflumilast.
  • the dosage of the Roflumilast-N-oxide is simplified and the storage stability increased when the hydrated form is present.
  • the hydrated forms are particularly preferred, because their handling is unproblematic and does not require specific safety conditions due to the reduced hygroscopicity of the crystals and in some cases the avoidance of dangerous micronization procedures involving a highly potent active ingredient.
  • the pharmaceutical composition of this invention is preferably used for sustained-release formulations. This has the advantage of avoiding rapid drug absorption. This can be achieved by a depot injection.
  • a depot injection is an injection, usually subcutaneous or intramuscular, of a pharmacological agent, which releases its active compound in a consistent way over a long period of time. Depot injections are usually either solid or oil-based. The advantages of using a long-acting depot injection include increased medication compliance due to reduction in the frequency of dosing, as well as more consistent serum concentrations, while high maximum concentrations are being avoided.
  • Roflumilast-N-oxide hydrates of the invention can be employed at low concentrations. Surprisingly, they are exceptionally suitable for sustained release formulations. When using the above mentioned hydrated forms H-l or H-2, many of the side effects can be avoided, because of their good processability at low concentrations.
  • the present combination of Roflumilast-N-oxide and depot injection works well when the drug is prepared as a microcapsule or microsphere. These can be injected and remain effective even with very low release rates.
  • the pharmaceutical composition of this invention is preferably used for treatment by intramuscular or subcutaneous injection.
  • intramuscular injection the medication is delivered directly into a muscle.
  • Many drugs injected intramuscularly are absorbed into the muscle fairly quickly, while others are more gradual.
  • Injections to the buttocks are known to reach the bloodstream quickly due to the large amount of muscular tissue and corresponding blood supply.
  • intramuscular injections are not self-administered, but rather are administered by a trained medical professional.
  • prescribed self-administered intramuscular injections are becoming more common for patients who require these injections routinely. This has the advantage that the injection has fewer side effects than for example an intravenous injection.
  • a nurse or doctor without further specific training can easily inject a depot dose into a muscle without adverse effects.
  • an injection into the muscle has the advantage that the release of the drug can take place over a long-term period such as weeks or months, because the composition is not immediately dissolved into the blood stream. Therefore, the medication with Rofiumilast-N-oxide could even be extended to four weeks with a constant plasma level.
  • Subcutaneous injection has the advantage that possibly the patient himself or nursing staff can administer the PDE4-inhibitor composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or a combination of solid state forms, as described above, and at least one pharmaceutically acceptable excipient administered in the form of microparticies or microcapsules.
  • the hydrated form of Roflumilast-N-oxide can be encapsulated into a biodegradable polymer.
  • Preferred methods of microcapsule formulation are according to Example 2 of WO 02/47664 or Example 20 of WO 02/49620 or Example 9 in EP 1 344 520 Bl.
  • Water-in-oil-in-water (w/o/w) preparations are possible, which avoid micronization pre-treatment.
  • the enhanced water-solubility simplifies the process as in the CA
  • Microparticies of the H-l or H-2 form of Roflumilast-N-oxide are particularly preferred, because of their good dosage uniformity at very low
  • compositions include leukotriene receptor antagonists, tumor necrosis factor-alpha (TNF-alpha) antagonists or Interleukin traps (specifically IL-1, IL-6, IL-15, IL-17), in order to block the inflammation, e.g., in rheumatoid arthritis.
  • TNF-alpha tumor necrosis factor-alpha
  • Interleukin traps specifically IL-1, IL-6, IL-15, IL-17
  • Rofiumilast-N-oxide preferably with the H-1 and/or H-2 form of Roflumilast-N-oxide.
  • composition of the invention may also comprise further pharmaceutically acceptable carriers, excipients, or adjuvants.
  • the carrier type depends on the form of administration, which is typically either oral or parenteral, e.g., by intramuscular depot injection.
  • oral administration capsules or tablets are employed.
  • Powder compositions or granules of the inventive crystals are also possible, in particular for microparticle formulations or injection administration.
  • the pharmaceutical carrier employed can be, for example, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, or stearic acid.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • Pharmaceutical compositions of the present invention suitable for mjectible use include aqueous solutions or dispersions.
  • microcrystals or powders according to the invention may also be employed for injection purposes.
  • Such compositions can be in the form of sterile powders for the preparation of injectible solutions or dispersions.
  • Solvent B 0.01 M K2HP04 pH 2.3
  • Detector wave length 230 nni and 254 nm selected for quantification (Area %) Differential Scanning Calorimetry (DSC):
  • Anti scatter slit 6.17 mm
  • Detector slit 10.39 mm
  • Second beta filter Ni filter 0.1 mm (0.5 %)
  • Example 2 The product of Example 2 was dried at 40° C under vacuum (30 mbar) for 16 hours. The resulting crystals of this Form H-2 were analyzed by XRPD (XRPD peaks are listed in Table 3 below) and DSC, and this data are provided in the Figures herein.
  • Example 1 The material of Example 1 was dried at 40 °C in vacuum (30 mbar) for

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Abstract

La présente invention concerne de nouveaux inhibiteurs de PDE4 sous une forme hydratée, en particulier le roflumilast-N-oxyde, des procédés pour la fabrication de ceux-ci et des compositions pharmaceutiques comprenant des inhibiteurs de PDE4 pour administration parentérale.
PCT/US2011/041619 2010-06-23 2011-06-23 Forme hydratée du roflumilast-n-oxyde anti-inflammatoire WO2011163469A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103073490A (zh) * 2012-12-21 2013-05-01 北京万全德众医药生物技术有限公司 罗氟司特活性代谢物的制备方法
WO2014115127A1 (fr) 2013-01-28 2014-07-31 Incozen Therapeutics Pvt. Ltd. Procédés de traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation de n-oxyde de roflumilast
US10357486B2 (en) 2013-08-16 2019-07-23 Universiteit Maastricht Treatment of cognitive impairment with PDE4 inhibitor

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2099941A1 (fr) 1992-07-16 1994-01-17 Masao Kobayashi Methode de production d'une preparation de microspheres a liberation prolongee
WO2001090076A1 (fr) 2000-05-25 2001-11-29 Merck Frosst Canada & Co. Inhibiteur de pde4 n-oxyde dichloropyridinyl benzamide a substitution fluoroalcoxy
WO2002047664A2 (fr) 2000-12-13 2002-06-20 Merckle Gmbh Microparticules presentant un meilleur profil de liberation et procede de fabrication
WO2002049620A2 (fr) 2000-12-21 2002-06-27 Inhale Therapeutic Systems, Inc. Induced phase transition method for the production of microparticles containing hydrophobic active agents
WO2005013967A1 (fr) * 2003-07-28 2005-02-17 Boehringer Ingelheim International Gmbh Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires
EP1344520B1 (fr) 2002-03-15 2007-10-03 Alrise Biosystems GmbH Microparticules et leur procédé de fabrication

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2099941A1 (fr) 1992-07-16 1994-01-17 Masao Kobayashi Methode de production d'une preparation de microspheres a liberation prolongee
WO2001090076A1 (fr) 2000-05-25 2001-11-29 Merck Frosst Canada & Co. Inhibiteur de pde4 n-oxyde dichloropyridinyl benzamide a substitution fluoroalcoxy
WO2002047664A2 (fr) 2000-12-13 2002-06-20 Merckle Gmbh Microparticules presentant un meilleur profil de liberation et procede de fabrication
WO2002049620A2 (fr) 2000-12-21 2002-06-27 Inhale Therapeutic Systems, Inc. Induced phase transition method for the production of microparticles containing hydrophobic active agents
EP1344520B1 (fr) 2002-03-15 2007-10-03 Alrise Biosystems GmbH Microparticules et leur procédé de fabrication
WO2005013967A1 (fr) * 2003-07-28 2005-02-17 Boehringer Ingelheim International Gmbh Medicaments comprenant des inhibiteurs de pde iv et un nouvel anticholinergique, et leur utilisation pour le traitement de troubles respiratoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Ph. Eur.6th edition", 2008, article "section 2.5.12"

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103073490A (zh) * 2012-12-21 2013-05-01 北京万全德众医药生物技术有限公司 罗氟司特活性代谢物的制备方法
WO2014115127A1 (fr) 2013-01-28 2014-07-31 Incozen Therapeutics Pvt. Ltd. Procédés de traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation de n-oxyde de roflumilast
US9649302B2 (en) 2013-01-28 2017-05-16 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
EP3763366A1 (fr) 2013-01-28 2021-01-13 Incozen Therapeutics Pvt. Ltd. N-oxyde de roflumilast pour l'utilisation dans le traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation
US11103488B2 (en) 2013-01-28 2021-08-31 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
US10357486B2 (en) 2013-08-16 2019-07-23 Universiteit Maastricht Treatment of cognitive impairment with PDE4 inhibitor

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