US20040242597A1 - Combination - Google Patents
Combination Download PDFInfo
- Publication number
- US20040242597A1 US20040242597A1 US10/489,920 US48992004A US2004242597A1 US 20040242597 A1 US20040242597 A1 US 20040242597A1 US 48992004 A US48992004 A US 48992004A US 2004242597 A1 US2004242597 A1 US 2004242597A1
- Authority
- US
- United States
- Prior art keywords
- inn
- acid
- methyl
- alpha
- ester
- 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.)
- Abandoned
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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
Definitions
- the invention relates to the combination of certain known active compounds for therapeutic purposes.
- the substances used in the combination according to the invention are known active compounds from the PDE4-inhibitor class and active compounds from the non-steroidal anti-inflammatory drug (NSAID) class.
- NSAID non-steroidal anti-inflammatory drug
- NSAIDs nonsteroidal anti-inflammatory drugs
- GI gastrointestinal
- celecoxib selectively increased coronary heart flow at doses consistent with its inhibitory potency on PDE4 and 5, but had no effect on left ventricular pressure and heart rate, thereby excluding inhibition of PDE3.
- diclofenac 3-100 mg/kg, p.o.
- ED 50 56 mg/kg
- NSAIDs with preferential COX-2 selectivity possess PDE4 and PDE5 inhibitory potency on isolated enzymes, an effect which was confirmed in the Langendorff heart by an increase in coronary flow. It seems that the intrinsic PDE4—but not the intrinsic PDE5—inhibitory component of NSAIDs with preferential COX-2 selectivity most likely contribute to the gastrointestinal safety of these drugs. Furthermore, gastrointestinal side effects of conventional NSAIDs can be attentuated or even prevented, if these class of compounds is applied in combination with a compound from the class of selective PDE4 inhibitors.
- the invention thus relates to the combined use of a PDE4 inhibitor and a conventional NSAID in the treatment of an inflammatory disease and/or an inflammation-associated disorder while minimizing gastrointestinal side effects, such as gastric erosions and ulcer, which are frequently associated with the use of conventional NSAIDs.
- Combined use in the context of the invention means the simultaneous, sequential or separate administration of the conventional NSAID on the one hand and of the PDE4 inhibitor on the other hand.
- Simultaneous administration includes—aside from the simultaneous uptake of two separate dosage forms containing the conventional NSAID in the one and the PDE4 inhibitor in the other dosage form—pharmaceutical compositions containing both active ingredients in one single dosage form (fixed unit dose form).
- Simultaneous administration also includes the oral administration of the PDE4 inhibitor during i. v. administration (e.g. by infusion) of the conventional NSAID, or shortly after intramuscular or intravenous injection of the conventional NSAID.
- Sequential administration in the context of the invention means the administration of the conventional NSAID on the one hand and of the PDE4 inhibitor on the other hand in separate dosage forms within less than 12 hours, more preferably within less than one hour, most preferably within 5 minutes or less, including regimen where the PDE4 inhibitor is administered first.
- Sequential and separate administration also include the oral administration of the PDE4 inhibitor and the i. v. administration (e.g. by infusion) or intramuscular or intravenous injection of the conventional NSAID.
- “Combined use” in the context of the invention also includes a pharmaceutical product comprising both the conventional NSAID and the PDE4 inhibitor as discrete separate dosage forms, in separate containers or e.g. in blisters containing both types of drugs in discrete solid dosage units, preferably in a form in which the dosage units which have to be taken together or which have to be taken within one day are grouped together in a manner which is convenient for the patient.
- Said pharmaceutical product itself or as a part of a kit may contain instructions for the simultaneous, sequential or separate administration of the discrete separate dosage units, to a patient in need thereof.
- PDE4 inhibitor is meant a phosphodiesterase inhibitor, which selectively inhibits the type 4 phosphodiesterase when compared to other known types of phosphodiesterase, e.g. type 1, 2, 3, 5 etc., whereby the compound has a lower IC 50 (more potent) for the type 4 phosphodiesterase, such as where the IC 50 for PDE4 inhibition is about factor 100 lower compared to IC 50 for inhibition of other known type of phosphodiesterase, e.g. type 1, 2, 3, 5 etc.
- NSAID a cyclooxygenase inhibitor which inhibits both, the constitutive form (COX-1) and the inducible form (COX-2) of the cyclooxygenase and does not contain any of the following residues: —S(O) 2 NH 2 , —S(O) 2 CH 3 , —S(O) 2 N(H)C(O)CH 2 CH 3 and —N(H)—S(O) 2 —CH 3 .
- PDE4 inhibitors within the meaning of the present invention are those which are named expressis verbis as an example or described and/or claimed generically in the following patent applications and patents: EP0428302, EP0731099, WO9212961, WO9319749, WO9402465, WO9500516, WO9501338, WO9611690, WO9603399, WO9636625, WO9636626, WO9723457, WO9728131, WO9735854, WO9743288, WO9807715, WO9808841, WO9809946, WO9821207, WO9821209, WO9822453, WO9831674, WO9905111, WO9905112, WO9905113, WO9931090, WO9957115, WO9964414, WO0001695, WO0026208, WO0042017, WO0042018, WO0042019, WO0042020, WO0042034,
- Preferred PDE4 inhibitors which are selected from the above-defined PDE4 inhibitors are the compounds with the research codes CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V 11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code: Cl-1018, N-(3,5-dichloro-4-pyridinyl)
- PDE4-inhibitors are cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST].
- Preferred conventional NSAIDs which are selected from the above-defined group of conventional NSAIDs are 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN],], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].
- An particularly preferred conventional NSAID is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC].
- a pharmaceutically acceptable derivative of an active ingredient means a pharmaceutically acceptable salt or solvate (e.g. hydrate), a pharmaceutically acceptable solvate of such salt, a pharmaceutically acceptable N-oxide or a pharmaceutically acceptable salt or solvate of the latter.
- Suitable pharmacologically tolerable salts are on the one hand in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation—depending on whether it is a mono- or polybasic acid and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
- the active compounds mentioned can benzoic acid
- salts with bases are also suitable.
- examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
- Certain of the active ingredients used in the present invention are capable of existing in stereoisomeric forms.
- the invention encompasses all stereoisomers of the active ingredients and mixtures thereof including racemates. Tautomers and mixtures thereof of the active ingredients are also part of the present invention.
- a pharmaceutical composition comprising, in admixture, a first active ingredient which is a PDE4-inhibitor selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenz-yl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code:
- a pharmaceutical composition comprising, in admixture, a first active ingredient which is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, and a second active ingredient which is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropi
- a PDE4-inhibitor selected from cis-[4-
- a pharmaceutical composition comprising, in admixture, a first active ingredient which selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its Pharmaceutically acceptable derivatives, and a second active ingredient which is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and its pharmaceutically acceptable derivatives.
- a first active ingredient which selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its Pharmaceutically acceptable derivatives
- a second active ingredient which is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and its pharmaceutically acceptable derivatives
- the invention provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a PDE4-inhibitor selected from CDC-998, SH-636, D4396, IC485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code: Cl-1018, N-(3,5-
- the invention provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, and a preparation of a second active ingredient which is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutyl
- a PDE4-inhibitor selected from cis-
- the invention provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable derivatives, and a preparation of a second active ingredient which is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and its pharmaceutically acceptable derivatives, for simultaneous, sequential or separate use in therapy.
- a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable derivatives
- a preparation of a second active ingredient which is selected from 2-[(2,
- the invention provides a kit comprising a preparation of a first active ingredient which is a PDE4-inhibitor selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyrdine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code: Cl-1018, N-(3,5-dichloro-4
- the invention provides a kit comprising a preparation of a first active ingredient which is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, a preparation of a second active ingredient which is conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylprop
- the invention provides a kit comprising a preparation of a first active ingredient which is selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable derivatives, a preparation of a second active ingredient which is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and its pharmaceutically acceptable derivatives, and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
- a preparation of a first active ingredient which is selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable derivatives
- a preparation of a second active ingredient which is selected from 2-[(2,6-dich
- the pharmaceutical composition of the present invention may be prepared by mixing the first active ingredient with the second active ingredient.
- a) in a first step be mixed as such, afterwards be processed with pharmaceutically acceptable auxiliaries and/or excipients and finally pressed to tablets or caplets
- a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a PDE4-inhibitor selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research-Code
- an eleventh aspect which is an embodiment of the tenth aspect—there is provided a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, with a second active ingredient which is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylpheny
- a process for the preparation of a pharmaceutical composition which comprises mixing a first active ingredient which is selected from 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and its pharmaceutically acceptable derivatives, with a second active ingredient which is selected from 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] and its pharmaceutically acceptable derivatives.
- the present invention further provides the use of a pharmaceutical composition, or pharmaceutical product according to the invention in the manufacture of a medicament for the treatment of an inflammatory disease and/or an inflammation associated disorder.
- the present invention provides a method of an effective treatment of an inflammatory disease and/or an inflammation associated disorder which can be treated with a conventional NSAID while minimizing gastrointestinal side effects comprising the simultaneous, sequential or separate administration of i) a first amount of a conventional NSAID or a pharmaceutically acceptable derivative therof; and ii) a second amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof, wherein the sum of the first and the second amount is a therapeutically effective amount, to a patient in need thereof.
- the present invention provides a method of minimizing gastrointestinal side effects frequently associated with the use of conventional NSAIDs comprising the simultaneous, sequential or separate administration of i) a first amount of a conventional NSAID or a pharmaceutically acceptable derivative therof; and ii) a second amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof, wherein the sum of the first and the second amount is a therapeutically effective amount, to a patient in need thereof.
- Said methods also include a pharmaceutical product or kit containing a conventional NSAID and a written description which discloses that said conventional NSAID can be administered together with a PDE4 inhibitor (a) for the treatment of an inflammatory disease and/or an inflammation associated disorder while minimizing gastrointestinal side effects or (b) for the attenuation of gastrointestinal side effects frequently associated with the use of conventional NSAIDs.
- said methods include a pharmaceutical product or kit containing a PDE4 inhibitor and a written description which discloses that said PDE4 inhibitor can be administered together with a conventional NSAID (a) for the treatment of an inflammatory disease and/or an inflammation associated disorder while minimizing gastrointestinal side effects or (b) for the attenuation of gastrointestinal side effects frequently associated with the use of conventional NSAIDs.
- “Inflammatory diseases” which may be mentioned in particular are arthritis, including but not limited to rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, irritable bowel syndrome and ulcerative colitis; asthma, bronchitis and skin related disorders such as psoriasis, eczema, burns and dermatitis.
- Inflammation associated disorders which may be mentioned are, for example, pain, migraine, fever and headaches.
- the active ingredients may, and indeed will, as part of the pharmaceutical composition, the pharmaceutical product or preparation, be used in admixture with one or more pharmaceutically acceptable auxiliaries and/or excipients.
- excipients or auxiliaries are suitable for the desired pharmaceutical composition, product or preparation.
- solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins).
- combined use is preferably understood as meaning the oral administration of both active ingredients.
- Further methods of administration which may be mentioned are the parenteral (for example intravenous injection or infusion or intramuscular or intraarticular injection) and the topical administration of the active ingredients.
- the pharmaceutical compositions or products according to the invention are preferably in the form of tablets, coated tablets, chewing tablets, lemonade tablets, dragees, capsules, caplets, suppositories, emulsions, (sterile parenteral) suspensions or solutions, the active ingredient content advantageously being between 0.1 and 95% and by appropriate choice of the excipients and the auxiliaries, it being possible to achieve a pharmaceutical administration form precisely tailored to the active ingredient(s) and/or to the desired onset of action (e.g. a sustained release form or an enteric form).
- the compounds according to the invention also can be used in form of pharmaceutical compositions or products which are suitable for topical application.
- suitable pharmaceutical formulations which may be mentioned in this connection are, for example, ointments, fatty ointments, creams, pastes or gels.
- the pharmaceutical compositions or products for topical application can preferably also be in form of a patch (e.g. as TTS).
- dosages administered will, of course, vary with the first and second active ingredients employed, the mode of administration, the treatment desired and the disorder indicated.
- the total daily dosage of first active ingredient(s), the PDE4 inhibitor(s), when taken oral is in the range from 1-2000 ⁇ g/kg of body weight.
- the daily dosage is in a range from 2-20 ⁇ g/kg of body weight.
- the total daily dosage of the second active ingredient(s), the conventional NSAIDs also can vary within a wide range.
- the daily doses are in a range from 100-2000 ⁇ g/kg.
- ASS acetylsalicylic acid; diclofenac, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid; indomethacin, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid; nimesulide, 4′-nitro-2′-phenoxymethansulfonamide; CGP28238, 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone; L-745337 5-methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone); celecoxib, (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
- celecoxib selectively increased coronary heart flow at doses consistent with its inhibitory potency on PDE4 and 5, but had no effect on left ventricular pressure and heart rate, thereby excluding inhibition of PDE3.
- diclofenac 3-100 mg/kg, p.o.
- ED 60 56 mg/kg
- mice Male NMRI mice (Charles River Laboratories, Sulzfeld, Germany) weighting 23-25 g were housed in groups of 5 under standard conditions at a temperature of 22° C.+/ ⁇ 2° C. and a 12 h light-dark cycle. If not otherwise stated animals had free access to tap water and standard food pellets. Diclofenac was administrated at doses from 1-100 mg/kg p.o.; rolipram, roflumliast and RP73401 were given at doses from 1-100 mg/kg p.o. Preventive treatment: Diclofenac was given at time point 0h.
- Hemoglobin was extracted in 2.5 ml of acetic acid/H 2 O (30/70 vol/vol) by the addition of 4.5 ml ethyl acetate. The sample was rigorously shacked and the supernatant was used following a centrifugation step for optical detection of hemoglobin.
- Tolidine was prepared freshly from a stock solution (0.4 g tolidine in 10 ml ethanol) by mixing equal volumes of stock solution, H 2 O and acetic acid and equilibrated at room temperature. 20 ⁇ l of extracted supernatant was diluted to 100 ⁇ l ethyl acetate in a 96er crystall plate and incubated with 50 ⁇ l of the working solution.
- the reaction was initiated by the injection of 25 ⁇ l hydrogen peroxide (6%) in a Wallac Victor spectro-photometer (Turku, Finnland).
- the increase of OD 690 was monitored by a kinetic analysis and expressed as ⁇ D690/min.
- Table 2 shows the % reduction of the ⁇ OD 690 /min when a PDE4 inhibitor was administered (preventive or curative) compared to the ⁇ OD 690 /min obtained without the administration of a PDE4-inhibitor.
- NSAID 30 mg/kg NSAID: 100 mg/kg diclofenac indomethacin Rolipram 30 90% mg/kg (prevent- ive) Rollpram 10 82% mg/kg (cur- ative) Roflumilast 10 95% mg/kg (prevent- ive) Roflumilast 3 95% mg/kg (cur- ative) Rolipram 100 65% mg/kg (cur- ative) RP73401 100 96% mg/kg (cur- ative)
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/003,129 US8242146B2 (en) | 2001-09-19 | 2007-12-20 | Combination of a NSAID and a PDE-4 inhibitor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01000473.7 | 2001-09-19 | ||
EP01000473 | 2001-09-19 | ||
PCT/EP2002/010424 WO2003024489A2 (en) | 2001-09-19 | 2002-09-17 | Combination of a nsaid and a pde-4 inhibitor |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/003,129 Division US8242146B2 (en) | 2001-09-19 | 2007-12-20 | Combination of a NSAID and a PDE-4 inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040242597A1 true US20040242597A1 (en) | 2004-12-02 |
Family
ID=8176065
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/489,920 Abandoned US20040242597A1 (en) | 2001-09-19 | 2002-09-17 | Combination |
US12/003,129 Expired - Fee Related US8242146B2 (en) | 2001-09-19 | 2007-12-20 | Combination of a NSAID and a PDE-4 inhibitor |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/003,129 Expired - Fee Related US8242146B2 (en) | 2001-09-19 | 2007-12-20 | Combination of a NSAID and a PDE-4 inhibitor |
Country Status (25)
Country | Link |
---|---|
US (2) | US20040242597A1 (de) |
EP (1) | EP1429807B1 (de) |
JP (1) | JP4588998B2 (de) |
KR (1) | KR100949528B1 (de) |
CN (1) | CN100496607C (de) |
AT (1) | ATE355080T1 (de) |
AU (1) | AU2002337105B2 (de) |
BR (1) | BR0212606A (de) |
CA (1) | CA2459757C (de) |
CY (1) | CY1108011T1 (de) |
DE (1) | DE60218497T2 (de) |
DK (1) | DK1429807T3 (de) |
EA (1) | EA008108B1 (de) |
ES (1) | ES2282469T3 (de) |
HK (1) | HK1066730A1 (de) |
HU (1) | HU229442B1 (de) |
IL (2) | IL160271A0 (de) |
MX (1) | MXPA04002562A (de) |
NO (1) | NO331756B1 (de) |
NZ (1) | NZ532278A (de) |
PL (1) | PL210463B1 (de) |
PT (1) | PT1429807E (de) |
SI (1) | SI1429807T1 (de) |
WO (1) | WO2003024489A2 (de) |
ZA (1) | ZA200402654B (de) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050059741A1 (en) * | 2003-08-07 | 2005-03-17 | B.M.R.A. Corporation B.V. | Compositions and methods involving the combination of a thromboxane A2 receptor antagonist and an inhibitor of cyclooxygenase-1 |
EP1688413A1 (de) * | 2005-02-03 | 2006-08-09 | Hikma Pharmaceuticals Co. Ltd. | Benzoxazolderivate zur Prophylaxe und Behandlung von entzündlichen Darmerkrankungen |
US20060286041A1 (en) * | 2005-06-17 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Mrp iv inhibitors for the treatment of respiratory diseases |
US20080171746A1 (en) * | 2005-03-14 | 2008-07-17 | Thomas Klein | Method for Preventing Cardiovascular Diseases |
US9120788B2 (en) | 2013-02-19 | 2015-09-01 | Pfizer Inc. | Azabenzimidazole compounds |
US9598421B2 (en) | 2014-08-06 | 2017-03-21 | Pfizer Inc. | Imidazopyridazine compounds |
US10131669B2 (en) | 2014-07-24 | 2018-11-20 | Pfizer Inc. | Pyrazolopyrimidine compounds |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004110424A1 (en) * | 2003-05-28 | 2004-12-23 | Glaxo Group Limited | Method and pharmaceutical formulation for reducing stress-induced accelerated colonic transit in a mammal |
BRPI0415753A (pt) * | 2003-10-21 | 2006-12-19 | Pharmacia Corp | método para tratamento e prevenção da inflamação respiratória com um inibidor de ciclooxigenase-2 em associação com um inibidor de fosfodiesterase 4 e composições que os contêm |
EP1683521A1 (de) * | 2005-01-21 | 2006-07-26 | Centre National De La Recherche Scientifique (Cnrs) | Peptid-Deformylase-Inhibitoren, deren Verwendung und pharmazeutische Zusammensetzungen, welche sie enthalten |
EP2012763B1 (de) * | 2006-04-28 | 2011-03-23 | Grünenthal GmbH | Pharmazeutische kombination mit 3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol und einem nsar |
FR2909876A1 (fr) * | 2006-12-19 | 2008-06-20 | Galderma Res & Dev S N C Snc | Utilisation du nepafenac ou ses derives pour le traitement de desordres dermatologiques |
BRPI0906809A2 (pt) | 2008-01-25 | 2015-07-14 | High Point Pharmaceuticals Llc | Compostos tricíclicos como moduladores da síntese do tnf-(alfa) e como inibidores da pde4. |
JP5745861B2 (ja) * | 2008-03-04 | 2015-07-08 | ファイザー・リミテッドPfizer Limited | 炎症性疼痛を治療する方法 |
EP2400962B1 (de) * | 2009-02-27 | 2017-11-08 | Boehringer Ingelheim International GmbH | Arzneimittelkombinationen enthaltend pde4-inhibitoren und nsaids |
EP2400961B1 (de) * | 2009-02-27 | 2017-11-22 | Boehringer Ingelheim International GmbH | Arzneimittelkombinationen enthaltend pde4-inhibitoren und nsaids |
US20210031012A1 (en) | 2018-01-26 | 2021-02-04 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a pde4 inhibitor |
EP3883634A1 (de) | 2018-11-19 | 2021-09-29 | Progenity, Inc. | Verfahren und vorrichtungen zur behandlung einer krankheit mit biotherapeutika |
EP4069213A1 (de) * | 2019-12-03 | 2022-10-12 | The USA, as represented by The Secretary, Department of Health and Human Services | Cyclooxygenase-2 hemmung zur behandlung von saa-high-asthma |
EP4309722A2 (de) | 2019-12-13 | 2024-01-24 | Biora Therapeutics, Inc. | Einnehmbare vorrichtung zur abgabe eines therapeutischen mittels an den magen-darm-trakt |
IL311534A (en) * | 2021-09-22 | 2024-05-01 | Iolyx Therapeutics Inc | Methods for treating ocular inflammatory diseases |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6174878B1 (en) * | 1999-08-31 | 2001-01-16 | Alcon Laboratories, Inc. | Topical use of kappa opioid agonists to treat otic pain |
US6410563B1 (en) * | 1999-12-22 | 2002-06-25 | Merck Frosst Canada & Co. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1229075B (it) | 1985-04-05 | 1991-07-17 | Fidia Farmaceutici | Medicamenti per uso topico, ottenuti tramite l'impiego dell'acido ialuronico |
GB2228736A (en) | 1989-02-10 | 1990-09-05 | Sterivet Lab Ltd | Cosmetic formulation |
ES2137113B1 (es) * | 1997-07-29 | 2000-09-16 | Almirall Prodesfarma Sa | Nuevos derivados de triazolo-piridazinas heterociclicos. |
EP1028946A1 (de) | 1997-11-04 | 2000-08-23 | Pfizer Products Inc. | Bioisosterer indazolersatz für catechol in therapeutisch aktiven verbindungen |
JP2003503360A (ja) | 1999-06-24 | 2003-01-28 | ファルマシア コーポレイション | 炎症性疾患の処置のための併用療法 |
CA2381802C (en) * | 1999-08-21 | 2010-12-07 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Synergistic combination of roflumilast and salmeterol |
AR029189A1 (es) * | 1999-11-02 | 2003-06-18 | Smithkline Beecham Corp | Uso de un inhibidor de fosfodiesterasa 4 y un corticoesteroide antiinflamatorio en forma combinada, separadamente o separadamente secuencial para la preparacion de un medicamento |
US6372777B1 (en) * | 1999-12-23 | 2002-04-16 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
AU2700201A (en) * | 2000-01-31 | 2001-08-14 | Pfizer Products Inc. | Nicotinamide benzofused-heterocyclyl derivatives useful as selective inhibitors of pde4 isozymes |
PL356447A1 (en) * | 2000-02-08 | 2004-06-28 | Smithkline Beecham Corporation | Method and compositions for treating an inflammatory disease |
PL364910A1 (en) * | 2001-01-31 | 2004-12-27 | Pfizer Products Inc. | Ether derivatives useful as inhibitors of pde4 isozymes |
EE05386B1 (et) * | 2001-02-15 | 2011-02-15 | ALTANA�Pharma�AG | Ftalasinoon-piperidinoderivaadid,ÁnendeÁkasutamineÁjaÁravim |
-
2002
- 2002-09-17 CA CA2459757A patent/CA2459757C/en not_active Expired - Fee Related
- 2002-09-17 PT PT02772313T patent/PT1429807E/pt unknown
- 2002-09-17 AU AU2002337105A patent/AU2002337105B2/en not_active Ceased
- 2002-09-17 NZ NZ532278A patent/NZ532278A/en not_active IP Right Cessation
- 2002-09-17 HU HU0401582A patent/HU229442B1/hu not_active IP Right Cessation
- 2002-09-17 EA EA200400410A patent/EA008108B1/ru not_active IP Right Cessation
- 2002-09-17 DK DK02772313T patent/DK1429807T3/da active
- 2002-09-17 BR BR0212606-0A patent/BR0212606A/pt not_active IP Right Cessation
- 2002-09-17 AT AT02772313T patent/ATE355080T1/de active
- 2002-09-17 EP EP02772313A patent/EP1429807B1/de not_active Expired - Lifetime
- 2002-09-17 PL PL369472A patent/PL210463B1/pl unknown
- 2002-09-17 WO PCT/EP2002/010424 patent/WO2003024489A2/en active IP Right Grant
- 2002-09-17 SI SI200230534T patent/SI1429807T1/sl unknown
- 2002-09-17 CN CNB028182413A patent/CN100496607C/zh not_active Expired - Fee Related
- 2002-09-17 JP JP2003528583A patent/JP4588998B2/ja not_active Expired - Fee Related
- 2002-09-17 ES ES02772313T patent/ES2282469T3/es not_active Expired - Lifetime
- 2002-09-17 MX MXPA04002562A patent/MXPA04002562A/es active IP Right Grant
- 2002-09-17 DE DE60218497T patent/DE60218497T2/de not_active Expired - Lifetime
- 2002-09-17 IL IL16027102A patent/IL160271A0/xx active IP Right Grant
- 2002-09-17 KR KR1020047004047A patent/KR100949528B1/ko not_active IP Right Cessation
- 2002-09-17 US US10/489,920 patent/US20040242597A1/en not_active Abandoned
-
2004
- 2004-02-08 IL IL160271A patent/IL160271A/en not_active IP Right Cessation
- 2004-04-05 ZA ZA2004/02654A patent/ZA200402654B/en unknown
- 2004-04-19 NO NO20041596A patent/NO331756B1/no not_active IP Right Cessation
- 2004-12-09 HK HK04109770A patent/HK1066730A1/xx not_active IP Right Cessation
-
2007
- 2007-05-07 CY CY20071100595T patent/CY1108011T1/el unknown
- 2007-12-20 US US12/003,129 patent/US8242146B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6174878B1 (en) * | 1999-08-31 | 2001-01-16 | Alcon Laboratories, Inc. | Topical use of kappa opioid agonists to treat otic pain |
US6410563B1 (en) * | 1999-12-22 | 2002-06-25 | Merck Frosst Canada & Co. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050059741A1 (en) * | 2003-08-07 | 2005-03-17 | B.M.R.A. Corporation B.V. | Compositions and methods involving the combination of a thromboxane A2 receptor antagonist and an inhibitor of cyclooxygenase-1 |
EP1688413A1 (de) * | 2005-02-03 | 2006-08-09 | Hikma Pharmaceuticals Co. Ltd. | Benzoxazolderivate zur Prophylaxe und Behandlung von entzündlichen Darmerkrankungen |
US20070043003A1 (en) * | 2005-02-03 | 2007-02-22 | Hikma Pharmaceuticals Co., Ltd. | Novel compounds for the prophylaxis and treatment of inflammatory bowel diseases |
US20080171746A1 (en) * | 2005-03-14 | 2008-07-17 | Thomas Klein | Method for Preventing Cardiovascular Diseases |
US20060286041A1 (en) * | 2005-06-17 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Mrp iv inhibitors for the treatment of respiratory diseases |
US9120788B2 (en) | 2013-02-19 | 2015-09-01 | Pfizer Inc. | Azabenzimidazole compounds |
US9815832B2 (en) | 2013-02-19 | 2017-11-14 | Pfizer Inc. | Azabenzimidazole compounds |
US10131669B2 (en) | 2014-07-24 | 2018-11-20 | Pfizer Inc. | Pyrazolopyrimidine compounds |
US9598421B2 (en) | 2014-08-06 | 2017-03-21 | Pfizer Inc. | Imidazopyridazine compounds |
US10077269B2 (en) | 2014-08-06 | 2018-09-18 | Pfizer Inc. | Imidazopyridazine compounds |
US10669279B2 (en) | 2014-08-06 | 2020-06-02 | Pfizer Inc. | Imidazopyridazine compounds |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8242146B2 (en) | Combination of a NSAID and a PDE-4 inhibitor | |
AU2002337105A1 (en) | Combination of a NSAID and a PDE-4 inhibitor | |
AU760735B2 (en) | A method for treating inflammatory diseases by administering a thrombin inhibitor | |
EP3411026B1 (de) | Verwendung von stimulatoren der löslischen guanylatzyklase zur behandlung von nichtalkoholischer steatohepatitis (nash) | |
JP2010516689A (ja) | メタボリック症候群治療用の新規組成物 | |
WO2006056711A3 (fr) | Medicament oral a liberation modifiee d'au moins un principe actif sous forme multimicrocapsulaire | |
JP2012520883A (ja) | アルツハイマー病及び骨粗鬆症の治療並びに老化の軽減 | |
JP2012255039A (ja) | ニコチン性アセチルコリンα7受容体アゴニストの組合せ剤 | |
WO2016044441A1 (en) | Sgc stimulators | |
JP2019502686A (ja) | 消化管括約筋機能障害の治療へのsGC刺激薬の使用 | |
JP7016853B2 (ja) | sGC刺激剤のリンプロドラッグ | |
Sorbera et al. | Lumiracoxib | |
WO2003094924A1 (en) | Combination therapy for treating cyclooxygenase-2 mediated diseases in patients at risk of thrombotic cardiovascular events | |
UA77812C2 (en) | Anelated pyrrol substances as proton pump inhibitors for treating gastric ulcer | |
US20060154954A1 (en) | Combinations and use of selected pharmaceutically active compounds | |
AU3948699A (en) | Use of a cox-2 inhibitor and a nk-1 receptor antagonist for treating inflammation | |
Benhalima et al. | Niacin, an old drug with new perspectives for the management of dyslipidaemia | |
HELMUT BUSCHMANN | Analgesics and Antipyretics | |
Hurley | Celebrex: generic name: celecoxib | |
RU2005129323A (ru) | Режим дозирования нестероидного противовоспалительного лекарственного средства |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NYCOMED GMBH, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:ALTANA PHARMA AG;REEL/FRAME:019783/0625 Effective date: 20070614 Owner name: NYCOMED GMBH,GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:ALTANA PHARMA AG;REEL/FRAME:019783/0625 Effective date: 20070614 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |