EP0817631A2 - Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen - Google Patents

Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen

Info

Publication number
EP0817631A2
EP0817631A2 EP96910921A EP96910921A EP0817631A2 EP 0817631 A2 EP0817631 A2 EP 0817631A2 EP 96910921 A EP96910921 A EP 96910921A EP 96910921 A EP96910921 A EP 96910921A EP 0817631 A2 EP0817631 A2 EP 0817631A2
Authority
EP
European Patent Office
Prior art keywords
ridogrel
pharmaceutically acceptable
body weight
inflammatory bowel
bowel diseases
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.)
Withdrawn
Application number
EP96910921A
Other languages
English (en)
French (fr)
Inventor
Maria-Helena Joris Jozef Verlinden
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.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
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 Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to EP96910921A priority Critical patent/EP0817631A2/de
Publication of EP0817631A2 publication Critical patent/EP0817631A2/de
Withdrawn legal-status Critical Current

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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the use of ridogrel at low dosages in the treatment of inflammatory bowel diseases and to corresponding low dose ridogrel formulations.
  • EP-0,221,601 describes (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl] methylene]amino)oxy]pentanoic acid (generically known as ridogrel) for use in various pathological conditions. This document also generically discloses pharmaceutical compositions comprising ridogrel.
  • EP-0,448,274 describes a tablet formulation comprising 400 mg of ridogrel for use in ulcerative and inflammatory conditions of the gastrointestinal tract.
  • ridogrel in the treatment of inflammatory bowel diseases as described in the prior-art shows limited clinical efficacy and displays undesired side-effects.
  • the use as described in claim 1 solves this problem by administering ridogrel at low doses, thereby unexpectedly increasing the clinical efficacy in inflammatory bowel diseases and reducing adverse side-effects.
  • Ridogrel as defined herein refers to (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl) phenyl]methylene]amino]oxy]pentanoic acid and can be prepared in accordance with the procedures described in EP-0,221,601. Ridogrel can also be used according to this invention as a pharmaceutically acceptable acid or base addition salt thereof. When a pharmaceutically acceptable acid or base addition salt is used, the dose referred to hereinabove and hereinunder is based upon the amount of ridogrel as such.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric. nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic.
  • acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric. nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic.
  • acids to form acid addition salts are hydrochloric acid, which forms a ( 1 : 1 ) salt with ridogrel and nitric acid, which also forms a (1: 1) salt with ridogrel.
  • said acid addition salt forms can be converted in the free base forms by treatment with an appropriate base.
  • the compounds of formula (I) which are acidic may form base addition salt forms.
  • the pharmaceutically acceptable base addition salts as mentioned hereinabove are meant to comprise the base addition salts forms which can conveniently be obtained by treating the acid form of the compounds of formula (I) with appropriate bases.
  • bases may include lithium, sodium, potassium, calcium, aluminium, gold and silver salts.
  • salts with pharmaceutically acceptable amines such as ammonia, primary, secondary and tertiary amines, such as alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • said base addition salt forms can be converted in the free acid forms by treatment with an appropriate acid.
  • Preferred counter ions in a base addition salt form are lithium and sodium.
  • the present invention relates to the use of ridogrel or a pharmaceutically acceptable acid or base addition salt thereof for the manufacture of a medicament for treating inflammatory bowel diseases, wherein ridogrel or its pharmaceutically acceptable acid or base addition salt form is administered in a daily dose from 0.01 mg/kg body weight to 1 mg/kg body weight, suitably to 0.5 mg/kg body weight (the dose based upon the amount of ridogrel present as such).
  • the invention relates to a method of treating humans suffering from inflammatory bowel diseases, said method comprising the administration to said humans of ridogrel or a pharmaceutically acceptable acid or base addition salt form thereof in an amount from 0.01 mg/kg body weight to 1 mg/kg body weight, suitably to 0.5 mg/kg body weight.
  • ridogrel or a pharmaceutically acceptable acid or base addition salt form thereof is used in a daily dose from 0.02 mg/kg body weight to 0.1 mg/kg body weight, more particularly in a dose of about 0.05 mg/kg body weight.
  • the above cited dose ranges in mg/kg body weight correspond to a dose range from about 1 mg/day to about 50 mg/day, in particular from about 2 mg/day to 10 mg/day, more in particular of about 5 mg/day.
  • Inflammatory bowel diseases include, for example, ulcerative colitis, Crohn's disease and the like.
  • ridogrel is used in the treatment of ulcerative colitis. Ulcerative colitis is characterized by the presence of lesions in the mucous membranes of the colon.
  • thromboxane plays an active role in the development of these lesions.
  • Ridogrel has been described to show both thromboxane synthetase inhibitory activity and thromboxane receptor antagonistic activity.
  • ridogrel is a mere thromboxane synthetase inhibitor, lacking thromboxane receptor antagonistic activity.
  • the treatment of inflammatory bowel diseases includes both the treatment of the acute disease state, thereby inducing remission of the disease or improvement of the lesions or clinical condition, as well as the use in maintenance therapy.
  • a satisfactory treatment of inflammatory bowel diseases, in particular ulcerative colitis, is characterized by a good clinical efficacy and a low occurrence of adverse events.
  • the following findings are desirable:
  • Adverse events that may occur are e.g. nausea, vomiting, diarrhoea, abdominal cramps, oedema, paraesthesia, hematoma, ecchymoses, and the like.
  • Ridogrel or its pharmaceutically acceptable acid or base addition salt form is suitably administered systemically, such as orally, rectally, intraperitoneally or parenterally.
  • ridogrel is administered orally or rectally.
  • ridogrel or a pharmaceutically acceptable acid or base addition salt form thereof is administered once daily (o.d.) or twice daily (b.i.d.), preferably formulated in an appropriate pharmaceutical composition.
  • the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and ridogrel or its pharmaceutically acceptable acid or base addition salt form in an amount effective to be used as defined hereinabove.
  • the invention relates to a pharmaceutical composition comprising from 0.5 to 5 mg ridogrel per dosage unit form and a pharmaceutically acceptable carrier.
  • Solid pharmaceutical compositions such as tablets, capsules, suppositories and the like, suitably comprise ridogrel in an amount from 0.5 to 5 mg per dosage unit form, in particular from 1 to 5 mg per dosage unit form.
  • the active ingredient is preferably ridogrel as such.
  • Liquid pharmaceutical compositions such as oral solutions, oral suspensions, oral syrups, injectable solutions, rectal enema's or rectal solutions, rectal foams and the like, suitably comprise ridogrel in an amount from 0.1 to 1 mg ml, preferably from 0.5 to 1 mg/ml.
  • ridogrel is preferably present as the sodium salt of the ridogrel.
  • Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of ridogrel.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of ridogrel is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • Solid compositions according to the present invention will preferably comprise pharmaceutically acceptable carriers and excipients, such as fillers e.g. lactose, sucrose, mannitol, maize starch, microcrystalline cellulose or calcium hydrogen phosphate; lubricants e.g. stearic acid, polyethylene glycol, magnesium stearate, talc or silica; disintegrants e.g.
  • compositions comprise by weight based on the total weight of the composition from 60% to 90% fillers, from 3% to 10% disintegrants and from 0.5% to 5% binding agents.
  • ridogrel is blended with suitable excipients and granulated.
  • ridogrel is granulated with the filler or fillers before admixture of the other excipients.
  • Liquid compositions may comprise any of the usual pharmaceutical media such as water, glycols, oils, alcohols and the like. interesting liquid compositions are aqueous solutions or suspensions, in particular for rectal administration.
  • Liquid oral compositions may comprise, apart from ridogrel or a pharmaceutically acceptable acid or preferably base addition salt form and water, flavouring substances; sweeteners; suspending agents, e.g. cellulose derivatives; wetting agents, e.g.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • convenuonal compositions such as suppositories or enemas may be used.
  • rectal solutions may be used for rectal administration.
  • Said rectal solutions comprise apart from the active ingredient ridogrel or its pharmaceutically acceptable acid or preferably base addition salt, water (suitably demineralised, preferably free of pyrogenics), a suitable buffer, such as the combination of disodium hydrogen phosphate and sodium dihydrogen phosphate, a thickening and stabilising agent such as for example hydroxyethyl cellulose, and an agent to make the solution isotonic, such as sodium chloride.
  • a suitable buffer such as the combination of disodium hydrogen phosphate and sodium dihydrogen phosphate
  • a thickening and stabilising agent such as for example hydroxyethyl cellulose
  • an agent to make the solution isotonic such as sodium chloride.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • Particular pharmaceutical compositions are controlled release formulations, from which the active ingredient is gradually released after administration.
  • micronized form of ridogrel is used in the present compositions.
  • These micronized forms may be prepared by micronization techniques known in the art, e.g. by milling in appropriate mills and sieving through appropriate sieves.
  • ridogrel may be administered in combination with another agent effective in the treatment of inflammatory bowel diseases, e.g. sulphasalazine, mesalazine, olsalazine, balsalazide, a corticosteroid and the like.
  • Another agent effective in the treatment of inflammatory bowel diseases e.g. sulphasalazine, mesalazine, olsalazine, balsalazide, a corticosteroid and the like.
  • the combined use includes the simultaneous, separate or sequential administration of the therapeutic agents.
  • the invention relates to a product containing (a) ridogrel and (b) sulphasalazine, mesalazine or a corticosteroid, as a combined preparation for simultaneous, separate or sequential use in the treatment of inflammatory bowel diseases.
  • compositions 1. 1 mg oral tablet
  • Tablets having the composition shown hereinunder were prepared according to art-known formulation procedure.
  • Croscarmellose sodiumO 2 mg 2.00 %
  • Croscarmellose sodium is the British Approved Name of sodium carboxymethyllcellulose.
  • Hypromellose 2910 15 mPa.s is the British Approved Name for methylhydroxypropylcellulose, the four digit number (2910) is an indication of the substitution on cellulose, i.e. the first two digits represent the approximate percentage composition of methoxyl groups, and the third and fourth digits the approximate percentage composition of hydroxypropyl groups.
  • the grade used in this example is indicated by the viscosity of a 2 % solution at 20°C, i.e. 15 mPa.s
  • Hypromellose 2910 15 mPa.s 2 2 mg 2.00 % w/w)
  • colloidal anhydrous silica 0.3 mg 0.30 % ( ⁇ w/w)
  • the percentages are based on the total weight of the tablet.
  • the pH of the final solution should range between about 6.5 and 8.5, preferably the pH should be between 7.2 and 7.6.
  • the solutions are packaged in enema bottles containing 40 ml or 80 ml of the above described solution.
  • Analogous solutions containing 2.5 mg to 10 mg of ridogrel in 40 ml of rectal solution or 2.5 mg to 10 mg of ridogrel in 80 ml of rectal solution can be prepared according to the above described preparation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
EP96910921A 1995-03-28 1996-03-18 Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen Withdrawn EP0817631A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP96910921A EP0817631A2 (de) 1995-03-28 1996-03-18 Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP95200768 1995-03-28
EP95200768 1995-03-28
EP96910921A EP0817631A2 (de) 1995-03-28 1996-03-18 Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen
PCT/EP1996/001229 WO1996030016A2 (en) 1995-03-28 1996-03-18 Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases

Publications (1)

Publication Number Publication Date
EP0817631A2 true EP0817631A2 (de) 1998-01-14

Family

ID=8220134

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96910921A Withdrawn EP0817631A2 (de) 1995-03-28 1996-03-18 Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen

Country Status (10)

Country Link
EP (1) EP0817631A2 (de)
JP (1) JPH10511097A (de)
AR (1) AR002727A1 (de)
AU (1) AU5397496A (de)
CA (1) CA2215160A1 (de)
HU (1) HUP9900309A3 (de)
IL (1) IL117670A (de)
NO (1) NO974486L (de)
WO (1) WO1996030016A2 (de)
ZA (1) ZA962461B (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9620709D0 (en) * 1996-10-04 1996-11-20 Danbiosyst Uk Colonic delivery of weak acid drugs
EP1370244A1 (de) * 2001-03-12 2003-12-17 Novo Nordisk A/S Neue tabletten und kapseln und verfahren zu ihrer herstellung
ITRM20050389A1 (it) 2005-07-22 2007-01-23 Giuliani Spa Composti e loro sali specifici per i recettori ppar ed i recettori per l'egf e loro uso in campo medico.
UA107562C2 (uk) 2008-12-05 2015-01-26 Спосіб лікування псоріазу
SI2805746T1 (sl) 2009-02-16 2020-10-30 Nogra Pharma Limited Alkilamido spojine in njihova uporaba
CA2864059C (en) 2012-02-09 2020-04-28 Nogra Pharma Limited Methods of treating fibrosis
MX2014012652A (es) 2012-04-18 2014-11-25 Nogra Pharma Ltd Metodo de tratamiento de la intolerancia a la lactosa.
WO2017046343A1 (en) * 2015-09-17 2017-03-23 Nogra Pharma Limited Compositions for rectal administration in the treatment of ulcerative colitis and methods of using same
EP4495101A3 (de) 2019-02-08 2025-04-30 Nogra Pharma Limited Verfahren zur herstellung von 3-(4'-aminophenyl)-2-methoxypropionsaure, sowie analoge uno zwischenprodukte davon

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4746671A (en) * 1985-11-04 1988-05-24 Janssen Pharmaceutica N.V. Pharmaceutical use of [[[(3-pyridinyl)methylen]amino]oxy]alkanoic acids and esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9630016A2 *

Also Published As

Publication number Publication date
JPH10511097A (ja) 1998-10-27
WO1996030016A3 (en) 1997-01-30
IL117670A (en) 2000-02-29
CA2215160A1 (en) 1996-10-03
HUP9900309A2 (hu) 1999-05-28
MX9707394A (es) 1997-11-29
ZA962461B (en) 1997-09-29
AR002727A1 (es) 1998-04-29
IL117670A0 (en) 1996-07-23
AU5397496A (en) 1996-10-16
WO1996030016A2 (en) 1996-10-03
NO974486D0 (no) 1997-09-29
HUP9900309A3 (en) 1999-11-29
NO974486L (no) 1997-09-29

Similar Documents

Publication Publication Date Title
EP1083931B1 (de) Stabilisierung von zusammensetzungen enthaltend ace-hemmer durch magnesiumoxid
CZ301737B6 (cs) Farmaceutický prípravek obsahující derivát benzamidu se zlepšenou rozpustností a orální absorptivitou
CN101633662A (zh) 普拉格雷的药用酸加成盐及其制备方法和药物应用
SK280283B6 (sk) Farmaceutický prostriedok na liečenie žalúdočných
JP7607577B2 (ja) ピリダジノンｔｒｐｃ５阻害剤の噴霧乾燥された製剤
EP0817631A2 (de) Niedrigdosierte ridogrelformulierungen und deren verwendung zur behandlung entzündlicher darmerkrankungen
EP1092431B1 (de) Lasofoxifen enthaltende Zusammensetzungen
PL201388B1 (pl) Preparaty farmaceutyczne w postaci stałej lub ciekłej zawierające pochodną benzamidu jako substancję czynną
WO1997034602A1 (en) Paroxetine in treatment of depression
EP2329819A1 (de) Pharmazeutische zusammensetzung zur behandlung von sexuell übertragbaren infektionen
KR100192534B1 (ko) 소마토스타틴 분비증가제와 분비저하 억제제
US6372763B1 (en) Treatment and prevention of cardiac disorders using selective serotonin re-uptake inhibitors (SSRI)
US7229980B2 (en) Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof
CA2286904A1 (en) Pharmaceutical tablet of amiodarone salt
US5525605A (en) Remedy for inflammatory intestinal diseases
US9393236B2 (en) Use of 4-cyclopropylmethoxy-N-(3,5-dichloro-1-oxido-4-pyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide in the treatment of cranial traumas
EP2123277B1 (de) Vorbeuge- oder heilmittel für entzündliche darmerkrankungen
MXPA97007394A (en) Formulations of low dose ridogrel and its use the treatment of inflamator intestinal diseases
US4788183A (en) Method for treatment of dyslipidemia in humans
EP0567498A1 (de) Arzneimittel, das granisetron und dexamethasone enthält
AU712071B2 (en) Anti-HIV composition containing imidazole derivatives
CA1249521A (en) Antiinflammatory compositions and methods
JP3254712B2 (ja) 医薬組成物
US4812455A (en) Antiinflammatory compositions and methods
CN1179716A (zh) 低剂量利多瑞尔制剂及其在治疗炎性肠疾病中的应用

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19971028

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: LT PAYMENT 971028;LV PAYMENT 971028;SI PAYMENT 971028

17Q First examination report despatched

Effective date: 19990517

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19990928

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1008178

Country of ref document: HK