CA1194419A - Use of 4-aminosalicylic acid as an anti-inflammatory agent - Google Patents
Use of 4-aminosalicylic acid as an anti-inflammatory agentInfo
- Publication number
- CA1194419A CA1194419A CA000398527A CA398527A CA1194419A CA 1194419 A CA1194419 A CA 1194419A CA 000398527 A CA000398527 A CA 000398527A CA 398527 A CA398527 A CA 398527A CA 1194419 A CA1194419 A CA 1194419A
- Authority
- CA
- Canada
- Prior art keywords
- asa
- pharmaceutical composition
- carrier
- pharmaceutically acceptable
- aminosalicylic acid
- 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.)
- Expired
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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
- A61K9/0031—Rectum, anus
Abstract
Abstract of the Disclosure 4-Aminosalicylic acid is used in the treatment of inflammation, e.g., inflammatory bowel disease.
Description
, USE OF 4-AI~INOSALIC~LIC ~CID -.:
AS AN ANT~-INFLAMM~TO~ AGENT -Bac~ground o~ -the Inven-tion Salicylazosulfapyridine ~SASP) has been know~
to be e~fective in the treatrnent o~ ulcerative colitis and has been used clinically ~or -tha-t purpose for o~e~ . _ 30 years. When the drug is orally ingested most reaches the colon intact where it sufers reductive azo-cleavage as a result of action o~ colonic bac-teria to give sul-~a- ~ -pyridirle (SP~ and 5-aminosalicylic acid ~5-ASA). SP is absorbed, distribute~ throughout the body, and excreted in urine as glucuronide conjugatesO Appro~imately 30%
o~ the 5-ASA is absorbed from the colon, acetylated and excreted in the urine and the remainder is excre-ted i~
~he Eeces.
It was determined that the therapeutic mechanism o~ SASP was primarily a ~unction o-~ the an-ti-in~lammatory 5-ASA and most o~ the deleterious side e~-~ects were asso-cia-ted with SP. Accordingly, 5~ASA has been formulated 20 in a form bound to a sui-table polymer for site speci~ic ~.-release of 5~ASA in the colon while avoïding the presence -;
o~ the toxic SP portion o~ SASP. This is described in Parkinson, et al U.S. Patent ~,190,716~ .
,, ~, '''.
, .
.
~ . ~
5-~S~ is unique in that before the present invention, it was the only non-s-teroidal anti-in-flammatory agent known to be use-ful in the -treatment o~ ulceratîve colitis. Other salicylates such as aspi.rin (acetylsali~
5 ~ylic acid) and othex a~ti-in~lammatories such as indo- -~ethacin (which is a more potent anti-in~lammatory agent) are not ef~ective in the treatment o~ ulcerative colitis.
4-Aminosalicylic acid (4-ASA) is a well known pharmaceutical agent which has ~een used ~or many years in the treatment of tuberculosis. 4-ASA has a bacterio~
static e~fect on the organism ~Iycobac-terium tuberculosis and inhibits the deYelopment o~ bacterial resistance to streptomycin and isoniazid. 4-ASA has invariably been administered as part o~ a multi-dru~ regimen including one or both of these drugs.
.Even though 4-ASA and 5-~SA are position isomers, they are well recognized to be quite distinct chemically.
The salicylic acid backbone is a carboxy-substituted phenol and it is well known that the phenolic hydroxy group or alko~ide ion is a very power~ul activator of the benzene ring direct.ing ortho- and para- in electrophylic aro~atic substitution~ As a result, meta-substituted salicylic acids on one hand, and para- or ortho-substituted salicylic acids on the other hand, are prepared.via different pro-2O cesses and undergo dif~eren-t reactions. For example~ the meta-substituted 5-AS~ is produced by the reduction of a nitro compound by zinc dust and hydrochloric acid or by `elect~olytic reduction. The para-substituted ~-AS~ is prepared by heating 3-aminophenol ~rith ammonium carbonate 30 or potassium bicarbonate under pressure or from the corres-ponding sodiu~ salt (U.S. Patent 2,~44,625). The me-ta-substituted 5-~SA is very unstable and is known to quickly break down to a dark purple presumed quinone containing tar.
The para-substituted ~-AS~ also breaks clown into a brownish 3~ or purplish ma-terial but at a muc~l slower rate. Pour-ASA, in the presence o~ moisture readily decarbo~yla-tes, whereas ~ 3 5- ASA does no~. Salts o~ ~-ASA resist decarboxylation~
~ur-ther, even though 4-ASA ~as-been used for -the treatment o~ millions o~ tuberculosis pa*ien-ts, there has been no recognition o~ the an-ti-inflammatory activity of this 5 compound. Simila~ly, 5-ASA is not known to be anti--tubercular. Still further, 4-ASA cannot, because o-P the steric and activity differences -~rom 5-A$A, be bound to the same polymers as 5-ASA or -~o o-ther polymers using methods applicable to 5-ASA.
Xn view of -the well recognized distinc-tion chemically between 4-ASA and 5-ASA, it was quite surpri-sing to discover tha-t not only did 4-ASA have anti-inPla7n-matory. activity but also it was roughly 50% more po-tent than 5-AS~. Since the 4-amino compound is more potent and 15 as a sal-t is also more resistant -to degrada~tion, doses which are smaller in absolute amounts can be administered -thereb~
decreasing the magnitude and/or occurence of adverse side effects It is accordingly the object o~ this invention to ~o provide a new anti-inflammatory agent which is useful, inter alia, în the treatment of ulcerative colitis and more broadly in in~lammatory bowel disease. This and other objects of the invention will become apparent to those skilled in the art ~rom the following detailed disclosure.
.
Summary of -the Invention This inve~tion relates to the use of 4-~$~ as an anti-in~lammatory agent ~or the trea-tment of va~rlous in-~lam-mations including, but not limited to, in-Elammatory bo~el disease, e.g., Crohn's disease and particularly ulcera~ive 30 colitis.
Description of the Invention In accordance with the presen-t invention, 4-~SA
can be used as such or in any of i-ts ~rell ~non.Jn p~arma-.
ceuticall~ acceptable estersg sal-ts and com~lexes for -the .
.
, . . _ treatment of inflammation. It is useful for the treatment of inflamatory bowel disease) particularly ulcerative colitis. At presentl the sodium salt is pre-erred over the acid since i~ is more stable than the acid form of the drug.
Four~ASA~ its esters, sal-ts and complexes are chemical compounds which were commonly used as pharmaceutical agents in the treatrnent o~ tuherculosis in man and domestic animals.
It can be administered in any of the various forms which haYe been utilized for ~-ASA heretofore or in the various forrnulations which ~ASP or 5 ASA have been used. See, e.g~, U.S. patents 2,445,242, 2,540,104, 2,540,785, 2 9 55S~298,
AS AN ANT~-INFLAMM~TO~ AGENT -Bac~ground o~ -the Inven-tion Salicylazosulfapyridine ~SASP) has been know~
to be e~fective in the treatrnent o~ ulcerative colitis and has been used clinically ~or -tha-t purpose for o~e~ . _ 30 years. When the drug is orally ingested most reaches the colon intact where it sufers reductive azo-cleavage as a result of action o~ colonic bac-teria to give sul-~a- ~ -pyridirle (SP~ and 5-aminosalicylic acid ~5-ASA). SP is absorbed, distribute~ throughout the body, and excreted in urine as glucuronide conjugatesO Appro~imately 30%
o~ the 5-ASA is absorbed from the colon, acetylated and excreted in the urine and the remainder is excre-ted i~
~he Eeces.
It was determined that the therapeutic mechanism o~ SASP was primarily a ~unction o-~ the an-ti-in~lammatory 5-ASA and most o~ the deleterious side e~-~ects were asso-cia-ted with SP. Accordingly, 5~ASA has been formulated 20 in a form bound to a sui-table polymer for site speci~ic ~.-release of 5~ASA in the colon while avoïding the presence -;
o~ the toxic SP portion o~ SASP. This is described in Parkinson, et al U.S. Patent ~,190,716~ .
,, ~, '''.
, .
.
~ . ~
5-~S~ is unique in that before the present invention, it was the only non-s-teroidal anti-in-flammatory agent known to be use-ful in the -treatment o~ ulceratîve colitis. Other salicylates such as aspi.rin (acetylsali~
5 ~ylic acid) and othex a~ti-in~lammatories such as indo- -~ethacin (which is a more potent anti-in~lammatory agent) are not ef~ective in the treatment o~ ulcerative colitis.
4-Aminosalicylic acid (4-ASA) is a well known pharmaceutical agent which has ~een used ~or many years in the treatment of tuberculosis. 4-ASA has a bacterio~
static e~fect on the organism ~Iycobac-terium tuberculosis and inhibits the deYelopment o~ bacterial resistance to streptomycin and isoniazid. 4-ASA has invariably been administered as part o~ a multi-dru~ regimen including one or both of these drugs.
.Even though 4-ASA and 5-~SA are position isomers, they are well recognized to be quite distinct chemically.
The salicylic acid backbone is a carboxy-substituted phenol and it is well known that the phenolic hydroxy group or alko~ide ion is a very power~ul activator of the benzene ring direct.ing ortho- and para- in electrophylic aro~atic substitution~ As a result, meta-substituted salicylic acids on one hand, and para- or ortho-substituted salicylic acids on the other hand, are prepared.via different pro-2O cesses and undergo dif~eren-t reactions. For example~ the meta-substituted 5-AS~ is produced by the reduction of a nitro compound by zinc dust and hydrochloric acid or by `elect~olytic reduction. The para-substituted ~-AS~ is prepared by heating 3-aminophenol ~rith ammonium carbonate 30 or potassium bicarbonate under pressure or from the corres-ponding sodiu~ salt (U.S. Patent 2,~44,625). The me-ta-substituted 5-~SA is very unstable and is known to quickly break down to a dark purple presumed quinone containing tar.
The para-substituted ~-AS~ also breaks clown into a brownish 3~ or purplish ma-terial but at a muc~l slower rate. Pour-ASA, in the presence o~ moisture readily decarbo~yla-tes, whereas ~ 3 5- ASA does no~. Salts o~ ~-ASA resist decarboxylation~
~ur-ther, even though 4-ASA ~as-been used for -the treatment o~ millions o~ tuberculosis pa*ien-ts, there has been no recognition o~ the an-ti-inflammatory activity of this 5 compound. Simila~ly, 5-ASA is not known to be anti--tubercular. Still further, 4-ASA cannot, because o-P the steric and activity differences -~rom 5-A$A, be bound to the same polymers as 5-ASA or -~o o-ther polymers using methods applicable to 5-ASA.
Xn view of -the well recognized distinc-tion chemically between 4-ASA and 5-ASA, it was quite surpri-sing to discover tha-t not only did 4-ASA have anti-inPla7n-matory. activity but also it was roughly 50% more po-tent than 5-AS~. Since the 4-amino compound is more potent and 15 as a sal-t is also more resistant -to degrada~tion, doses which are smaller in absolute amounts can be administered -thereb~
decreasing the magnitude and/or occurence of adverse side effects It is accordingly the object o~ this invention to ~o provide a new anti-inflammatory agent which is useful, inter alia, în the treatment of ulcerative colitis and more broadly in in~lammatory bowel disease. This and other objects of the invention will become apparent to those skilled in the art ~rom the following detailed disclosure.
.
Summary of -the Invention This inve~tion relates to the use of 4-~$~ as an anti-in~lammatory agent ~or the trea-tment of va~rlous in-~lam-mations including, but not limited to, in-Elammatory bo~el disease, e.g., Crohn's disease and particularly ulcera~ive 30 colitis.
Description of the Invention In accordance with the presen-t invention, 4-~SA
can be used as such or in any of i-ts ~rell ~non.Jn p~arma-.
ceuticall~ acceptable estersg sal-ts and com~lexes for -the .
.
, . . _ treatment of inflammation. It is useful for the treatment of inflamatory bowel disease) particularly ulcerative colitis. At presentl the sodium salt is pre-erred over the acid since i~ is more stable than the acid form of the drug.
Four~ASA~ its esters, sal-ts and complexes are chemical compounds which were commonly used as pharmaceutical agents in the treatrnent o~ tuherculosis in man and domestic animals.
It can be administered in any of the various forms which haYe been utilized for ~-ASA heretofore or in the various forrnulations which ~ASP or 5 ASA have been used. See, e.g~, U.S. patents 2,445,242, 2,540,104, 2,540,785, 2 9 55S~298,
2,580,195, 2,640,854, 2,658,073, 2,~44,625, 2,552,~86, 2,647,853, 2,667,440, 2,977,281, ~,639,294, 2,655,529, 2,655,532, 2,668,852, 2,711,423, 2,766,278 and 2,874,177.
Four-ASA can also be formulated into a l'pro-drug", i.e., a compound which breaks down in vivo to liberate the active drug. Preferred administration is orally or topically~
The therapeutically effective doses o~ 4-ASA are about 60% on a molar basis as the molar dosage effective 20 with SASP or 5-ASA since 4-ASA is about 50,~ mare potent.
The recommended daily dosage of SASP is 3-4 g (6-8 tablets) for adult patients and 40-60 mg (divided into 3-4 doses~ for pediatric patients. On this basis, a dosage regimen of about ~.5-0.75 g per day divided into 2 or 3 doses can be used. It would be appreciated, however, that the p~ecise amount o-f the 4-A5A -to be administered is best determined by the attending clinician. ln the ~treatment of tuberculosis, the recommended daily dosage of 4-ASA is 10-1~ g p~r os for adults and 200-300 mg/kg for pediatric therapy. It will be appreciated, therefore, that a~ an anti-inflammatory, greatly reduced amounts o~ 4-ASA need be adminis-tered.
As previously noted, formation o~ a polymeric bound 5-ASA by the procedure set forth in Parkinson, U.S.
Pate~t 4,190,716 cannot be directly applied to ~-ASA
because the para-substituted salicylic acid will not bond to the same polymers or through the same bonding reactions.
The resulting 5-ASA polymer material does, however, con-tain a trace amount of 4-ASA. This trace amount has never been recogni~ed as contributing any anti-in~lammatory properties to the material and is, in any event, below the pharmaceutically e~ective threshold oE 4-ASA. In adults, such a threshold is in the neighborhood o-f about 0.2 ~
per day when administered in a single dose per day and higher in ~he case of divided daily doses.
A series of animal and clinical studies have been conducted to demonstrate the utîlity o~ 4-ASA in the mammilian gastrointestinal tract and to compare it with 5-ASA.
In -the animal s-tudy, ~Vistar rats were housed for a period o~ one wee~ prior to the commencement of testing to determine suitability of each animal and a'cclimation to the housing environment (2 or 3 rats to a cage in standard suspended cages with wire bottoms~. Food and water were available ad libitum. The housing facilities were condi-tioned ~or photocycle (1~ hours dark/12 hours light) andfor temperature (21.4 ~ or - 1.4C) and humidity ~49 -~ or -9% RH~, The test procedure was based on *he carrageenin induced rat paw edema of Winter, e-t al, Proc~ Soc. Exp, Biol. Med. iii, 544-547 (1962) in which each rat was given a sub-plantar injection o~ 50 ul of a 1% carrageenin in saline solution (positive control) or saline (negative control) in a paw whose volume had been previously determined.
In the test groups, each rat was given an intr,aperi-toneal injection of 10 mg/kg ~ 4-ASA or 5--ASA or phenylbutazone prior to challenge with the carrageenin suspension. A-t 3, 5 and 7 hours a~ter treatment with carrageenin or saline>
the volume of each treated paw was measured.
Mean* Paw Edema in mlO
TreatmentTime of reading (hours a.fter carragennin Groupor saline lnjec-tion)
Four-ASA can also be formulated into a l'pro-drug", i.e., a compound which breaks down in vivo to liberate the active drug. Preferred administration is orally or topically~
The therapeutically effective doses o~ 4-ASA are about 60% on a molar basis as the molar dosage effective 20 with SASP or 5-ASA since 4-ASA is about 50,~ mare potent.
The recommended daily dosage of SASP is 3-4 g (6-8 tablets) for adult patients and 40-60 mg (divided into 3-4 doses~ for pediatric patients. On this basis, a dosage regimen of about ~.5-0.75 g per day divided into 2 or 3 doses can be used. It would be appreciated, however, that the p~ecise amount o-f the 4-A5A -to be administered is best determined by the attending clinician. ln the ~treatment of tuberculosis, the recommended daily dosage of 4-ASA is 10-1~ g p~r os for adults and 200-300 mg/kg for pediatric therapy. It will be appreciated, therefore, that a~ an anti-inflammatory, greatly reduced amounts o~ 4-ASA need be adminis-tered.
As previously noted, formation o~ a polymeric bound 5-ASA by the procedure set forth in Parkinson, U.S.
Pate~t 4,190,716 cannot be directly applied to ~-ASA
because the para-substituted salicylic acid will not bond to the same polymers or through the same bonding reactions.
The resulting 5-ASA polymer material does, however, con-tain a trace amount of 4-ASA. This trace amount has never been recogni~ed as contributing any anti-in~lammatory properties to the material and is, in any event, below the pharmaceutically e~ective threshold oE 4-ASA. In adults, such a threshold is in the neighborhood o-f about 0.2 ~
per day when administered in a single dose per day and higher in ~he case of divided daily doses.
A series of animal and clinical studies have been conducted to demonstrate the utîlity o~ 4-ASA in the mammilian gastrointestinal tract and to compare it with 5-ASA.
In -the animal s-tudy, ~Vistar rats were housed for a period o~ one wee~ prior to the commencement of testing to determine suitability of each animal and a'cclimation to the housing environment (2 or 3 rats to a cage in standard suspended cages with wire bottoms~. Food and water were available ad libitum. The housing facilities were condi-tioned ~or photocycle (1~ hours dark/12 hours light) andfor temperature (21.4 ~ or - 1.4C) and humidity ~49 -~ or -9% RH~, The test procedure was based on *he carrageenin induced rat paw edema of Winter, e-t al, Proc~ Soc. Exp, Biol. Med. iii, 544-547 (1962) in which each rat was given a sub-plantar injection o~ 50 ul of a 1% carrageenin in saline solution (positive control) or saline (negative control) in a paw whose volume had been previously determined.
In the test groups, each rat was given an intr,aperi-toneal injection of 10 mg/kg ~ 4-ASA or 5--ASA or phenylbutazone prior to challenge with the carrageenin suspension. A-t 3, 5 and 7 hours a~ter treatment with carrageenin or saline>
the volume of each treated paw was measured.
Mean* Paw Edema in mlO
TreatmentTime of reading (hours a.fter carragennin Groupor saline lnjec-tion)
- 3 5 7 Carrag~enin 0.4B2 0~575 0.420 Control Saline Control 00082 0~098 0~086 Carrageenin 0.257 0~265 0,238 and 4-ASA
Carrageenin 0.379 0.379 0.255 and 5-~A
Carrageenin and 0.345 0.362 0.284 phenylbutazone * - 10 paws The foregoing data show that phenylvbutazone and 5-ASA are of a si~ilar order o~ ac-tivity a-t the dose levels tested while ~-ASA has a si~n.i~icantly greater anti-inflammatory activity.
In the clinical study, eight volunteers ~i-th proven ulcerative c.olitis and not receiving oral cortico~
steroids or azathioprine were given either an enema con~
. taining 1 g of 4~ASA sodium salt or a control enema nightly~
The study was conducted on a double blind basis. The -four patients receiving the 4-ASA sodium salt responded well clinically and of the four patients receiving ~the placebo, three had no clinical response.and one had a slight clini-cal response.
Various changes and modi-fications can be made in the process o~ the present invention without depar-ting fro~
the spirit and scope thereof. The various embodiments which have been disclosed herein were -~or the purpose of ~urther illustrating the invention but were not intended to limit it.
Carrageenin 0.379 0.379 0.255 and 5-~A
Carrageenin and 0.345 0.362 0.284 phenylbutazone * - 10 paws The foregoing data show that phenylvbutazone and 5-ASA are of a si~ilar order o~ ac-tivity a-t the dose levels tested while ~-ASA has a si~n.i~icantly greater anti-inflammatory activity.
In the clinical study, eight volunteers ~i-th proven ulcerative c.olitis and not receiving oral cortico~
steroids or azathioprine were given either an enema con~
. taining 1 g of 4~ASA sodium salt or a control enema nightly~
The study was conducted on a double blind basis. The -four patients receiving the 4-ASA sodium salt responded well clinically and of the four patients receiving ~the placebo, three had no clinical response.and one had a slight clini-cal response.
Various changes and modi-fications can be made in the process o~ the present invention without depar-ting fro~
the spirit and scope thereof. The various embodiments which have been disclosed herein were -~or the purpose of ~urther illustrating the invention but were not intended to limit it.
Claims (8)
1. A pharmaceutical composition for use in treat-ing inflammation which comprises an anti-inflammatory effect ive amount of 4-aminosalicyclic acid or a pharmaceutically acceptable ester, salt, pro-drug or complex thereof in combination with a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of Claim 1 wherein said 4-aminosalicyclic acid is employed in the form of its sodium salt.
3. The pharmaceutical composition of Claim 2 wherein said anti-inflammatory effective amount is is at least 0.2 g.
4. The pharmaceutical composition of Claim 1 wherein said anti-inflammatory effective amount is at least 0.2 g.
5. The pharmaceutical composition of Claim 1, wherein said pharmaceutically acceptable carrier is an oral carrier.
6. The pharmaceutical composition of Claim 1 wherein said pharmaceutically acceptable carrier is a topical carrier.
7. The pharmaceutical composition of Claim 1 wherein said pharmaceutical carrier is an intra-rectal carrier.
8. The pharmaceutical composition of Claim 1 which is a free-flowing powder mixture for admixture with water so as to form an enema composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US245,035 | 1981-03-18 | ||
| US06/245,035 US4440763A (en) | 1981-03-18 | 1981-03-18 | Use of 4-aminosalicyclic acid as an anti-inflammatory agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1194419A true CA1194419A (en) | 1985-10-01 |
Family
ID=22925050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000398527A Expired CA1194419A (en) | 1981-03-18 | 1982-03-16 | Use of 4-aminosalicylic acid as an anti-inflammatory agent |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4440763A (en) |
| EP (1) | EP0062000B1 (en) |
| AT (1) | ATE31243T1 (en) |
| AU (1) | AU554443B2 (en) |
| CA (1) | CA1194419A (en) |
| DE (2) | DE3277801D1 (en) |
| LU (1) | LU90386I2 (en) |
Families Citing this family (81)
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|---|---|---|---|---|
| JPS57500432A (en) * | 1980-03-20 | 1982-03-11 | ||
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| DE3151196A1 (en) * | 1981-12-23 | 1983-06-30 | Kurt Heinz Prof. Dr. 7800 Freiburg Bauer | METHOD FOR PRODUCING EASILY SOLUBLE 5-AMINOSALICYL ACID MEDICAL PREPARATIONS |
| USRE33239E (en) * | 1983-09-06 | 1990-06-26 | Farmaceutisk Laboratorium Ferring A/S | Packaged stable enema solution or suspension containing 5-aminosalicyclic acid |
| US4657900A (en) * | 1983-09-27 | 1987-04-14 | Rowell Laboratories | Pharmaceutical article of manufacture comprising a bisulfite stabilized aqueous solution of 5-aminosalicylic acid and method |
| AU1388388A (en) * | 1987-04-01 | 1988-10-06 | Dak-Laboratoriet A/S | Benzoic acid derivatives and use thereof |
| DE3839839A1 (en) * | 1988-11-25 | 1990-05-31 | Henning Berlin Gmbh | AGENTS FOR TREATING CHRONICALLY INFLAMMABLE COLON DISEASES |
| US5484605A (en) * | 1988-11-25 | 1996-01-16 | Henning Berlin Gmbh Chemie-Und Pharmawerk | Agent for treating chronically inflammatory intestinal diseases |
| GB8909559D0 (en) * | 1989-04-26 | 1989-06-14 | Smith Kline French Lab | Pharmaceutical compositions |
| US5378470A (en) * | 1989-07-25 | 1995-01-03 | Henning Berlin Gmbh | Rectally administered pharmaceutical preparation |
| DE3924570A1 (en) * | 1989-07-25 | 1991-01-31 | Henning Berlin Gmbh | PHARMACEUTICAL PREPARATION FOR RECTAL ADMINISTRATION |
| SE9000485D0 (en) * | 1990-02-09 | 1990-02-09 | Pharmacia Ab | FOAMABLE COMPOSITION FOR PHARMACEUTICAL USE, USE THEREOF AND METHOD OF TREATMENT |
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| US6551632B2 (en) | 1997-04-01 | 2003-04-22 | Thomas Julius Borody | Methods and compositions for treating inflammatory bowel disease |
| NZ500696A (en) * | 1997-04-01 | 2002-05-31 | Borody Thomas J | Methods and compositions for treating inflammatory bowel disease comprising mycobacterial agents, including macrolides |
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| WO2006125293A1 (en) * | 2005-05-27 | 2006-11-30 | Antibe Therapeutics Inc. | Derivatives of 4- or 5-aminosalicylic acid |
| US7498355B2 (en) * | 2005-05-27 | 2009-03-03 | Antibe Therapeutics Inc. | Derivatives of 4- or 5-aminosalicylic acid |
| US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
| RU2008152751A (en) * | 2006-06-06 | 2010-07-20 | Антиб Терапьютикс Инк. (Ca) | Salts of trimebutine and n-desmethyltrimebutine |
| CA2663377A1 (en) | 2006-09-18 | 2008-03-27 | Raptor Pharmaceutical Inc. | Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates |
| US20100136125A1 (en) * | 2006-12-28 | 2010-06-03 | Jacobus Pharmaceutical Company, Inc. | Method of treating inflammatory bowel disease |
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| US2639294A (en) * | 1947-12-11 | 1953-05-19 | Ferrosan Ab | Method of producing nu-substituted derivatives of 4-amino-2-hydroxybenzoic acid |
| US2580195A (en) * | 1948-01-31 | 1951-12-25 | Ferrosan Ab | Method of purifying 4-aminosalicylic acid |
| US2766278A (en) * | 1951-08-10 | 1956-10-09 | Rheinpreussen Ag | 4-monoalkylaminosalicylic acids and 4-monoalkyloxyalkylaminosalicylic acids |
| US2711423A (en) * | 1953-07-06 | 1955-06-21 | American Cyanamid Co | Neutral calcium 4-aminosalicylate hemihydrate and preparation of the same |
| US2874177A (en) * | 1955-06-25 | 1959-02-17 | Gohei Tanabe & Co Ltd | Novel complex salt of 4-aminosalicylic acid and processes for producing the same |
| GB2021409B (en) * | 1977-05-25 | 1982-09-22 | Fisons Ltd | Pharmaceutical composition |
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- 1982-03-18 EP EP82810125A patent/EP0062000B1/en not_active Expired
- 1982-03-18 DE DE8282810125T patent/DE3277801D1/en not_active Expired
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| DE19975031I2 (en) | 2004-09-23 |
| EP0062000A3 (en) | 1983-07-27 |
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| LU90386I2 (en) | 1999-06-24 |
| US4440763A (en) | 1984-04-03 |
| EP0062000B1 (en) | 1987-12-09 |
| AU8165982A (en) | 1982-09-23 |
| EP0062000A2 (en) | 1982-10-06 |
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