CA2215160A1 - Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases - Google Patents
Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases Download PDFInfo
- Publication number
- CA2215160A1 CA2215160A1 CA002215160A CA2215160A CA2215160A1 CA 2215160 A1 CA2215160 A1 CA 2215160A1 CA 002215160 A CA002215160 A CA 002215160A CA 2215160 A CA2215160 A CA 2215160A CA 2215160 A1 CA2215160 A1 CA 2215160A1
- Authority
- CA
- Canada
- Prior art keywords
- ridogrel
- body weight
- pharmaceutically acceptable
- pharmaceutical composition
- administered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- 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]
Abstract
The present invention relates to the use of ridogrel for the manufacture of a medicament for treating inflammatory bowel diseases, wherein ridogrel is administered in a daily dose from 0.01 mg/kg body weight to 0.5 mg/kg body weight; pharmaceutical compositions comprising ridogrel.
Description
Wo 96/30016 ~ ''01229 LOW DOSE RIDOGREL FORMULATIONS AND
TBIR USE FOR THE TREATMENT OF I~JFLAM-MATORY BOW~ DISEASES
The present invention relates to the use of ridogrel at low ClQS5~S in the 1~ ll of infl~mm~tory bowel rlice~ces and to cvll~s~ollding low dose ridogrel form~ tions.
EP-0,22 1,601 describes (E)-s-t[[(3-pyridinyl)[3-(trifluor~llwlllyl)phenyl]
methylene]amino]oxy]pe~f~noir acid (~ ;f~lly known as ridogrel) for use in various pathological conditions. This clocllm~nt also g~n~rir~lly discloses pl~ r..l;r~
compositions compricing ridogrel.
EP-0,448,274 describes a tablet formulation co.,.l.. ;~;..~ 400 mg of ridogrel for use in 15 ulcerative and infl~ c,ly conditions of the gasL~ l tract.
~'~ce.ll~c et al., 1992, Gastroenterology 102 (4, Suppl.), p. A601, and Casellas et al., 1993, Gastroenterology 104 (4, Suppl.), p. A677 describe the clinical effect of the ~tlminicfration of ridogrel, 300 mg b.i.d., in ulcerative colitis.
20 The use of ridogrel in the tre~tm~nt of infl~ u~ y bowel ~lice~ces 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 ~minict~ring ridogrel at low doses, thereby unexpectedly increasing the clinical efficacy in infl~------~lc,ly 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 ph~rm~reutically acceptable acid or base addition salt thereof. When a 30 ph~rm~t~elltically 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 ph~rm~reutic~lly acceptable acid addition salts as mentioned hereinabove are meant to comprise the acid addition salt forms which can conveniently be obtained by treating 35 the base form of the compounds of formula (I) with ~p~ iate 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. Iactic, pyruvic, oxalic, malonic, succinic. maleic, fumaric, , WO 96/30016 PCTtEP96tO1229 malic, tartaric, citric, meth~n~snlfonic, eth~n~slllfonic, be..,~ lfonic, p-tolll~n~slllfonic, cyclamic, salicylic, p-~minos~ ylic, pamoic and the like acids.
E~GrGllc;d acids to form acid addition salts are hydl~--l.loric acid, which forms a (1:1) salt with ridogrel and nitric acid, which also forms a (1:1) salt with ridogrel.
S Conversely, said acid addition salt forms can be converted in the free base forms by tre~tm.-nt with an aL~lu~iate base. The compounds of formula (I) which are acidic may form base addition salt forms. The ph~ GI 11 ;r~lly acceptable base addition salts as mentioned hereinabove are meant to comprise the base ~ ition salts forms which can co,lvelliently be obtained by treating the acid form of the c0~ 7uullds of formula (I) with 10 ~lu~liate bases. Examples of such salts may include lithillm, sodium, pot~c~illm, calcium, ~lu~ gold and silver salts. Also colllr,~ te~1 are salts with ph~rrn~-~e~ltic~lly ~cept~kle arnines such as ammonia, primary, secondary and tertiary ~min~s, such as alkyl arnines, hydroxyalkylarnines, N-methyl,glllc~min~ and the like.
Conversely, said base addition salt forms can be converted in the free acid forms by 15 tre~tm~nt with an ~L)plU~ G acid.
Piefe"Gd counter ions in a base addition salt form are lithium and sodium.
The present invention relates to the use ûf ridogrel ûr a ph~rm~t ellti~lly acceptable acid 20 or base addition salt thereof for the manufacture of a medicament for treating infl~mm~t-~ry bowel ~ e~es, WhG1Gi11 ridogrel or its pharm~eutic~lly acceptable acid or base addition salt form is ~lmini~tcred 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).
~ltPrn~tively, the invention relates to a method of treating humans suffering from infl~"".,~t-,ly bowel ~lice~ec, said method comprising the ~lminictration to said hllm~n~
of ridogrel or a rh~rm~euti~lly acceptable acid or base addition salt form thereûf in an amûunt from 0.01 mg/kg body weight to 1 mg/kg body weight, suitably to 0.5 mg/kg30 body weight.
In particular, ridogrel or a ph~rm~relltically 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.
35 For adult human beings, 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.
CA 0221~160 1997-09-11 Tnfl~mm~tory bowel ~ e~çs include, for e~mple, ulcerative colitis, Crohn's disease and the like. In particular, ridogrel is used in the treatment of ulcerative colitis.
Ulcerative colitis is l,l,al ---L~ 1 by the presence of lesions in the mucous membranes of the colon. It is generally believed that thromboxane plays an active role in the5 development of these lesions. Ridogrel has been llesrribe~l to show both thromboxane synth~t~e inhihitory activity and thromboxane receptor antagonistic activity.
Unexpectedly, it has been shown that at the doses of the present invention, however, ridogrel is a mere thromboxane synthrt~e inhibitor, lacking llL v~l~oxane receptor antagonistic activity.
The trç~tmrnt of infl~mm~tory bowel ~li.ce~crs includes both the tle~Llllent 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 m~intrn~nre therapy. A satisfactory trç~tment of infl~mm~tory bowel ~iice~ce~, in particular ulcerative colitis, is characterized by a good 15 clinical efficacy and a low occurrence of adverse events. In particular, after 8 weeks of tre~tm~-nt, the following finrlin~c are desirable:
- an endoscopic improvement in more than 45% of the patients, preferably in more than 50% of the p~tirnt~;
- a complete endoscopic cure in more than 10% of the patients, preferably in more than 20 . 30% of the patients;
- a median percentage of days with bloody stools during the last 2 weeks of treatment of below 50%, preferably below 10%;
- a percentage of patients wherein the investigator's global evaluation of the effect of the tre~tmrnt is good or excellent of more than 40%, preferably more than 60%; and 25 - an occurrence of adverse events in less than 40% of the patients. Adverse events that may occur are e.g. nausea, vomiting, diarrhoea, abdominal cramps, oedema, paraesthesia, hematoma, ecchymoses, and the like.
Ridogrel or its pharm~reutic~lly acceptable acid or base addition salt form is suitably 30 ~lmini~tered systemically, such as orally, rectally, hlLla~eliLolleally orparenterally.
Preferably, ridogrel is ~lmini~tered orally or rectally. Suitably, ridogrel or aph~rrn~re~ltic~lly acceptable acid or base addition salt form thereof is atlmini~trred once daily (o.d.) or twice daily (b.i.d.), preferably formulated in an a~pro~liate pharm~re lfical composition. Hence, the invention relates to a ph~rrn~re~ltic~l 35 composition co~ lishlg a phal " ~r~ ir~lly acceptable carrier and ridogrel or its ph~rm~reutically acceptable acid or base addition salt form in an amount effective to be used as defined hereinabove. In particular, the invention relates to a pharm~relltical CA 0221~160 1997-09-11 WO 96/30016 P~ /01229 composition compri~in~ from 0.5 to 5 mg ridogrel per dosage unit form and a ph~rm~(-e~lti~lly acceptable carrier.
Solid ph~ l compositions such as tablets, c~rsllles, ~u~osil~ s and the like, suitably co~ ,ise ridogrel in an amount from 0.5 to 5 mg per dosage unit form, in S particular from 1 to 5 mg per dosage unit form. In solid ph~rm~l~e~lti~l com~osilions the ~f active ingredient is preferably ridogrel as such. Liquid ph~rm~-,eutical c~ o~iLions 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. In liquid ph~rm~celltic~l compositions ridogrel is preferably present as the sodium salt of the ridogrel.
Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit cc,~ g a pre~l~-tt-rmin~l quantity of ridogrel. Examples of such 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.
As d~,u~,iate compositions there may be cited all compositions usually employed for systemically a~1mini~t~ring drugs. To prepare the ph~rm~relltical compositions of this invention, an effective amount of ridogrel is combined in i 1 l I i 1 l ~r adll~i~Lulc; with a ph~rm~e~tic~lly acceptable carrier, which carrier may take a wide variety of forms depending on the form of ~ ~dlion desired for ~rlmini~tration Solid compositions according to the present invention will preferably comprise pharmaceutically acceptable carriers and excipients, such as fillers e.g. lactose, sucrose, m~nnitol, maize starch, microcrystalline cellulose or calcium hydrogen phosphate;
lubricants e.g. stearic acid, polyethylene glycol, m~r,llt~ill~ll stearate, talc or silica;
disintegrants e.g. rice, potato or maize starch, sodium starch glycolate or croscarmellose sodium; binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl-methylcellulose and wetting agents e.g. sodium dioctylsulfos~lccin~t.- and Polysorbates. Interesting solid 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. For the L~le~aldlion of solid compositions according to the invention, ridogrel is blended with suitable excipients and gr~n~ t~fl Preferably, ridogrel is granulated with the filler or fillers before admixture of the other excipients.
Most preferably the fillers employed will be lactose monohydrate and maize starch, especiallly in combination with calcium hydrogen phosphate. Because of their ease in ~lmini~tration, tablets and capsules represent the most advantageous oral dosage unit form.
CA 0221~160 1997-09-11 _5_ Liquid co~ o~iLions may comprise any of the usual ph~rm~enti~l media such as water, glycols, oils, alcohols and the like. Interesting liquid compositions are aqueous solutions or sucpeT-~ions, in particular for rectal ~llmini~tration. Liquid oral compositions 5 may comprise, apart from ridogrel or a ph~rm~cellti~lly acceptable acid or preferably base addition salt form and water, flavouring substances; sweeteners; suspending agents, e.g. cellulose derivatives; wetting agents, e.g. polyoxyethylene derivatives of sorbitan esters; buffer systems; st~bili7ing agents; preservatives; solubility enhancers and the like.
For pdl~"t~al compositions, the carrier will usually comprise sterile water, at least in 10 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 ~ Lul~ of saline and glucose solution. Injectable suspensions may also be prepared in which case a~pl~pliate liquid carriers, suspending agents and the like may be employed.
15 For rectal ~lmini~tration, conventional con.~osiLions such as suppositories or enemas may be used. Preferably, rectal solutions may be used. Said rectal solutions comprise apart from the active ingredient ridogrel or its ph~rm~centi~lly acceptable acid or preferably base addition salt, water (suitably ~lemin~ralised, preferably free of pyrogenics), a suitable buffer, such as the combination of disodium hydrogen phosphate 20 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.
Also included are solid form ~le~aldLions which are intended to be converted, shortly 25 before use, to liquid form ~ a dLions. Particular ph~rn~eutical compositions are controlled release formulations, from which the active ingredient is gradually released after ~rlminictration.
It may be advantageous that a micronized form of ridogrel is used in the present30 compositions. These micronized forms may be prepared by micronization techniques known in the art, e.g. by milling in d~ niate mills and sieving through ~p~upliate sieves.
Optionally, ridogrel may be ~lminictered in combination with another agent effective in 35 the treatment of infl~mm~tory bowel diseases, e.g. sulphasalazine, m.-s~1~7ine, olc~l~7in~, balsalazide, a corticosteroid and the like. The combined use includes the simultaneous, separate or sequential ~lmini~tration of the therapeutic agents.
CA 0221~160 1997-09-11 In a further aspect, the invention relates to a product cc,. .l ;.;. .; . .g (a) ridogrel and (b) slllph~ 7in--, m~s~l~7ine or a corticosteroid, as a cu,nbil,ed pl~ lion for .cimlllt~n~ous, sep~r~t~ or sequential use in the tr~trn~qnt of infl~ bowel ~ e~es.
S
Experim~-nt~l part Ph~rm~f~entic~l compositions 1. 1 m~ oral tablet Tablets having the composition shown hereinunder were prepared according to art-15 known formulation procedure.
Ridogrel 1 mg 1.00 %
Calciumhydrogenphosphatedihydrate0.94 mg 0.94 %
T ~rt~se monohydrate 56.01 mg 56.01 %
Maizestarch 24mg 24.00 %
Crosc~nnPllosesodium(l) 2mg 2.00 %
Sodium lauryl sulphate0.25 mg 0.25 %
Hypromellose 2910 15 mPa.s(2) 2 mg 2.00 %
Microcrystalline cellulose10 mg 10.00 %
Croscarmellose sodiuml 3 mg 3.00%
Colloidal anhydrous silica0.3 mg 0.30 %
M~gn~ lm stearate 0.5 mg 0.50 %
(1) Croscarmellose sodium is the British Approved Name of sodium carboxymethyllcellulose.
TBIR USE FOR THE TREATMENT OF I~JFLAM-MATORY BOW~ DISEASES
The present invention relates to the use of ridogrel at low ClQS5~S in the 1~ ll of infl~mm~tory bowel rlice~ces and to cvll~s~ollding low dose ridogrel form~ tions.
EP-0,22 1,601 describes (E)-s-t[[(3-pyridinyl)[3-(trifluor~llwlllyl)phenyl]
methylene]amino]oxy]pe~f~noir acid (~ ;f~lly known as ridogrel) for use in various pathological conditions. This clocllm~nt also g~n~rir~lly discloses pl~ r..l;r~
compositions compricing ridogrel.
EP-0,448,274 describes a tablet formulation co.,.l.. ;~;..~ 400 mg of ridogrel for use in 15 ulcerative and infl~ c,ly conditions of the gasL~ l tract.
~'~ce.ll~c et al., 1992, Gastroenterology 102 (4, Suppl.), p. A601, and Casellas et al., 1993, Gastroenterology 104 (4, Suppl.), p. A677 describe the clinical effect of the ~tlminicfration of ridogrel, 300 mg b.i.d., in ulcerative colitis.
20 The use of ridogrel in the tre~tm~nt of infl~ u~ y bowel ~lice~ces 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 ~minict~ring ridogrel at low doses, thereby unexpectedly increasing the clinical efficacy in infl~------~lc,ly 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 ph~rm~reutically acceptable acid or base addition salt thereof. When a 30 ph~rm~t~elltically 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 ph~rm~reutic~lly acceptable acid addition salts as mentioned hereinabove are meant to comprise the acid addition salt forms which can conveniently be obtained by treating 35 the base form of the compounds of formula (I) with ~p~ iate 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. Iactic, pyruvic, oxalic, malonic, succinic. maleic, fumaric, , WO 96/30016 PCTtEP96tO1229 malic, tartaric, citric, meth~n~snlfonic, eth~n~slllfonic, be..,~ lfonic, p-tolll~n~slllfonic, cyclamic, salicylic, p-~minos~ ylic, pamoic and the like acids.
E~GrGllc;d acids to form acid addition salts are hydl~--l.loric acid, which forms a (1:1) salt with ridogrel and nitric acid, which also forms a (1:1) salt with ridogrel.
S Conversely, said acid addition salt forms can be converted in the free base forms by tre~tm.-nt with an aL~lu~iate base. The compounds of formula (I) which are acidic may form base addition salt forms. The ph~ GI 11 ;r~lly acceptable base addition salts as mentioned hereinabove are meant to comprise the base ~ ition salts forms which can co,lvelliently be obtained by treating the acid form of the c0~ 7uullds of formula (I) with 10 ~lu~liate bases. Examples of such salts may include lithillm, sodium, pot~c~illm, calcium, ~lu~ gold and silver salts. Also colllr,~ te~1 are salts with ph~rrn~-~e~ltic~lly ~cept~kle arnines such as ammonia, primary, secondary and tertiary ~min~s, such as alkyl arnines, hydroxyalkylarnines, N-methyl,glllc~min~ and the like.
Conversely, said base addition salt forms can be converted in the free acid forms by 15 tre~tm~nt with an ~L)plU~ G acid.
Piefe"Gd counter ions in a base addition salt form are lithium and sodium.
The present invention relates to the use ûf ridogrel ûr a ph~rm~t ellti~lly acceptable acid 20 or base addition salt thereof for the manufacture of a medicament for treating infl~mm~t-~ry bowel ~ e~es, WhG1Gi11 ridogrel or its pharm~eutic~lly acceptable acid or base addition salt form is ~lmini~tcred 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).
~ltPrn~tively, the invention relates to a method of treating humans suffering from infl~"".,~t-,ly bowel ~lice~ec, said method comprising the ~lminictration to said hllm~n~
of ridogrel or a rh~rm~euti~lly acceptable acid or base addition salt form thereûf in an amûunt from 0.01 mg/kg body weight to 1 mg/kg body weight, suitably to 0.5 mg/kg30 body weight.
In particular, ridogrel or a ph~rm~relltically 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.
35 For adult human beings, 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.
CA 0221~160 1997-09-11 Tnfl~mm~tory bowel ~ e~çs include, for e~mple, ulcerative colitis, Crohn's disease and the like. In particular, ridogrel is used in the treatment of ulcerative colitis.
Ulcerative colitis is l,l,al ---L~ 1 by the presence of lesions in the mucous membranes of the colon. It is generally believed that thromboxane plays an active role in the5 development of these lesions. Ridogrel has been llesrribe~l to show both thromboxane synth~t~e inhihitory activity and thromboxane receptor antagonistic activity.
Unexpectedly, it has been shown that at the doses of the present invention, however, ridogrel is a mere thromboxane synthrt~e inhibitor, lacking llL v~l~oxane receptor antagonistic activity.
The trç~tmrnt of infl~mm~tory bowel ~li.ce~crs includes both the tle~Llllent 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 m~intrn~nre therapy. A satisfactory trç~tment of infl~mm~tory bowel ~iice~ce~, in particular ulcerative colitis, is characterized by a good 15 clinical efficacy and a low occurrence of adverse events. In particular, after 8 weeks of tre~tm~-nt, the following finrlin~c are desirable:
- an endoscopic improvement in more than 45% of the patients, preferably in more than 50% of the p~tirnt~;
- a complete endoscopic cure in more than 10% of the patients, preferably in more than 20 . 30% of the patients;
- a median percentage of days with bloody stools during the last 2 weeks of treatment of below 50%, preferably below 10%;
- a percentage of patients wherein the investigator's global evaluation of the effect of the tre~tmrnt is good or excellent of more than 40%, preferably more than 60%; and 25 - an occurrence of adverse events in less than 40% of the patients. Adverse events that may occur are e.g. nausea, vomiting, diarrhoea, abdominal cramps, oedema, paraesthesia, hematoma, ecchymoses, and the like.
Ridogrel or its pharm~reutic~lly acceptable acid or base addition salt form is suitably 30 ~lmini~tered systemically, such as orally, rectally, hlLla~eliLolleally orparenterally.
Preferably, ridogrel is ~lmini~tered orally or rectally. Suitably, ridogrel or aph~rrn~re~ltic~lly acceptable acid or base addition salt form thereof is atlmini~trred once daily (o.d.) or twice daily (b.i.d.), preferably formulated in an a~pro~liate pharm~re lfical composition. Hence, the invention relates to a ph~rrn~re~ltic~l 35 composition co~ lishlg a phal " ~r~ ir~lly acceptable carrier and ridogrel or its ph~rm~reutically acceptable acid or base addition salt form in an amount effective to be used as defined hereinabove. In particular, the invention relates to a pharm~relltical CA 0221~160 1997-09-11 WO 96/30016 P~ /01229 composition compri~in~ from 0.5 to 5 mg ridogrel per dosage unit form and a ph~rm~(-e~lti~lly acceptable carrier.
Solid ph~ l compositions such as tablets, c~rsllles, ~u~osil~ s and the like, suitably co~ ,ise ridogrel in an amount from 0.5 to 5 mg per dosage unit form, in S particular from 1 to 5 mg per dosage unit form. In solid ph~rm~l~e~lti~l com~osilions the ~f active ingredient is preferably ridogrel as such. Liquid ph~rm~-,eutical c~ o~iLions 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. In liquid ph~rm~celltic~l compositions ridogrel is preferably present as the sodium salt of the ridogrel.
Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit cc,~ g a pre~l~-tt-rmin~l quantity of ridogrel. Examples of such 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.
As d~,u~,iate compositions there may be cited all compositions usually employed for systemically a~1mini~t~ring drugs. To prepare the ph~rm~relltical compositions of this invention, an effective amount of ridogrel is combined in i 1 l I i 1 l ~r adll~i~Lulc; with a ph~rm~e~tic~lly acceptable carrier, which carrier may take a wide variety of forms depending on the form of ~ ~dlion desired for ~rlmini~tration Solid compositions according to the present invention will preferably comprise pharmaceutically acceptable carriers and excipients, such as fillers e.g. lactose, sucrose, m~nnitol, maize starch, microcrystalline cellulose or calcium hydrogen phosphate;
lubricants e.g. stearic acid, polyethylene glycol, m~r,llt~ill~ll stearate, talc or silica;
disintegrants e.g. rice, potato or maize starch, sodium starch glycolate or croscarmellose sodium; binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl-methylcellulose and wetting agents e.g. sodium dioctylsulfos~lccin~t.- and Polysorbates. Interesting solid 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. For the L~le~aldlion of solid compositions according to the invention, ridogrel is blended with suitable excipients and gr~n~ t~fl Preferably, ridogrel is granulated with the filler or fillers before admixture of the other excipients.
Most preferably the fillers employed will be lactose monohydrate and maize starch, especiallly in combination with calcium hydrogen phosphate. Because of their ease in ~lmini~tration, tablets and capsules represent the most advantageous oral dosage unit form.
CA 0221~160 1997-09-11 _5_ Liquid co~ o~iLions may comprise any of the usual ph~rm~enti~l media such as water, glycols, oils, alcohols and the like. Interesting liquid compositions are aqueous solutions or sucpeT-~ions, in particular for rectal ~llmini~tration. Liquid oral compositions 5 may comprise, apart from ridogrel or a ph~rm~cellti~lly acceptable acid or preferably base addition salt form and water, flavouring substances; sweeteners; suspending agents, e.g. cellulose derivatives; wetting agents, e.g. polyoxyethylene derivatives of sorbitan esters; buffer systems; st~bili7ing agents; preservatives; solubility enhancers and the like.
For pdl~"t~al compositions, the carrier will usually comprise sterile water, at least in 10 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 ~ Lul~ of saline and glucose solution. Injectable suspensions may also be prepared in which case a~pl~pliate liquid carriers, suspending agents and the like may be employed.
15 For rectal ~lmini~tration, conventional con.~osiLions such as suppositories or enemas may be used. Preferably, rectal solutions may be used. Said rectal solutions comprise apart from the active ingredient ridogrel or its ph~rm~centi~lly acceptable acid or preferably base addition salt, water (suitably ~lemin~ralised, preferably free of pyrogenics), a suitable buffer, such as the combination of disodium hydrogen phosphate 20 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.
Also included are solid form ~le~aldLions which are intended to be converted, shortly 25 before use, to liquid form ~ a dLions. Particular ph~rn~eutical compositions are controlled release formulations, from which the active ingredient is gradually released after ~rlminictration.
It may be advantageous that a micronized form of ridogrel is used in the present30 compositions. These micronized forms may be prepared by micronization techniques known in the art, e.g. by milling in d~ niate mills and sieving through ~p~upliate sieves.
Optionally, ridogrel may be ~lminictered in combination with another agent effective in 35 the treatment of infl~mm~tory bowel diseases, e.g. sulphasalazine, m.-s~1~7ine, olc~l~7in~, balsalazide, a corticosteroid and the like. The combined use includes the simultaneous, separate or sequential ~lmini~tration of the therapeutic agents.
CA 0221~160 1997-09-11 In a further aspect, the invention relates to a product cc,. .l ;.;. .; . .g (a) ridogrel and (b) slllph~ 7in--, m~s~l~7ine or a corticosteroid, as a cu,nbil,ed pl~ lion for .cimlllt~n~ous, sep~r~t~ or sequential use in the tr~trn~qnt of infl~ bowel ~ e~es.
S
Experim~-nt~l part Ph~rm~f~entic~l compositions 1. 1 m~ oral tablet Tablets having the composition shown hereinunder were prepared according to art-15 known formulation procedure.
Ridogrel 1 mg 1.00 %
Calciumhydrogenphosphatedihydrate0.94 mg 0.94 %
T ~rt~se monohydrate 56.01 mg 56.01 %
Maizestarch 24mg 24.00 %
Crosc~nnPllosesodium(l) 2mg 2.00 %
Sodium lauryl sulphate0.25 mg 0.25 %
Hypromellose 2910 15 mPa.s(2) 2 mg 2.00 %
Microcrystalline cellulose10 mg 10.00 %
Croscarmellose sodiuml 3 mg 3.00%
Colloidal anhydrous silica0.3 mg 0.30 %
M~gn~ lm stearate 0.5 mg 0.50 %
(1) Croscarmellose sodium is the British Approved Name of sodium carboxymethyllcellulose.
(2) 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 a~ hllate 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 2 5 m~ oral tablet Tablets having the composition shown hereinunder were prepared according to art-known forrnulation procedure.
CA 0221~160 1997-09-11 WO 96/30016 P~ 1229 Ridogrel S mg5.00 % (w/w) lcill~m hydrogenrhosph~t~ dihydrate 4.7 mg 4.70 % (w/w) T ~(~tose monohydrate48.25 mg48.25 % (w/w) J S Maizestarch 24 mg24.00 % (w/w) Crosc~rmellose sodiuml 2mg2.00% (w/w) Sodium lauryl sulphate0.25 mg0.25 % (w/w) Hypromellose 2910 15 mPa.s2 2 mg 2.00 % (w/w) Micl~ly~L~lline cellulose10 mg10.00 % (w/w) Crosc~nnellosesodiuml 3 mg3.00 % (w/w) Colloidal anhydrous silica0.3 mg0.30 % (w/w) ~ PCilllll stearate 0.5 mg0.50 % (w/w) The ~l~;~llL~ges are based on the total weight of the tablet.
CA 0221~160 1997-09-11 WO 96/30016 P~ 1229 Ridogrel S mg5.00 % (w/w) lcill~m hydrogenrhosph~t~ dihydrate 4.7 mg 4.70 % (w/w) T ~(~tose monohydrate48.25 mg48.25 % (w/w) J S Maizestarch 24 mg24.00 % (w/w) Crosc~rmellose sodiuml 2mg2.00% (w/w) Sodium lauryl sulphate0.25 mg0.25 % (w/w) Hypromellose 2910 15 mPa.s2 2 mg 2.00 % (w/w) Micl~ly~L~lline cellulose10 mg10.00 % (w/w) Crosc~nnellosesodiuml 3 mg3.00 % (w/w) Colloidal anhydrous silica0.3 mg0.30 % (w/w) ~ PCilllll stearate 0.5 mg0.50 % (w/w) The ~l~;~llL~ges are based on the total weight of the tablet.
3. Oral solution 0.25 m~/ml The rectal solution of 1 litre having the composition as shown hereinunder were prepared as follows ( the ~mollntc shown hereinunder are given for the ~ alaLion of 1 ml of 20 rectal solution):
800 ml of demineralised water was basified by adding approximately 1.6 ml of a aqueous sodium hydroxide solution (0.1 N). Said solution was heated to a temperature ranging from 60 to 70 ~C. The 6.5 g hydroxy ethylcellulose wac added to the solution while stirring vigorously. Said mixture is stirred for about 10 minutes at the above-25 mentioned temperature after which the heating is stopped. The stirring is continued untilthe hydroxy ethylcellulose is dissolved completely. Subsequently 250 mg ridogrel is added to the solution as well as 2.085 g disodium hydrogen phosphate anhydrous and 477 mg of sodium dihydrogen phosphate. Furthermore the 3.5 g of sodium chloride are added and 200 ml of deminieralised water is added.
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 cont"ining 40 ml or 80 ml of the above 35 described solution.
It is important use the correct amount and grade of hydroxy ethyl cellulose in view of stability of the obtained solutions.
CA 0221~160 1997-09-11 WO 96/30016 PCTIEP96/OlZ29 Composition:
Ridogrel 0.25 mg0.025 % ,, Hydroxyethylcelllllose (4800-6000rnPa.s) 6.5 mg 0.65 %
DisodiumHydrogen Phosphate anhydrous 2.085 mg 0.285 % y Sodium Dihydrogen Phosphate Monohydrategermpoor 0.477 mg 0.0477 %
Sodium Hydroxide q.s to dissolve the Ridogrel Sodium Chloride 3.5 mg 0.35 %
Purified waterqs ad 1000 ,ulq.s. ad 100 %
Analogous solutions co..l;.i..i..g 2.5 mg to 10 mg of ridogrel in 40 rnl 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 ~l~aldlion.
Clinical example Three groups of patients suffering from mild to severe ulcerative colitis were treated orally for eight weeks with 5 mg ridogrel o.d. (group 1), 25 mg ridogrel b.i.d. (group 2) and 150 mg ridogrel b.i.d. (group 3).
The following fin-ling~ were recorded:
Group 1Group 2 Group 3 (5 mg/day) (50 mg/day) (300 mg/day) 1. Primary parameters Endoscopic improvement 55% 46% 42%
Complete endoscopic cure 36% 17% 8%
2. Secondary parameters Median percentage of days with bloody stools during the last 2 weeks of treatment 0% 43% 92%
Percentage of patients wherein the investigator's global evaluation of the effect of the treatment was good or excellent 64% 46% 25%
3. Adverse events Occurrence of adverse events 36% 38% 54%
- =
Conclusion Both the tre~tm--nt with 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. show il.lpr~v~;d clinical efficacy when co"".d,~d with the 150 mg ridogrel b.i.d. l.~ Also the 5 oc~;u-lcnce of adverse events is significantly less with the 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. tre~tm~nt compared with the 150 mg ridogrel b.i.d. tre~tmf nt Both the 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. treatment meet the definitions of a s~ti~f~tory tre~tm--nt of ulcerative colitis as set forth hereinbefore.
800 ml of demineralised water was basified by adding approximately 1.6 ml of a aqueous sodium hydroxide solution (0.1 N). Said solution was heated to a temperature ranging from 60 to 70 ~C. The 6.5 g hydroxy ethylcellulose wac added to the solution while stirring vigorously. Said mixture is stirred for about 10 minutes at the above-25 mentioned temperature after which the heating is stopped. The stirring is continued untilthe hydroxy ethylcellulose is dissolved completely. Subsequently 250 mg ridogrel is added to the solution as well as 2.085 g disodium hydrogen phosphate anhydrous and 477 mg of sodium dihydrogen phosphate. Furthermore the 3.5 g of sodium chloride are added and 200 ml of deminieralised water is added.
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 cont"ining 40 ml or 80 ml of the above 35 described solution.
It is important use the correct amount and grade of hydroxy ethyl cellulose in view of stability of the obtained solutions.
CA 0221~160 1997-09-11 WO 96/30016 PCTIEP96/OlZ29 Composition:
Ridogrel 0.25 mg0.025 % ,, Hydroxyethylcelllllose (4800-6000rnPa.s) 6.5 mg 0.65 %
DisodiumHydrogen Phosphate anhydrous 2.085 mg 0.285 % y Sodium Dihydrogen Phosphate Monohydrategermpoor 0.477 mg 0.0477 %
Sodium Hydroxide q.s to dissolve the Ridogrel Sodium Chloride 3.5 mg 0.35 %
Purified waterqs ad 1000 ,ulq.s. ad 100 %
Analogous solutions co..l;.i..i..g 2.5 mg to 10 mg of ridogrel in 40 rnl 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 ~l~aldlion.
Clinical example Three groups of patients suffering from mild to severe ulcerative colitis were treated orally for eight weeks with 5 mg ridogrel o.d. (group 1), 25 mg ridogrel b.i.d. (group 2) and 150 mg ridogrel b.i.d. (group 3).
The following fin-ling~ were recorded:
Group 1Group 2 Group 3 (5 mg/day) (50 mg/day) (300 mg/day) 1. Primary parameters Endoscopic improvement 55% 46% 42%
Complete endoscopic cure 36% 17% 8%
2. Secondary parameters Median percentage of days with bloody stools during the last 2 weeks of treatment 0% 43% 92%
Percentage of patients wherein the investigator's global evaluation of the effect of the treatment was good or excellent 64% 46% 25%
3. Adverse events Occurrence of adverse events 36% 38% 54%
- =
Conclusion Both the tre~tm--nt with 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. show il.lpr~v~;d clinical efficacy when co"".d,~d with the 150 mg ridogrel b.i.d. l.~ Also the 5 oc~;u-lcnce of adverse events is significantly less with the 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. tre~tm~nt compared with the 150 mg ridogrel b.i.d. tre~tmf nt Both the 5 mg ridogrel o.d. and 25 mg ridogrel b.i.d. treatment meet the definitions of a s~ti~f~tory tre~tm--nt of ulcerative colitis as set forth hereinbefore.
Claims (10)
1. The use of ridogrel for the manufacture of a medicament for treating inflammatory bowel diseases, wherein ridogrel is administered in a daily dose from 0.01 mg/kgbody weight to 1 mg/kg body weight.
2. The use according to claim 1 wherein the daily dose of ridogrel is from 0.02 mg/kg body weight to 0.1 mg/kg body weight.
3. The use according to claim 1 wherein ridogrel is administered orally or rectally.
4. The use according to claim 1 wherein ridogrel is administered in combination with sulphasalazine, mesalazine or a corticosteroid.
5. The use of ridogrel for the manufacture of a medicament for treating inflammatory bowel diseases in adult human beings, wherein ridogrel is administered in a dosefrom 1 mg/day to 50 mg/day.
6. A pharmaceutical composition comprising from 0.5 to 10 mg ridogrel per dosage unit form and a pharmaceutically acceptable carrier.
7. A solid pharmaceutical composition comprising from 0.5 to 10 mg ridogrel per dosage unit form and a pharmaceutically acceptable carrier.
8. A solid pharmaceutical composition according to claim 7 consisting essentially of ridogrel 1 mg 1.00 %
Calcium hydrogen phosphate dihydrate 0.94 mg 0.94 %
Lactose monohydrate 56.01 mg 56.01 %
Maize starch 24 mg 24.00 %
Croscarmellose sodium 2 mg 2.00 %
Sodium lauryl sulphate 0.25 mg 0.25 %
Hypromellose 2910 15 mPa.s 2 mg 2.00 %
Microcrystalline cellulose 10 mg 10.00 %
Croscarmellose sodium 3 mg 3.00%
Colloidal anhydrous silica 0.3 mg 0.30 %
Magnesium stearate 0.5 mg 0.50 %
Calcium hydrogen phosphate dihydrate 0.94 mg 0.94 %
Lactose monohydrate 56.01 mg 56.01 %
Maize starch 24 mg 24.00 %
Croscarmellose sodium 2 mg 2.00 %
Sodium lauryl sulphate 0.25 mg 0.25 %
Hypromellose 2910 15 mPa.s 2 mg 2.00 %
Microcrystalline cellulose 10 mg 10.00 %
Croscarmellose sodium 3 mg 3.00%
Colloidal anhydrous silica 0.3 mg 0.30 %
Magnesium stearate 0.5 mg 0.50 %
9. A liquid pharmaceutical composition comprising from 0.1 to 1 mg/ml ridogrel and a pharmaceutically acceptable carrier.
10. A process for preparing a composition as claimed in claim 6 characterized in that ridogrel is intimately mixed with the pharmaceutically acceptable carriers.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP95200768.0 | 1995-03-28 | ||
| EP95200768 | 1995-03-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2215160A1 true CA2215160A1 (en) | 1996-10-03 |
Family
ID=8220134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002215160A Abandoned CA2215160A1 (en) | 1995-03-28 | 1996-03-18 | Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0817631A2 (en) |
| JP (1) | JPH10511097A (en) |
| AR (1) | AR002727A1 (en) |
| AU (1) | AU5397496A (en) |
| CA (1) | CA2215160A1 (en) |
| HU (1) | HUP9900309A3 (en) |
| IL (1) | IL117670A (en) |
| NO (1) | NO974486D0 (en) |
| WO (1) | WO1996030016A2 (en) |
| ZA (1) | ZA962461B (en) |
Families Citing this family (9)
| 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 (en) * | 2001-03-12 | 2003-12-17 | Novo Nordisk A/S | Novel tablets and capsules and a process for its preparation |
| ITRM20050389A1 (en) | 2005-07-22 | 2007-01-23 | Giuliani Spa | COMPOUNDS AND THEIR SPECIFIC SALTS FOR PPAR RECEPTORS AND RECEPTORS FOR EGF AND THEIR USE IN MEDICAL FIELDS. |
| UA107562C2 (en) | 2008-12-05 | 2015-01-26 | METHOD OF TREATMENT OF PSORIASIS | |
| HUE032999T2 (en) | 2009-02-16 | 2017-11-28 | Nogra Pharma Ltd | Alkylamido compounds and uses thereof |
| CN109999017A (en) | 2012-02-09 | 2019-07-12 | 诺格拉制药有限公司 | The method for treating fibrosis |
| CA2870490A1 (en) | 2012-04-18 | 2013-10-24 | Nogra Pharma Limited | Methods of treating lactose intolerance |
| 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 |
| MX2021009498A (en) | 2019-02-08 | 2021-09-08 | Nogra Pharma Ltd | Process of making 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof. |
Family Cites Families (1)
| 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 |
-
1996
- 1996-03-18 EP EP96910921A patent/EP0817631A2/en not_active Withdrawn
- 1996-03-18 HU HU9900309A patent/HUP9900309A3/en unknown
- 1996-03-18 AU AU53974/96A patent/AU5397496A/en not_active Abandoned
- 1996-03-18 WO PCT/EP1996/001229 patent/WO1996030016A2/en not_active Application Discontinuation
- 1996-03-18 CA CA002215160A patent/CA2215160A1/en not_active Abandoned
- 1996-03-18 JP JP8528894A patent/JPH10511097A/en active Pending
- 1996-03-27 ZA ZA9602461A patent/ZA962461B/en unknown
- 1996-03-27 IL IL11767096A patent/IL117670A/en active IP Right Grant
- 1996-03-27 AR ARP960101944A patent/AR002727A1/en unknown
-
1997
- 1997-09-29 NO NO974486A patent/NO974486D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9900309A2 (en) | 1999-05-28 |
| AR002727A1 (en) | 1998-04-29 |
| HUP9900309A3 (en) | 1999-11-29 |
| IL117670A (en) | 2000-02-29 |
| AU5397496A (en) | 1996-10-16 |
| MX9707394A (en) | 1997-11-29 |
| ZA962461B (en) | 1997-09-29 |
| NO974486L (en) | 1997-09-29 |
| NO974486D0 (en) | 1997-09-29 |
| IL117670A0 (en) | 1996-07-23 |
| EP0817631A2 (en) | 1998-01-14 |
| JPH10511097A (en) | 1998-10-27 |
| WO1996030016A2 (en) | 1996-10-03 |
| WO1996030016A3 (en) | 1997-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2614164B2 (en) | Composition for enhancing antitumor effect and for treating tumor | |
| EP1083931B1 (en) | Stabilization of compositions containing ace inhibitors using magnesium oxide | |
| CZ301737B6 (en) | Pharmaceutical composition containing benzamide derivative exhibiting enhanced solubility and absorptivity | |
| CZ287892A3 (en) | Pharmaceutical preparations | |
| AU2007341218B2 (en) | Isosorbide mononitrate derivatives for the treatment of intestinal disorders | |
| CA2215160A1 (en) | Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases | |
| CA2144155A1 (en) | Ibuprofen-h2 antagonist combinations | |
| EP1092431B1 (en) | Lasofoxifene compositions | |
| JPH07242626A (en) | Stomach acid secretion inhibitor and antiulceric agent | |
| AU2011270133B2 (en) | Sustained-release therapeutic agent for hypertension and renal dysfunction | |
| KR100192534B1 (en) | Agent for increasing somatostatin or for inhibiting decrease of somatostatin | |
| US4874757A (en) | Antinflammatory compositions and methods | |
| JP2008533186A (en) | Use of macrolides for the treatment of enteritis | |
| AU712071B2 (en) | Anti-HIV composition containing imidazole derivatives | |
| JP4737686B2 (en) | New medicine | |
| JPS641470B2 (en) | ||
| CA1249521A (en) | Antiinflammatory compositions and methods | |
| JP3254712B2 (en) | Pharmaceutical composition | |
| US4812455A (en) | Antiinflammatory compositions and methods | |
| US4672061A (en) | Antiinflammatory compositions and methods | |
| MXPA97007394A (en) | Formulations of low dose ridogrel and its use the treatment of inflamator intestinal diseases | |
| JPH0132804B2 (en) | ||
| KR20220152073A (en) | Pharmaceutical composition for treatment or prevention of Crohn's disease comprising pyrimethamine as an active ingredient | |
| JPH10330265A (en) | Therapeutic agent for liver disease | |
| WO2010133907A1 (en) | Hexadentate chelators in inflammatory bowel disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |