WO1989004179A1 - Pharmaceutical formulations for transdermal administration - Google Patents

Pharmaceutical formulations for transdermal administration Download PDF

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Publication number
WO1989004179A1
WO1989004179A1 PCT/EP1988/000958 EP8800958W WO8904179A1 WO 1989004179 A1 WO1989004179 A1 WO 1989004179A1 EP 8800958 W EP8800958 W EP 8800958W WO 8904179 A1 WO8904179 A1 WO 8904179A1
Authority
WO
WIPO (PCT)
Prior art keywords
active
dmi
dimethylisosorbide
emulsion
transdermal administration
Prior art date
Application number
PCT/EP1988/000958
Other languages
French (fr)
Inventor
Luciano Cocchi
Simos Contos
Original Assignee
Also Laboratori S.A.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Also Laboratori S.A.S. filed Critical Also Laboratori S.A.S.
Publication of WO1989004179A1 publication Critical patent/WO1989004179A1/en

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Classifications

    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

  • the present invention concerns pharmaceutical compositions for the transdermal application of active principles.
  • transdermal administration of pharmacologicaly active substances has recently been more and more widely studied in order to obtain a controlled release of drugs, mainly for particular kind of drugs with short half-life, asking for repeated administration over a certain period of time.
  • Example of drugs presently used by transdermal route are nitroglycerine, ⁇ copolamine, clonidine, some anti-inflammatory drugs and some hormones.
  • plasters wherein the active principle is suitably absorbed in a reservoir and is made available therefrom, optionally through a membrane, for the cutaneous absorption.
  • a problem common to the known formulations consists in the high variability of absorption according to the chemico-physical characteristics of each active principle. This asks for the need of developing new and different formulations suitable for the single active principle.
  • Dimethylsulfoxide for instance, is used to make the diffusion of the active principles through the horny layer easier, but it does not provide an ideal solution because of its toxicity.
  • GB 2146525, E-A 120262 and DD 217989 disclose pharmaceutical formulations suited for the transdermal administration which may contain, inter alia, also DMI as a solvent, in admixture with different vehicles or solvents contributing to the transdermal administration system.
  • DMI is therefore used only as a hydrophilic solvent and always in combination with other excipients or ve-hicle-s.
  • JP-A-60-64418 discloses the USE of DMI as an agent for promoting the absorption of active principles through the skin.
  • DMI is never used as single component but it is used in weight percentages ranging from 5 to 50%. Values outside this range are said to be "snrpreferred", tbecause higher percentages would cause a lowering of cohesivenes ⁇ of the particular tape formulation.
  • the amount of drug to be contained in the tape preparation according to said JP-A- is from 1 to 1000 ⁇ g/cm 2 .
  • compositions suitable for the transdermal administration of active principle consisting of a solution or an emulsion of said active principle in dimethylisosorbide or in a dimethyl isosorbide-water mixture wherein the content of dimethylisosorbide is higher than 50% by weight of the total mixture and is preferably higher than 60%.
  • the formulations according to the invention allow an effective absorbtion of a wide variety of active principles, even of very different chemico-physical characteristics, and they are prepared in an easy, inexp- ensive way.
  • the invention provides plasters having the formulations of the invention absorbed on a suitable material.
  • the active principles which may be used according to the present invention belong to different therapeutic cathegories.
  • both steroidal and non steroidal antiinf lammatory agents calcium-antagonists, ⁇ -blockers, ⁇ -blockers, ⁇ -agonists, calcium blockers, ergot alkaloids, anti-hist aminics, anti-cholinergics, mucolytics, anti-oxidizing agents (vitamins, enzymes ⁇ uch a ⁇ superoxidismutase), bacterial extracts, thymic hormones, cardiac glycosides, pharmacologically active peptides, active principles of vegetal .kind, GingKo biloba, physiological substances (carnitine, taurine, glutathion, cerebrosides, phospholipids etc).
  • the amount of the active principles in the formulations of the invention depends on the activity and on the .absorption characteristics of the considered compounds: it will be anyhow determined by usual methods, relying on the average knowledge in the art.
  • the preparation of solutions or emulsion ⁇ of the different active principles is carried out by usual methods; for the solutions, the percent of hydratation of DMI will be ⁇ elected according to the hydrophilic degree of the active principle. Active principle ⁇ in saline form, for instance, will be solubilized with higher amounts of water, up to about 50%.
  • the di ⁇ solution temperature should not be higher than 40-50°C, in order to avoid degradation of the active principle .
  • solution of the active principle obtained as abov e described is added to sai base emulsion prepared from usual and compatible substances, preferably at a temp erature lower than 40°C, first in a mixer under vacuum and then in a piston homogenizer.
  • solutions or emul ⁇ ion ⁇ may be the further worked for the preparation of pharmaceutical forms suited for the topical administation, such as those described in "Remington's Pharmaceutical Sciences Handbook",hack Pub. CO., N.Y., U.S.A.
  • a compatible material for instance a viscosa-rayon non-wowen material, collagene or other natural or synthetic fibres unsoluble in DMI.
  • the carrier system according to the invention allows the preparation of solutions up to 60% of solid active principle and up to 90% for active principles in liquid form.
  • the plasters may comprise up to 1-1,5 ml of solution or emulsion
  • the maximum amount of active principle comprised in the plasters of the invention reaches about 600-900 mg, which is by far higher than that allowable by the known prior-art formulations.
  • the composition, form, size and materials of the plaster may change according to the active principle, to the application zone, and to packaging and/or presentation needs, etc.
  • the numeral 1 shows a first sheet, for example of aluminum, PVC or other material, to be applied on the skin during the drug release.
  • the absorption zone of the emulsion or solution of the active principle is indicated by 2 whereas 3 shows a ring of expanded or foamed material coated with acrylic or siliconic hypoallergenic adhesive.
  • a protective ring 4 covers the adhesive side of the ring 3; two thermosealed aluminum or plastic rings limit the zone 2 and the plaster's perimeter, respectively.
  • the numeral 6 shows the upper closure sheet, which can be of the same of different material as the sheet 1, to be discarded immediately before use.
  • a siliconic film or other suitable membrane may be placed between the zone 2 and the adhesive ring 3, in order to enhance the gradual release of the active principle.

Abstract

Pharmaceutical formulations, particularly in form of plasters, for the transdermal delivery of active principles are described, containing as an absorption promoter dimethylisosorbide in amounts higher than 50 % by weight.

Description

PHARMACEUTICAL FORMULATIONS FOR TRANSDERMAL
ADMINISTRATION
The present invention concerns pharmaceutical compositions for the transdermal application of active principles.
The transdermal administration of pharmacologicaly active substances has recently been more and more widely studied in order to obtain a controlled release of drugs, mainly for particular kind of drugs with short half-life, asking for repeated administration over a certain period of time.
Example of drugs presently used by transdermal route are nitroglycerine, εcopolamine, clonidine, some anti-inflammatory drugs and some hormones.
A particularly advantageous administration form for the practical use is provided by plasters wherein the active principle is suitably absorbed in a reservoir and is made available therefrom, optionally through a membrane, for the cutaneous absorption.
A problem common to the known formulations consists in the high variability of absorption according to the chemico-physical characteristics of each active principle. This asks for the need of developing new and different formulations suitable for the single active principle.
Another critical problem is provided by the choice of the vehicle which may remarkably affect the percutaneous absorption of a drug. Dimethylsulfoxide, for instance, is used to make the diffusion of the active principles through the horny layer easier, but it does not provide an ideal solution because of its toxicity.
US 4228162, DE 3442402, EP-A-131927 and GB 2139496 disclose the use of dimethylisosorbide (DMI) or 3,6-dimethoxyfuro [3,2-b] furan as a pharmaceutical solvent.
GB 2146525, E-A 120262 and DD 217989 disclose pharmaceutical formulations suited for the transdermal administration which may contain, inter alia, also DMI as a solvent, in admixture with different vehicles or solvents contributing to the transdermal administration system. In these documents, DMI is therefore used only as a hydrophilic solvent and always in combination with other excipients or ve-hicle-s.
JP-A-60-64418 discloses the USE of DMI as an agent for promoting the absorption of active principles through the skin.
Also in this case, however, DMI is never used as single component but it is used in weight percentages ranging from 5 to 50%. Values outside this range are said to be "snrpreferred", tbecause higher percentages would cause a lowering of cohesivenesε of the particular tape formulation.
Moreover, the amount of drug to be contained in the tape preparation according to said JP-A-is from 1 to 1000 μg/cm2, For an active principle to be administered in high dosages, this would involve an excessively wide body surface to be covered with the considered tape.
It has now been found that the above problems may be overcome by pharmaceutical formulations suitable for the transdermal administration of active principle consisting of a solution or an emulsion of said active principle in dimethylisosorbide or in a dimethyl isosorbide-water mixture wherein the content of dimethylisosorbide is higher than 50% by weight of the total mixture and is preferably higher than 60%.
The formulations according to the invention allow an effective absorbtion of a wide variety of active principles, even of very different chemico-physical characteristics, and they are prepared in an easy, inexp- ensive way.
Another advantage is the possibility of reaching a higher concentration of the active principle, allowing the administration of high doses, which was not possible according to the known formulations. According to a particularly preferred aspect, the invention provides plasters having the formulations of the invention absorbed on a suitable material.
The active principles which may be used according to the present invention belong to different therapeutic cathegories.
It is in fact possible to use advantageously, anti-inflammatory, analgesic, cardio-vasular, metabolic, antibiotic, antimycotic agents as well as drugs active on the gastro-enteric, central nervous, respiratory and immune systems.
In particular it is possible to use both steroidal and non steroidal antiinf lammatory agents, calcium-antagonists, α -blockers, β-blockers, β-agonists, calcium blockers, ergot alkaloids, anti-hist aminics, anti-cholinergics, mucolytics, anti-oxidizing agents (vitamins, enzymes εuch aε superoxidismutase), bacterial extracts, thymic hormones, cardiac glycosides, pharmacologically active peptides, active principles of vegetal .kind, GingKo biloba, physiological substances (carnitine, taurine, glutathion, cerebrosides, phospholipids etc).
The amount of the active principles in the formulations of the invention depends on the activity and on the .absorption characteristics of the considered compounds: it will be anyhow determined by usual methods, relying on the average knowledge in the art.
The preparation of solutions or emulsionε of the different active principles is carried out by usual methods; for the solutions, the percent of hydratation of DMI will be εelected according to the hydrophilic degree of the active principle. Active principleε in saline form, for instance, will be solubilized with higher amounts of water, up to about 50%.
In any case, the diεsolution temperature should not be higher than 40-50°C, in order to avoid degradation of the active principle . For emulsions, it is preferred to use first the base emulsion, by mixing a fatty phase at about 65° C and a aqueous phase at about 70° C, in a suitable mixer. solution of the active principle obtained as abov e described is added to sai base emulsion prepared from usual and compatible substances, preferably at a temp erature lower than 40°C, first in a mixer under vacuum and then in a piston homogenizer.
The so obtained solutions or emulεionε may be the further worked for the preparation of pharmaceutical forms suited for the topical administation, such as those described in "Remington's Pharmaceutical Sciences Handbook", Hack Pub. CO., N.Y., U.S.A.
A particularly preferred form iε provided by plasters wherein the solution or emulsion of the active principle in DMI is absorbed on a suitable zone of a compatible material, for instance a viscosa-rayon non-wowen material, collagene or other natural or synthetic fibres unsoluble in DMI. The carrier system according to the invention allows the preparation of solutions up to 60% of solid active principle and up to 90% for active principles in liquid form.
Considering that, in average, the plasters may comprise up to 1-1,5 ml of solution or emulsion, the maximum amount of active principle comprised in the plasters of the invention reaches about 600-900 mg, which is by far higher than that allowable by the known prior-art formulations. The composition, form, size and materials of the plaster may change according to the active principle, to the application zone, and to packaging and/or presentation needs, etc.
The choice of the most suited plasters for the various possible application is within the ordinary skill of any expert in the art.
In Figure 1 a possible configuration of a plaster of the invention is shown by way of exemplification.
With reference to the Figure, the numeral 1 shows a first sheet, for example of aluminum, PVC or other material, to be applied on the skin during the drug release.
The absorption zone of the emulsion or solution of the active principle is indicated by 2 whereas 3 shows a ring of expanded or foamed material coated with acrylic or siliconic hypoallergenic adhesive.
A protective ring 4 covers the adhesive side of the ring 3; two thermosealed aluminum or plastic rings limit the zone 2 and the plaster's perimeter, respectively. Finally, the numeral 6 shows the upper closure sheet, which can be of the same of different material as the sheet 1, to be discarded immediately before use.
Various changes may be carried out to the above shown configuration without practicing any inventive activity: for instance, a siliconic film or other suitable membrane may be placed between the zone 2 and the adhesive ring 3, in order to enhance the gradual release of the active principle.
The solution or emulsion of the active principle isabsorbed on the absorbing material during the plasters production, which is carried out by means of usual operations in a such as rolling, printing, glueing, thermosealing, cutting, packaging, which may be carried out continuosly. The following example further Illustrates the invention. EXAMPLE
Active principle Amount Solvent
1. Superoxydismutase 20 mg H2O/DMI 40/60 to 1 g
2. Superoxydismut ase+ 20 mg
Vit A palmitate 5000 U.I
Vit. C 70 mg H2O/DMI 40/60 to 1 g
Vit. E 15 mg
Sodium selenite 30 mg
3. Senna dry extract g 0,05 H2O/DMI 40/60 to 1 g
4. Bromelin 3.000.000 U. I.H2O/DMI 40/60 to 1 g
5. Diclofenac sodium 150 mg H2O/DMI 40/60 to 1 9
6. Indomethacin 100-50 mg DMI to 1 g
7. Piroxicam 10-20 mg DMI to 1 g
8. Salbutamolsuefate 2-6 mg H2O/DMI 40/60 to 1 g
9. Dhydroergotoxin 1,5 mg DMI to 1 g methansulfonate
10 .Dhydroergot amine 2 mg H2O/DMI 40/60 to 1 g
11 .Cyproeptadine HCl 6 mg DMI to 1 g
12 .Scopolamine 60 mg H2O/DMI 40/60 to bromobutylate 0,5 g
13 . Ibuprofen 240 mg H2O/DMI 40/60 to 1 g
14, .Ethinylestradiole 0,5 mg DMI to 0,2 g
15 .Naproxen 270 mg H2O/DMI 40/60 to 1 g
16 .Fluocinolone 40 mg DMI to 1 g acetonide
17.Cortisol 10 mg DMI to 1 g continued EXAMPLE (continued) Active principle Amount Solvent 18.Nicardipine 10-20-40 mg DMI to 1 g
19.Verapamil HCl 40 mg H2O/DMI 40/60 to 1 g
20.Thymostimoline 25 mg H O/DMI 20/80 to 1 g
21.Domperidone 30 mg DMI to 1 g 22.Syoscine HBr 1-5 mg H2O/DMI to 1
23. Bacterial extracts 0,5 mg DMI to 1 g
24. Acemethacine 30-60 mg DMI to 1 g
25.Tulobuterol 1,5-2-2,5 mg DMI to 1 g
26.Theophyllin 200-400 mg DMI to 1 g
27.Cyclopirox 1 mg DMI to 1 g
28.Ciprofloxacin 400 mg DMI to 1 g
29.Gingko biloba 40 mg H O/DMI 40/60 to 1 g
30 .Di ltiazem 60 mg DMI to 1 g 120 mg 18 0 mg

Claims

1. Pharmaceutical formulationε in form of solutions or emulsions for the transdermal administration of active principles comprising dimethylisosorbide as a transcutaneouε absorption promoter, characterized in that dimethylisosorbide is present in amount higher than 50% by weight to the total solution or emulsion.
2. Formulations according to claim 1 wherein the dimethylisosorbide concentration is higher than 60% by weight of the total emulsion or solution, the remaining consisting of water.
3. Formulations according to claim 1 wherein the emulsion or solution consists of pure dimethylisosorbide.
4. Formulations according to any one of the previous claims, characterized in that the active principles are εelected in the group consisting of steroid or non steroidal antiinflammatories, calcium antagonists, β-blockers, α -blockers, β-agonists, calcium-blockers, ergot alkaloids, antihistaminics, anticholinergics, mucolytics, antioxidants (vitamineε, enzymes such as superoxidismutases), bacterial extracts, thymic hormones, cardiac glycosideε, pharmacologically active peptideε, vegetal active principleε, physiologic substances (carnitine, taurine, glutathion, cerebrosides, phospholipids etc.), antibiotics, antimycotics.
5. Formulations according to claim 4, wherein the active principle is selected in the group consisting of superoxidismutases, vitamines, sodium selenite, dry Senna extract, bromeline, sodium diclofenac, indomethacin, piroxicam, salbutamol, dihydroergotoxine, dihydroergotamine, cyproheptadine, scopolamine, ibuprofen, ethinylestradiole, naproxene, fluocinolone acetonide, cortisol, nicardipine, diltiazem, verapamil, thymostimoline, domperidone, hyoscine, bacterial extracts, acemethacine, tulobϊiterolr theophylline, ciclopirox, cyprofloxacine, Gingko biloba.
6. Plasters for the transdermal administration of active principleε, characterized in that they contain on an area of a compatible material a formulation according to claims 1-5.
7. Plaεters according to claim 6, characterized in that the area in which the formulation iε abεorbed is made of viscose-rayon non wowen material.
PCT/EP1988/000958 1987-11-03 1988-10-26 Pharmaceutical formulations for transdermal administration WO1989004179A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT22501/87A IT1223343B (en) 1987-11-03 1987-11-03 PHARMACEUTICAL FORMULATIONS FOR TRANSDERMAL ADMINISTRATION
IT22501A/87 1987-11-03

Publications (1)

Publication Number Publication Date
WO1989004179A1 true WO1989004179A1 (en) 1989-05-18

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IT (1) IT1223343B (en)
WO (1) WO1989004179A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000725A1 (en) * 1990-07-13 1992-01-23 Farcon Ag Liquid oral pharmaceutical compositions having anti-inflammatory activity
WO1995022322A1 (en) * 1994-02-18 1995-08-24 Schering Aktiengesellschaft Sexual steroid-containing transdermal therapeutic systems
WO1999016434A1 (en) * 1997-09-26 1999-04-08 Sam Yang Co., Ltd. A transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof
AU724308B2 (en) * 1994-02-18 2000-09-14 Schering Aktiengesellschaft Transdermal therapeutic systems that contain sex steroids
WO2004002444A2 (en) * 2002-06-27 2004-01-08 Holden Development Limited A platform for transdermal formulations (ptf)
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2010059836A1 (en) 2008-11-20 2010-05-27 Decode Genetics Ehf Substituted aza-bridged bicyclics for cardiovascular and cns disease
WO2010084499A2 (en) 2009-01-26 2010-07-29 Israel Institute For Biological Research Bicyclic heterocyclic spiro compounds
EP2476680A1 (en) 2008-01-11 2012-07-18 Albany Molecular Research, Inc. (1-Azinone)-Substituted Pyridoindoles
EP2628727A2 (en) 2007-11-21 2013-08-21 Decode Genetics EHF Biaryl PDE4 inhibitors for treating pulmonary and cardiovascular disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4082881A (en) * 1976-12-23 1978-04-04 E. R. Squibb & Sons, Inc. Topical and other type pharmaceutical formulations containing isosorbide carrier
LU84514A1 (en) * 1982-12-09 1984-10-22 Oreal STABLE COMPOSITION FOR LOCAL CORTICOTHERAPY CONTAINING HYDROCORTISONE IN SOLUBILIZED CONDITIONS
EP0137278A2 (en) * 1983-09-12 1985-04-17 Schering Aktiengesellschaft Composition for transdermal drug application
GB2150024A (en) * 1983-11-21 1985-06-26 May & Baker Ltd Anthelmintic compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4082881A (en) * 1976-12-23 1978-04-04 E. R. Squibb & Sons, Inc. Topical and other type pharmaceutical formulations containing isosorbide carrier
LU84514A1 (en) * 1982-12-09 1984-10-22 Oreal STABLE COMPOSITION FOR LOCAL CORTICOTHERAPY CONTAINING HYDROCORTISONE IN SOLUBILIZED CONDITIONS
EP0137278A2 (en) * 1983-09-12 1985-04-17 Schering Aktiengesellschaft Composition for transdermal drug application
GB2150024A (en) * 1983-11-21 1985-06-26 May & Baker Ltd Anthelmintic compositions

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000725A1 (en) * 1990-07-13 1992-01-23 Farcon Ag Liquid oral pharmaceutical compositions having anti-inflammatory activity
WO1995022322A1 (en) * 1994-02-18 1995-08-24 Schering Aktiengesellschaft Sexual steroid-containing transdermal therapeutic systems
US5904931A (en) * 1994-02-18 1999-05-18 Schering Aktiengesellschaft Transdermal therapeutic systems that contain sex steroids and dimethyl isosorbide
AU724308B2 (en) * 1994-02-18 2000-09-14 Schering Aktiengesellschaft Transdermal therapeutic systems that contain sex steroids
WO1999016434A1 (en) * 1997-09-26 1999-04-08 Sam Yang Co., Ltd. A transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof
WO2004002444A3 (en) * 2002-06-27 2004-03-11 Holden Dev Ltd A platform for transdermal formulations (ptf)
WO2004002444A2 (en) * 2002-06-27 2004-01-08 Holden Development Limited A platform for transdermal formulations (ptf)
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
EP2628727A2 (en) 2007-11-21 2013-08-21 Decode Genetics EHF Biaryl PDE4 inhibitors for treating pulmonary and cardiovascular disorders
EP2674417A2 (en) 2007-11-21 2013-12-18 Decode Genetics EHF Biaryl PDE4 inhibitors for treating inflammation
EP2476680A1 (en) 2008-01-11 2012-07-18 Albany Molecular Research, Inc. (1-Azinone)-Substituted Pyridoindoles
WO2010059836A1 (en) 2008-11-20 2010-05-27 Decode Genetics Ehf Substituted aza-bridged bicyclics for cardiovascular and cns disease
WO2010084499A2 (en) 2009-01-26 2010-07-29 Israel Institute For Biological Research Bicyclic heterocyclic spiro compounds

Also Published As

Publication number Publication date
IT8722501A0 (en) 1987-11-03
AU2617288A (en) 1989-06-01
IT1223343B (en) 1990-09-19

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