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WO1981002672A1 - Composition pharmaceutique et procede de traitement de la colite ulcereuse et de la maladie de crohn - Google Patents

Composition pharmaceutique et procede de traitement de la colite ulcereuse et de la maladie de crohn Download PDF

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Publication number
WO1981002672A1
WO1981002672A1 PCT/DK1981/000028 DK8100028W WO8102672A1 WO 1981002672 A1 WO1981002672 A1 WO 1981002672A1 DK 8100028 W DK8100028 W DK 8100028W WO 8102672 A1 WO8102672 A1 WO 8102672A1
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WIPO (PCT)
Prior art keywords
disease
treatment
crohn
esters
asa
Prior art date
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Ceased
Application number
PCT/DK1981/000028
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English (en)
Inventor
S Halskov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Farmaceutisk Laboratorium Ferring AS
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Farmaceutisk Laboratorium Ferring AS
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Application filed by Farmaceutisk Laboratorium Ferring AS filed Critical Farmaceutisk Laboratorium Ferring AS
Publication of WO1981002672A1 publication Critical patent/WO1981002672A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • composition and method for the treatment of colitis ulcerosa and Crohn's disease are provided.
  • the present invention relates to a pharmaceu ical com ⁇ position useful for the treatment of colitis ulcerosa and Crohn's disease, currently denominated "inflammatory bowel diseases” (IED) .
  • the invention also relates to a method for the treatment of IBD.
  • Colitis ulcerosa is a chronic inflammatory disease of the colon of unknown etiology. In its acute stages it resembles an infectious disease, but no microorganism has been definitively established as its cause. The disease causes inflammations of the mucosa of the colon, with extension to the submucosa in severe cases. .Typi ⁇ cally, not only the colon, but also the rectum is attacked, but only rarely is the ileu involved. The ulcer formation and its extent vary with the develop ⁇ mental stage of the disease, but can often be detected macroscopically (sigmoidoscopy and colonoscopy) . For an exhaustive discussion of the disease and the various surgical and medical methods of treatment reference is made to "Ulcerative colitis", Goodman & Sparberg, Wiley, New York 1978.
  • Crohn's disease also known as regional enteritis or colitis granulomatosa, which is also discussed by Goodman & Sparberg, is most frequently located in the small intestine (small bowel) , especial ⁇ ly in the ileum, but may also affect the jejunum and any part of the colon, including the rectum. In the latter case the differentiation of Crohn's disease from ulcerative colitis give rise to great diagnostic problems. Generally, the inflammatory reactions differ from that of colitis ulcerosa by progressing to layers deeper than the mucosa and affecting the epithelium in a lesser degree.
  • corticosteroids e.g. prednisone, prednisolone and hydrocortisone.
  • a drug recently pro- posed is ⁇ -fluoro-ll ⁇ -hydroxy-3,20-dioxa-l ⁇ -methyl- l,4-pregnadiene-21-carboxylic acid butyl ester, cf. PCT Application No. WO 80/00122.
  • SASP sulfazalazine
  • SP pyridine
  • 5-ASA 5-aminosalicylic acid
  • Azad Khan et al., op. cit. who compared SASP, SP and 5-ASA administered rectally and concluded that the therapeutically active moiety was 5-ASA and that SP only acts as a "carrier" to ensure that 5-ASA is not released until it has reached the colon.
  • Azad Khan chose rectal administration and not oral admini ⁇ stration, which is the ordinary mode for SASP, because previous studies of absorption in healthy patients had shown that free 5-ASA is absorbed from the small bowel, in particular the jejunum, which was considered inappropriate as it prevented topical action in the colon.
  • Another serious disadvantage is that a considerable amount of the patients (up to 10%) are allergic to sulf drugs, thereby excluding SASP treatment.
  • the object of the present invention is to provide an improved pharmaceutical-composition useful for the treatment of colitis ulcerosa or Crohn's disease and a method for such treatment.
  • 5-AcASA possesses said biological effects because it was to.be expected that the organism would separate an inactive metabolization product of 5-AcASA .
  • 5-AcASA and its salts are stable in aqueous solution or suspension, obviating the problems of stability of 5-ASA described by Azad Khan et al.
  • the invention relates to a pharmaceutical composition useful for the treatment of colitis ulcerosa or Crohn's disease, which comprises as essential active ingredient ' an effective amount of 5-acetylaminosali- cylic acid or a pharmaceutically acceptable salt or ester thereof in admixture with a pharmaceutically acceptable carrier.
  • salts may be mentioned alkali metal salts (K, Na) , alkaline earth metal salts (Ca, Mg) , but again any pharmaceutically acceptable, non-toxic salt may be used.
  • 5-AcASA is a known compound, Beilste n XIV, p. 583, which crystallizes with 1/2 H-0 and has a melting point of 218°.
  • Other known salts are the Na, Mg, Ca, Ba, Pb, Ag, Sn, and Zn salts.
  • the alkali metal salts of which the Li, and K salts, as far as is known, are not identified in the literature, are particularly appropriate for the object of the invention on account of their good solubility and stability.
  • the alkali metal salts can be produced in a manner known per se by reacting the free acid with a suitable amount of alkali metal base, particularly NaOH or KOH, but also other bases are possible, such as the carbonates or bicarbonates and isolating the obtained salt, preferably by evaporation.
  • alkali metal base particularly NaOH or KOH
  • other bases such as the carbonates or bicarbonates and isolating the obtained salt, preferably by evaporation.
  • the French Brevet Special de Medicament No. 4,546M shows that the reaction product between 4-acetylamino- salicylic acid and the antirheumatic agent chloroquine has useful antalgic and antiinflammatory activities against chronic, antiinflammatory arthritis and similar rheumatoid diseases. Further, it is asserted that similar activities have been found to be possessed by 4-acetylaminosalicylic acid whose sodium salt is pro ⁇ quizd, and by 5-acetylaminosalicylic acid and its salts which are, however, not characterized in detail, let alone examined.
  • U.S. Patent 1,652,796 describes reaction products between 5-AcASA and aliphatic amines, such as N-propylamine and hexamethylenetetramine, having bactericidal,, analgetic and antipyretic activities.
  • esters of ortho-, meta- and para-salicylic acid are disclosed. Said esters are effective as ultra ⁇ violet ray screening compounds thereby rendering them ⁇ selves useful in preventing solar burning.
  • the cor ⁇ responding meta- (or 5-) acetylaminosalicylic esters and a number of related esters are also applicable in the composition according to the invention.
  • Applicable esters are e.g. '
  • alkenyl esters e.g. vinyl, allyl, undecenyl, oleyl, linolenyl, etc.
  • C_-Cg cycloalkyl esters e.g. cyclopropyl, cyclobutyl, - cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc. ,
  • aryl esters e.g. phenyl, toluyl, xylyl, naphthyl, etc. ,
  • alicyclic esters e.g. menthyl, etc., or
  • aralkyl esters e.g. benzyl, phenethyl, etc.
  • the proper selection of the active ingredient depends on the selected type of formulation, the disease pattern, especially the site and type of the disease, and the desired release .of the active ingredient, as shall be further expounded below together with the concept "effective amount”.
  • the physical state and solubility characteristics of the 5-ASA derivatives must be taken into account when selecting a suitable carrier composition for the ingredient.
  • the preferred active ingredient at present is the free acid, 5-acetylaminosalicylic acid.
  • a particularly interesting aspect of the invention is the use of the composition in the treatment of Crohn's disease.
  • SASP has not proved to be very effective, at least not in the most frequent case, where the disease is limited to the ileum.
  • the yellow colour of the ascorbic acid containing solutions was caused by the ascorbic acid alone.
  • antioxidants such as ascorbic acid, but preferably a pyrosulfite, e.g. sodium or potassium pyrosulfite, or by decreasing the temperature. If the glasses are filled in an inert atmosphere (argon) the stability is perfect..A suitable amount of antioxidant is 100 mg/100 ml.
  • the effective oral dose depends on the extent of the disease and for adults it usually amounts to 0.5 to 1.0 g calculated as 5-ASA twice a day. Generally, about 20 mg/kg body weight calculated as 5-ASA will be the initial daily dosage subject to adjustment in accordance with the observed results of the treatment. Dosage for children should like salicylic acid and its derivatives be adjusted by means of serum concentration measure ⁇ ments.
  • 5-ASA and its derivatives can be formulated as ordinary oral drugs such as tablets or capsules by admixture with conventional pharmaceutical carriers which are well-known to the artisan, e.g. lactose, maize starch, potato starch, and lubricants, e.g. magnesium stearate and talc.
  • a useful carrier constituent is a micro- crystalline cellulose having approximately the same density as 5-AcASA thereby preventing sedimentation and resulting heterogenicity during tablet production.
  • tablets possibly in the form of slow-release tablets are preferred.
  • sustained-release tablets they may be prepared in accordance with the above-mentioned co-pending appln. no. PCT/DK81/07.
  • a suitable enema volume is 100 ml which may contain 1.0 g of 5-AcASA, calculated like 5-ASA as active component, or about 1.4 g depending upon the derivative chosen.
  • the enemas may be formulated in conventional manner using e.g. sterile water as vehicle.
  • sterile water e.g. sterile water
  • the following preferred composi ⁇ tion may be mentioned:
  • the above solution was adjusted to 10100 g with sterile, water.
  • the resulting solution was dispensed in 100 ml portions in sterile enema containers,

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique contenant en tant qu'ingredient actif un acide 5-acetyle aminosalicylique suivant la formule (FORMULE) ou un sel ou un ester pharmaceutiquement acceptable permettant le traitement de la colite ulcereuse et de la maladie de Crohn.
PCT/DK1981/000028 1980-03-20 1981-03-20 Composition pharmaceutique et procede de traitement de la colite ulcereuse et de la maladie de crohn Ceased WO1981002672A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK120180 1980-03-20
DK1201/80 1980-03-20

Publications (1)

Publication Number Publication Date
WO1981002672A1 true WO1981002672A1 (fr) 1981-10-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1981/000028 Ceased WO1981002672A1 (fr) 1980-03-20 1981-03-20 Composition pharmaceutique et procede de traitement de la colite ulcereuse et de la maladie de crohn

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WO (1) WO1981002672A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4664256A (en) * 1983-09-06 1987-05-12 Farmaceutisk Laboratorium Ferring A/S Packaged stable enema solution or suspension containing 5-aminosalicyclic acid
EP0279093A1 (fr) * 1987-02-20 1988-08-24 Reid-Rowell, Inc. Récipient pour une solution aqueuse stabilisée de l'acide 5-aminosalicylique
US4781913A (en) * 1986-04-10 1988-11-01 Eiichi Masuhara Pharmaceutical composition for use in desensitizing hypersensitive dentin
USRE33239E (en) * 1983-09-06 1990-06-26 Farmaceutisk Laboratorium Ferring A/S Packaged stable enema solution or suspension containing 5-aminosalicyclic acid
US4960765A (en) * 1980-03-20 1990-10-02 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4980173A (en) * 1980-03-20 1990-12-25 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
EP0395329A3 (fr) * 1989-04-26 1991-11-21 Smith Kline & French Laboratories Limited composition sous forme de mousse contenant l'acide amino-5 salicylique pour administration intra-rectale
WO1992004369A1 (fr) * 1990-09-12 1992-03-19 Depha Team S.R.L. Derives d'acide aminosalicylique-5 destines au traitement des affections intestinales inflammatoires chroniques
WO1992006690A1 (fr) * 1990-10-22 1992-04-30 Borody Thomas J Traitement d'affections intestinales non-inflammatoires et non-infectieuses
CN101182298B (zh) * 2007-12-04 2010-09-08 西安交通大学 化合物2-羟基-5-丁酰胺基苯甲酸及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1652796A (en) * 1925-10-15 1927-12-13 Abbott Lab Compound of acetylaminosalicylic acid with aliphatic amines and process of making same
FR4546M (fr) * 1964-06-09 1966-11-02
CH513124A (fr) * 1968-07-15 1971-09-30 Pharma Chemie Procédé de préparation d'un nouveau dérivé de l'acide benzoïque

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1652796A (en) * 1925-10-15 1927-12-13 Abbott Lab Compound of acetylaminosalicylic acid with aliphatic amines and process of making same
FR4546M (fr) * 1964-06-09 1966-11-02
CH513124A (fr) * 1968-07-15 1971-09-30 Pharma Chemie Procédé de préparation d'un nouveau dérivé de l'acide benzoïque

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Gastroenterology, Volume 64, no. 2, issued 1973, (Batimore) M.A. Peppercorn and P. Goldman: "Distribution studies of salicylazosulfapyridine and its metaboilites", pages 240-245 *
Journal of Pharmaceutical Sciences, Volume 68, no. 10, issued 1979, October (Washington) H.J. Pieniaszek Jr. and T.R. Bates: "Capicity-limited gut wall metabolism of 5-aminosalicyclic acid, a therapeutically active metabolite of sulfasalazine, in rats", pages 1323-1325 *
Medicina et Pharmacologia Experimentalis, Volume 14, no. 6, issued 1966 (Basel-New York) N.P. BuuHoi: "Experimental studies on the problem of chemotherapy in pre-diabetes. I. Hypoglycaemic effects of aromatic and heterocyclic acids", pages 576-584 *
Medicina Experimentalis, Volume 11, no. 5, issued 1964 (Basel-New York) F. Delbarre et al: "Substances anti-inflammatoires non-stéroidiques. I. Dérivés des acides 4- et 5-aminosalicyliques", pages 325-332 *
Scandinavian Journal of Gastroenterology, Volume 15, no. 6, issued 1980, September (Oslo) C.P. Willoughby et al: "The effect of topical N-acetyl-5-aminosalicylic acid in ulcerative colitis", pages 715-719 *
The Journal of Pharmacology and Experimental Therapeutics, Volume 43, issued 1931, (Batimore) J.A. Kolmer and G.W. Raiziss: "The chemotherapy of Streptococcus infections of mice with special reference to salicyl compounds", pages 71-78 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4960765A (en) * 1980-03-20 1990-10-02 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US5041431A (en) * 1980-03-20 1991-08-20 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US5013727A (en) * 1980-03-20 1991-05-07 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
US4980173A (en) * 1980-03-20 1990-12-25 Farmaceutisk Laboratorium Ferring A/S Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
USRE33239E (en) * 1983-09-06 1990-06-26 Farmaceutisk Laboratorium Ferring A/S Packaged stable enema solution or suspension containing 5-aminosalicyclic acid
US4664256A (en) * 1983-09-06 1987-05-12 Farmaceutisk Laboratorium Ferring A/S Packaged stable enema solution or suspension containing 5-aminosalicyclic acid
US4781913A (en) * 1986-04-10 1988-11-01 Eiichi Masuhara Pharmaceutical composition for use in desensitizing hypersensitive dentin
EP0279093A1 (fr) * 1987-02-20 1988-08-24 Reid-Rowell, Inc. Récipient pour une solution aqueuse stabilisée de l'acide 5-aminosalicylique
EP0395329A3 (fr) * 1989-04-26 1991-11-21 Smith Kline & French Laboratories Limited composition sous forme de mousse contenant l'acide amino-5 salicylique pour administration intra-rectale
WO1992004369A1 (fr) * 1990-09-12 1992-03-19 Depha Team S.R.L. Derives d'acide aminosalicylique-5 destines au traitement des affections intestinales inflammatoires chroniques
US5424292A (en) * 1990-09-12 1995-06-13 Depha Team S.R.L. 5-aminosalicylic acid derivatives for the therapy of chronic inflammatory bowel diseases
WO1992006690A1 (fr) * 1990-10-22 1992-04-30 Borody Thomas J Traitement d'affections intestinales non-inflammatoires et non-infectieuses
CN101182298B (zh) * 2007-12-04 2010-09-08 西安交通大学 化合物2-羟基-5-丁酰胺基苯甲酸及其用途

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