WO2006032676A1 - Pharmaceutical composition comprising roflumilast or the n-oxide of roflumilast - Google Patents
Pharmaceutical composition comprising roflumilast or the n-oxide of roflumilast Download PDFInfo
- Publication number
- WO2006032676A1 WO2006032676A1 PCT/EP2005/054724 EP2005054724W WO2006032676A1 WO 2006032676 A1 WO2006032676 A1 WO 2006032676A1 EP 2005054724 W EP2005054724 W EP 2005054724W WO 2006032676 A1 WO2006032676 A1 WO 2006032676A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical preparation
- preparation according
- roflumilast
- solution
- salts
- Prior art date
Links
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
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
Definitions
- the present invention relates to the field of pharmaceutical technology and describes an aqueous pharmaceutical preparation comprising a slightly soluble PDE 4 inhibitor as active ingredient.
- the invention further relates also to processes for producing the pharmaceutical preparation and to the use of the pharmaceutical preparation for the treatment of disorders.
- PDE 4 inhibitors is currently undergoing advanced clinical trials, including a dosage form for oral administration comprising the active ingredient N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast).
- PDE cyclic nucleotide phosphodiesterase
- active ingredients are proposed in WO95/01338 also for the treatment of certain disorders of the skin (such as, for example, dermatoses).
- WO00/53182 proposes the use of roflumilast or its N-oxide for the treatment of multiple sclerosis.
- WO03/099334 describes pharmaceutical preparations for slightly soluble PDE 4 inhibitors such as, for example, ointments and aqueous or oily suspensions and emulsions.
- oral dosage forms it may also be necessary and advantageous to provide an active ingredient as parenteral form (preparation intended for injection), especially for groups of patients who have problems with taking oral dosage forms.
- Parenteral preparations must be produced with particular care in order to guarantee freedom from irritation and to avoid microbial and particulate contaminants.
- the most important solvent or dispersant is water. According to the pharmacopeoia, water for injections must always be used in these cases. Active ingredients to be administered intravenously must be completely dissolved. It must furthermore be ensured during development of the preparation that no precipitation takes place during the injection. Further requirements to be mentioned for parenteral preparations are in particular good tolerability for the patient. This may depend on the aqueous preparation being rendered isotonic or approximately isotonic and having an approximately physiological pH, and on the absence of particulate contaminants. The production of parenteral preparations or of general solutions of active ingredients which are slightly soluble in water therefore involves particular problems.
- roflumilast can be dissolved in water in an amount which is sufficient for injections when the solution has an alkaline pH. It is possible on this basis to obtain clear solutions having the properties necessary for parenteral preparations (in particular good tolerability for the patient, no particulate contaminants). In particular, the solution is also stable during storage and no precipitates of the active ingredient are observed. Furthermore, compatibility with the container material is good.
- the invention therefore relates to an aqueous pharmaceutical preparation comprising an active ingredient in a therapeutically effective and pharmacologically acceptable amount, where the active ingredient is selected from the group consisting of roflumilast, salts of roflumilast, the N-oxide of the pyridine residue of roflumilast or salts thereof and where the solution has an alkaline pH.
- the aqueous preparation is in particular a solution in which the active ingredient is completely dissolved.
- Roflumilast is the INN for a compound of the formula I
- R1 is difluoromethoxy
- R2 is cyclopropylmethoxy
- R3 is 3,5-dichloropyrid-4-yl.
- This compound has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4- difluoromethoxybenzamide (INN: roflumilast).
- the N-oxide of roflumilast has the chemical name 3- cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl 1-oxide)benzamide.
- Salts suitable for compounds of the formula I - depending on the substitution - are all acid addition salts but, in particular, all salts with bases. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases normally used in pharmaceutical technology. Pharmacologically unacceptable salts which, for example, may be the initial products of the process for preparing the compounds of the invention on the industrial scale are converted into pharmacologically acceptable salts by processes known to the skilled worker.
- water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid, or 3-hydroxy-2-naphthoic acid, the acids being employed to prepare the salts in the equimolar ratio of amounts, or one differing therefrom - depending on whether the acid is monobasic or polybasic and depending on which salt is desired.
- acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, ni
- salts with bases are also particularly suitable.
- basic salts which may be mentioned are lithium, sodium, potassium, calcium, magnesium, ammonium, meglumine or guanidinium salts, once again the bases being employed to prepare the salts in the equimolar ratio of amounts or one differing therefrom.
- An alkaline pH of the solution means according to the invention a pH of greater than 7, in particular greater than or equal to 8.
- the solution according to the invention preferably has an alkaline pH in the range from pH 10 to pH 13, preferably pH 10.5 to pH 12.5 and very particularly preferably pH 11 to pH 12.3.
- An alkaline pH is adjusted for the solution according to the invention preferably by adding a suitable compound with an alkaline reaction (base).
- a suitable compound with an alkaline reaction are according to the invention sodium hydroxide and/or sodium carbonate.
- the compound with an alkaline reaction is in this connection added to the solution according to the invention in an amount such that the desired pH is adjusted.
- the preparation according to the invention is preferably a preparation based on water, especially water for injection.
- the preparation according to the invention may if desired comprise further pharmaceutical excipients suitable for parenteral preparations.
- suitable for parenteral preparations examples which should be mentioned here are substances to improve the solubility (e.g. cosolvents and solubilizers), substances for rendering isotonic, buffers, antioxidants, chelating agents, preservatives, emulsifiers, organic acids, salts of organic acids or excipients to prolong the effect.
- Suitable cosolvents are in particular ethanol, glycerol, propylene glycol and polyethylene glycol or 1 ,3- butanediol. Preference is given in this connection to propylene glycol and polyethylene glycol (especially macrogol 300/400).
- solubilizers which should be mentioned are lecithin and poloxamer 188 (Pluronic F68®), with preference for poloxamer 188.
- Substances which are used for rendering isotonic and should be mentioned in particular are sodium chloride, glucose, mannitol, glycerol, propylene glycol and polyethylene glycol.
- Organic acids and/or salts thereof which may be mentioned in particular are glycine, lysine, acetic acid, sodium acetate or citric acid.
- the organic acid and/or salt thereof is preferably employed in an amount such that the molar ratio of roflumilast to organic acid and/or the salts is in the range from 1 :1 to 1 :2.
- a solubilizer which may be mentioned in particular is polyvinylpyrrolidone (e.g. Kollidon 12 or 17® from BASF).
- 100 ml of solution comprise from 0.1 mg to 0.9 g of active ingredient, preferably 0.5 mg to 0.85 g, very particularly preferably 1 mg to 0.7 g.
- Poloxamer 188 (Pluronic F 68®) can be employed in amounts of from 0.1 g to 10 g.
- the pharmaceutical preparation according to the invention can be produced by processes familiar to the skilled person.
- the active ingredient is preferably suspended in water, it being possible to add if desired also a solubilizer such as poloxamer 188 and/or an organic acid and/or salt thereof. It is additionally possible also to add further excipients suitable for parenteral preparations, such as agents for rendering isotonic or cosolvents.
- the preparation is then adjusted to the desired pH by adding the compound with an alkaline reaction, if desired with heating. A clear solution is obtained.
- the solution obtained in this way can then be sterilized by filtration and subsequently dispensed into suitable containers such as vials or ampoules.
- the solution can alternatively first be introduced into suitable containers, and this solution can then be subjected in the final container to a sterilization, for example by autoclaving.
- Poloxamer 188 1.00 g
- a clear solution of the poloxamer 188, glycerol and the glycine in water is prepared.
- the active ingredient is added, and the mixture is heated to about 80°C.
- Dilute sodium hydroxide solution is added until a pH of 11-12 is reached and the active ingredient has formed a clear solution.
- the solution is sterilized by filtration, dispensed into ampoules and sterilized.
- Poloxamer 188 0.5O g
- a clear solution of the poloxamer 188 and the polyethylene glycol 400 in water is prepared.
- the active ingredient is dispersed therein, and the preparation is heated to about 80°C.
- the active ingredient is dissolved and the pH is adjusted to 11-12 by adding sodium hydroxide solution.
- the solution is sterilized by filtration, dispensed into ampoules and sterilized.
- a clear solution of the poloxamer 188, sodium acetate and propylene glycol in water is prepared.
- the solution is heated to about 80° C and the active ingredient is dispersed.
- the active ingredient is dissolved and the pH is adjusted to 11-13 with sodium hydroxide solution.
- the solution is sterilized by filtration and dispensed under aseptic conditions into ampoules.
- the roflumilast is stirred into 10 grams of polyethylene glycol 400. 70 ml of water for injections are added, and a clear solution of the active ingredient is prepared with dilute sodium hydroxide solution. The pH is then about 11-12. The clear solution is made up to 100 ml, sterilized by filtration, dispensed into ampoules and sterilized.
- a clear solution of the glycine and the polyethylene glycol 400 in water is prepared.
- the active ingredient is added and the solution is heated to about 80°C.
- Dilute sodium hydroxide solution is added until a pH of 11-12 is reached and a clear solution of the active ingredient has formed.
- the solution is made up to 100 ml, sterilized by filtration, dispensed into ampoules and sterilized.
- the preparations of the invention can be employed for the treatment and prevention of all diseases regarded as treatable or preventable through the use of PDE 4 inhibitors.
- Selective cyclic nucleotide phosphodiesterase (PDE) inhibitors are suitable on the one hand as bronchial therapeutic agents (for the treatment of airway obstructions owing to their dilating effect but also owing to their effect increasing the respiratory rate and respiratory drive) and for eliminating erectile dysfunction owing to the vasodilating effect, but on the other hand especially for the treatment of disorders, especially of an inflammatory nature, e.g.
- mediators such as histamine, PAF (platelet-activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta- and gamma- interferon, tumour necrosis factor (TNF) or oxygen free radicals and proteases.
- mediators such as histamine, PAF (platelet-activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta- and gamma- interferon, tumour necrosis factor (TNF) or oxygen free radicals and proteases.
- the pharmaceutical preparations of the invention can therefore be used in human and veterinary medicine for example for the treatment and prophylaxis of the following diseases: acute and chronic (especially inflammatory and allergen-induced) airway disorders of various aetiologies (bronchitis, allergic bronchitis, bronchial asthma, COPD); dermatoses (especially of a proliferative, inflammatory and allergic nature) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; disorders based on excessive release of TNF
- disorders of the arthritic type rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic states
- disorders of the immune system AIDS, multiple sclerosis
- types of shock septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)] and generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis
- the pharmaceutical preparations of the invention are also suitable for the treatment of disorders of the skin such as dermatoses (especially of a proliferative, inflammatory and allergic nature) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders.
- dermatoses especially of a proliferative, inflammatory and allergic nature
- psoriasis vulgaris
- toxic and allergic contact eczema atopic eczema
- seborrhoeic eczema
- the preparations according to the invention in the form of a solution can be administered parenterally (e.g. as injection or infusion) for the treatment of the abovementioned diseases.
- the invention further relates to a method for the treatment of mammals, including humans, suffering from one of the abovementioned diseases.
- the method is characterized in that a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the group of compounds roflumilast, salts of roflumilast, the N-oxide of roflumilast and salts thereof is administered to the mammal with the disease, with the active pharmaceutical ingredient being administered in a pharmaceutical preparation of the invention.
- the method is characterized in that the administration takes place by parenteral administration (injection or infusion).
- the pharmaceutical preparations of the invention are moreover particularly suitable for adminstration to groups of patients who are suffering from the abovementioned diseases and have problems in taking pharmaceutical preparations to be administered orally, such as, for example, bedridden patients, patients in intensive medical care, patients with swallowing difficulties and children.
- the invention further relates to a method for the treatment of mammals, including humans, suffering from one of the abovementioned diseases.
- the method is characterized in that a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the group of compounds roflumilast, salts of roflumilast, the N-oxide of roflumilast and salts thereof is administered to the mammal with the disease, with the active pharmaceutical ingredient being administered in a topical pharmaceutical preparation of the invention.
- the disease is preferably acute and chronic (especially inflammatory and allergen-induced) airway disorders of various aetiologies (bronchitis, allergic bronchitis, bronchial asthma, COPD), and disorders of the arthritic type (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic states).
- the dosage forms of the invention comprise the active pharmaceutical ingredient in the dose customary for the treatment of the particular disease.
- the dosage of the active ingredient is of the order of magnitude customary for PDE inhibitors, it being possible to administer the daily dose in one or more dosage units.
- Customary dosages are disclosed for example in WO 95/01338.
- the normal dose on systemic therapy (oral) is between 0.001 and 3 mg per kilogram and day.
- Dosage forms preferred according to the invention for parenteral administration contain from 0.005 mg to 5 mg of roflumilast, preferably from 0.01 mg to 2.5 mg, particularly preferably 0.1 mg to 0.5 mg of roflumilast per dosage unit.
- Examples of pharmaceutical preparations of the invention contain 0.01 mg, 0.1 mg, 0.125 mg, 0.25 mg and 0.5 mg of roflumilast per dosage unit.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/662,888 US20080045572A1 (en) | 2004-09-22 | 2005-09-21 | Pharmaceutical Composition Comprising Roflumilast or the N-Oxide of Roflumilast |
AU2005286477A AU2005286477A1 (en) | 2004-09-22 | 2005-09-21 | Pharmaceutical composition comprising roflumilast or the N-oxide of roflumilast |
CA002580404A CA2580404A1 (en) | 2004-09-22 | 2005-09-21 | Pharmaceutical composition comprising roflumilast or the n-oxide of roflumilast |
EP05787168A EP1796633A1 (en) | 2004-09-22 | 2005-09-21 | Pharmaceutical composition comprising roflumilast or the n-oxide of roflumilast |
JP2007531768A JP2008513417A (en) | 2004-09-22 | 2005-09-21 | Roflumilast or pharmaceutical composition containing roflumilast N-oxide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004046236A DE102004046236A1 (en) | 2004-09-22 | 2004-09-22 | drug preparation |
DE102004046236.4 | 2004-09-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006032676A1 true WO2006032676A1 (en) | 2006-03-30 |
Family
ID=35295395
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/054724 WO2006032676A1 (en) | 2004-09-22 | 2005-09-21 | Pharmaceutical composition comprising roflumilast or the n-oxide of roflumilast |
Country Status (7)
Country | Link |
---|---|
US (1) | US20080045572A1 (en) |
EP (1) | EP1796633A1 (en) |
JP (1) | JP2008513417A (en) |
AU (1) | AU2005286477A1 (en) |
CA (1) | CA2580404A1 (en) |
DE (1) | DE102004046236A1 (en) |
WO (1) | WO2006032676A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2359826A1 (en) | 2006-07-05 | 2011-08-24 | Nycomed GmbH | Combination of HMG-COA reductase inhibitors, such as roflumilast, roflumilast-N-oxide with a phosphodiesterase 4 inhibitor, rosuvastatin, for the treatment of inflammatory pulmonary diseases |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9895359B1 (en) | 2017-06-07 | 2018-02-20 | Arcutis, Inc. | Inhibition of crystal growth of roflumilast |
US11129818B2 (en) | 2017-06-07 | 2021-09-28 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003099334A1 (en) * | 2002-05-28 | 2003-12-04 | Altana Pharma Ag | Topically applicable pharmaceutical preparation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0706513T3 (en) * | 1993-07-02 | 2002-09-09 | Altana Pharma Ag | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
US20030235631A1 (en) * | 2002-06-17 | 2003-12-25 | Pfizer Inc. | Combination treatment for depression and anxiety |
-
2004
- 2004-09-22 DE DE102004046236A patent/DE102004046236A1/en not_active Withdrawn
-
2005
- 2005-09-21 EP EP05787168A patent/EP1796633A1/en not_active Withdrawn
- 2005-09-21 CA CA002580404A patent/CA2580404A1/en not_active Abandoned
- 2005-09-21 WO PCT/EP2005/054724 patent/WO2006032676A1/en active Application Filing
- 2005-09-21 US US11/662,888 patent/US20080045572A1/en not_active Abandoned
- 2005-09-21 AU AU2005286477A patent/AU2005286477A1/en not_active Abandoned
- 2005-09-21 JP JP2007531768A patent/JP2008513417A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003099334A1 (en) * | 2002-05-28 | 2003-12-04 | Altana Pharma Ag | Topically applicable pharmaceutical preparation |
Non-Patent Citations (1)
Title |
---|
BUNDSCHUH D S ET AL: "IN VIVO EFFICACY IN AIRWAY DISEASE MODELS OF ROFLUMILAST, A NOVEL ORALLY ACTIVE PDE4 INHIBITOR", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND, US, vol. 297, no. 1, 2001, pages 280 - 290, XP001024809, ISSN: 0022-3565 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2359826A1 (en) | 2006-07-05 | 2011-08-24 | Nycomed GmbH | Combination of HMG-COA reductase inhibitors, such as roflumilast, roflumilast-N-oxide with a phosphodiesterase 4 inhibitor, rosuvastatin, for the treatment of inflammatory pulmonary diseases |
EP2363130A1 (en) | 2006-07-05 | 2011-09-07 | Nycomed GmbH | Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases |
US9713614B2 (en) | 2006-07-05 | 2017-07-25 | Astrazeneca Ab | Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases |
Also Published As
Publication number | Publication date |
---|---|
JP2008513417A (en) | 2008-05-01 |
DE102004046236A1 (en) | 2006-03-30 |
EP1796633A1 (en) | 2007-06-20 |
CA2580404A1 (en) | 2006-03-30 |
US20080045572A1 (en) | 2008-02-21 |
AU2005286477A1 (en) | 2006-03-30 |
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