CN100372533C - Therapeutic formulation for mainly of diarrhea large intesitine irritation syndrome - Google Patents
Therapeutic formulation for mainly of diarrhea large intesitine irritation syndrome Download PDFInfo
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- CN100372533C CN100372533C CNB2005800000636A CN200580000063A CN100372533C CN 100372533 C CN100372533 C CN 100372533C CN B2005800000636 A CNB2005800000636 A CN B2005800000636A CN 200580000063 A CN200580000063 A CN 200580000063A CN 100372533 C CN100372533 C CN 100372533C
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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Abstract
Use of 0.002 to 0.02 mg, in terms of daily dose, of ramosetron hydrochloride or an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof in order to produce a remedy for irritable bowel syndrome with diarrhea in male and female patients.
Description
Technical field
The present invention relates to a kind of medicine, or more specifically, the present invention relates to a kind ofly treat the preparation that diarrhoea is main large intesitine irritation syndrome, or relate to a kind of preparation that improves the large intesitine irritation syndrome symptom of diarrhea.
Background technology
The chemical name of ramosetron (Ramosetron) is (-)-(R)-5-((1-Methyl-1H-indole-3-yl) carbonyl)-4,5,6,7-tetrahydrochysene-1H-benzimidazole.
Ramosetron HCl is sold as a kind of preparation that improves the relevant the intestines and stomach symptom (nausea and vomiting) of cancer drug therapy (as cisplatin), its adult's dosage is generally once a day oral, each 0.1mg, or intravenous injection once a day, each 0.3mg (" Nasea OD tablet 0.1mg ", " Nasea injection 0.3mg ", see " Japanese pharmacy reference, japanese product and management " (JAPAN PHARMACEUTICALREFERENCE, PRODUCTS AND ADMINISTRATION in JAPAN), the 5th edition (1999) are published by Japan medical science product international trade association (Japan Medical Products InternationalTrade Association)).
In EP-A-381422, illustrated that openly a series of Tetrahydrobenzimidazderivative derivatives that comprise ramosetron and pharmaceutically acceptable salt thereof are to 5HT
3Receptor has antagonism.According to this effect, this patent proposes it may suppress the vomiting that cancer therapy drug (as cisplatin and radioactive ray irradiation) causes, and may prevent and treat that migraine, complicated headache, trigeminal neuralgia, anxiety neurosis, gastrointestinal motility are unusual, peptic ulcer, large intesitine irritation syndrome etc., and its clinical common dose has been described, adult's intravenous injection every day 0.1 to 10mg, with 0.5 to 50mg oral, once a day or be divided into repeatedly and give.
On the other hand, 5HT has been described in W099/17755
3Receptor can be used for the treatment to the non-constipation large intesitine irritation syndrome of women, and it treats effective dose in 0.01 to 500mg scope, and perhaps preferred every day 0.05 is to 50mg.More specifically say, the clinical research result who gives non-constipation large intesitine irritation syndrome patient 1 to 8mg alosetron (alosetron) every day for twice shows, compare with placebo, this medicine can significantly improve pain and discomfort, feces denseness, the frequency of bowel movement and the natural law ratio of urgency treatment of female patients, yet, in the andropathy people, compare with placebo, except the feces denseness, do not see other significant improvement.
In addition, in WO2002/007713, described every day and taken 1 to 16mg5HT three times
3Receptor antagonist, all effective in cure to masculinity and femininity patient large intesitine irritation syndrome.
Summary of the invention
It is the preparation of master's large intesitine irritation syndrome in the hope of createing novel treatment diarrhoea that inventor of the present invention has carried out extensive studies, and for this disease, does not obtain highly effective treatment preparation at present as yet.Inventor of the present invention once attempted taking Ramosetron HCl every day twice to the patient who suffers from large intesitine irritation syndrome, yet failed in this clinical research to determine that it compares with placebo and have notable therapeutic effect.
After this, inventor of the present invention imagines ramosetron may be far below 0.1 to 0.3mg to the treatment effective dose of large intesitine irritation syndrome, this dosage be adopt at present be used to improve the relevant used dosage of the intestines and stomach symptom of cancer drug therapy.Consider above these situations, we have developed a kind of stabilization formulations that contains seldom amount (0.001 to 0.01mg) Ramosetron HCl, and are that the male and female patient of main large intesitine irritation syndrome has carried out the research in 12 weeks by a definite date with said preparation to suffering from diarrhoea.Beat all is that result of study confirms that said preparation is significantly effective, thereby has finished this invention.
Therefore, the present invention relates to be used for the treatment of diarrhoea is the pharmaceutical composition of main large intesitine irritation syndrome male and female patient, this pharmaceutical composition daily dose contains 0.001 to 0.05mg Ramosetron HCl, perhaps the ramosetron of equimolar amounts or its pharmaceutically acceptable other salt are as active component, perhaps, the present invention relates to improve the pharmaceutical composition of large intesitine irritation syndrome male and female patient symptom of diarrhea, this pharmaceutical composition daily dose contains 0.001 to 0.05mg Ramosetron HCl, perhaps contains the ramosetron of equimolar amounts or its pharmaceutically acceptable other salt as active component.
In addition, the present invention relates to the Ramosetron HCl of 0.001 to 0.05mg dosage every day, perhaps equimolar amounts ramosetron or its pharmaceutically acceptable other salt, in production for treating diarrhoea is the purposes of main large intesitine irritation syndrome male and female patient medicine, perhaps the present invention relates to the Ramosetron HCl of 0.001 to 0.05mg dosage every day, perhaps equimolar amounts ramosetron or its pharmaceutically acceptable other salt improve purposes in the male and female patient symptom of diarrhea medicine of large intesitine irritation syndrome in production.
In addition, the present invention relates to treat diarrhoea is the method for main large intesitine irritation syndrome male and female patient, comprise the Ramosetron HCl that gives 0.001 to 0.05mg dosage every day, the perhaps ramosetron of equimolar amounts or its pharmaceutically acceptable other salt, perhaps the present invention relates to improve the method for large intesitine irritation syndrome male and female patient symptom of diarrhea, comprise the Ramosetron HCl that gives 0.001 to 0.05mg dosage every day, perhaps the ramosetron of equimolar amounts or its pharmaceutically acceptable other salt.
According to the present invention, it is main large intesitine irritation syndrome or the good preparation that improves the large intesitine irritation syndrome symptom of diarrhea that treatment diarrhoea might be provided now, no matter the patient is male or women.
With as shown in the test implementation example of mentioning 1, Ramosetron HCl is the oral dose of 0.005mg or 0.01mg once a day, is the patient of main large intesitine irritation syndrome for diarrhoea, no matter the men and women is all effective as hereinafter.Just can produce and give 0.01mg identical significant curative effect owing to give 0.005mg, can estimate this dosage further reduced by half still can obtain curative effect.Test implementation example 1 to as if the adult patient of Japan, and child's optimal dose is proposed may be littler, and usually be 2 times of Japanese's optimal dose for Europe and American's optimal dose.Therefore, although the concrete preferred dose of Ramosetron HCl is in 0.002 to 0.02mg scope, still can be according to patient's age and race's difference, every day 0.001 to 0.05mg dosage range can to treat diarrhoea be main large intesitine irritation syndrome or the symptom of diarrhea that improves large intesitine irritation syndrome.
The clinical dosage of having described the Tetrahydrobenzimidazderivative derivative that comprises ramosetron in EP-A-381422 is generally 0.1mg or higher every day, but has not both had to propose not illustrate that also the Ramosetron HCl of dosage range every day in 0.002 to 0.02mg can demonstrate therapeutic effect.In addition, the present invention is better than:
1) the at present commercially available Ramosetron HCl that contains is used to improve the preparation of the relevant the intestines and stomach symptom of cancer drug therapy as active component, is that the treatment effective dose of medicine of the present invention is low to moderate 1/5 to 1/50,
2) disclosed medicine among the WO99/17755 is that the present invention all can obtain sufficient curative effect to male and female patient, and
3) the disclosed medicine of WO2002/007713 is that every day of the present invention, dosage was low to moderate under 1/50 to 1/500 the situation, still can reach sufficient curative effect,
And these advantages can not predict in the art from above-mentioned.
Now, set forth by hereinafter the present invention being done in more detail.
Ramosetron and pharmaceutically acceptable salt thereof are not difficult with the preparation technology described in the EP-A-381422 or use method similar with it to produce to obtain.
About the pharmaceutically acceptable salt of ramosetron, its instantiation is: with the salt of mineral acid formation, as its hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromate; With the salt of organic acid formation, as its acetic acid, oxalic acid, maleic acid, malic acid, Fumaric acid, tartaric acid and mesylate; And the salt that forms with acidic amino acid, as glutamic acid and aspartate.Wherein, commercially available Ramosetron HCl is most preferred.
Can with being fit to organic or inorganic carrier, excipient and other additive oral or parenterai administration medication preparation of the present invention be become oral solid preparation, oral liquid or injection according to traditional method.Preferably those forms that can be taken and be convenient to preserve and carry by patient oneself are more specifically said, they are tablet, dilution powder, granule, granula subtilis, capsule, pill etc.
In this type of solid formulation, active substance mixes with a kind of inert diluent at least, as lactose, mannitol, glucose, microcrystalline Cellulose, starch, polyvinylpyrrolidone and metasilicic acid Mg aluminate.Said composition can contain with traditional method, and the additive except that inert diluent comprises binding agent, as hydroxypropyl cellulose and hydroxypropyl methylcellulose; Lubricant is as magnesium stearate, calcium stearate, Polyethylene Glycol, starch and Pulvis Talci; Disintegrating agent is as hydroxy acid cellulose calcium; Stabilizing agent is as lactose; Cosolvent is as glutamic acid and aspartic acid; Plasticizer is as Tween 80 and triacetin; And coloring agent, as titanium oxide and iron sesquioxide.As needs, cover for tablet or pill and go up sugar-coat or gastric solubility or enteric solubility matters, as sucrose, gelatin, agar, pectin, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
In addition, the same with commercially available " Nasea OD tablet 0.1mg ", said preparation can be mouthful tablet of interior disintegratable.For example, the tablet of disintegratable can basis in this mouthful, US5 for example, 466,464, US5,576,014, US6,589,554, WO 2003/009831, WO 2002/092058 etc. are prepared.
Because the dosage of the contained ramosetron of medicine of the present invention is very low, therefore especially preferably adopt the stable technology preparation of temperature and humidity.
For example, when adding a kind of specific compound that contains carbonyl, can improve the stability of ramosetron to temperature and humidity.About this specific carbonyl containing compound, its instantiation is that aliphatic carboxylic acid (more specifically is, saturated or undersaturated, the aliphatic list of straight or branched-, two-, or tri-carboxylic acids, or be specially, aliphatic carboxylic acid with 3 to 36 carbon atoms) or its ester, hydroxy carboxylic acid (more specifically is, saturated or undersaturated, the aliphatic hydroxyl list of straight chain or straight chain-, two-, or tri-carboxylic acids, perhaps concrete, hydroxy carboxylic acid with 3 to 36 carbon atoms) or its ester, acidic amino acid, bmap acid, the aromatic carboxyl chemical compound (more specifically is, the aromatic series list-, two-or tri-carboxylic acids, its alkyl or hydroxyl that can be contained 1 to 4 carbon atom replaces, and perhaps is specially, and have the macromolecular substances of carboxyl and available suitable mode wherein 2 kinds or multiple those chemical compounds of uniting use alone or in combination aromatic carboxylic acid with 7 to 20 carbon atoms) or its ester.
Concrete with regard to the specific compound that contains carbonyl, preferably hydroxy carboxylic acid or its ester, macromolecular compound, aromatic carboxyl chemical compound or its ester and bmap acid with carboxyl; Especially preferred is hydroxy carboxylic acid or its ester, the macromolecular substances with carboxyl and aromatic carboxyl chemical compound or its ester; More preferably hydroxy carboxylic acid or its ester and have the macromolecular compound of carboxyl.
About aliphatic carboxylic acid, preferably maleic acid, malonic acid, succinic acid and Fumaric acid.For hydroxy carboxylic acid, preferably tartaric acid, malic acid and citric acid, more preferably tartaric acid and citric acid.About acidic amino acid, preferably glutamic acid and aspartic acid.About the aromatic carboxyl chemical compound, preferably phthalic acid and propyl gallate, more preferably propyl gallate.About having the macromolecular substances of carboxyl, preferably carboxymethyl cellulose and alginic acid, more preferably carboxymethyl cellulose.About bmap acid, preferably ascorbic acid and arabo-ascorbic acid, more preferably ascorbic acid.
Found that above-mentioned carbonyl carboxyl compound with hydrate forms or anhydrous crystal anhydride form (as citric acid water compound and Citric anhydride) also can reach stablizing effect required for the present invention, thereby the present invention covers their all hydrates, anhydride and composition thereof.About the extent of polymerization of macromolecular substances, molecular mass etc., although this is had no particular limits, it is particularly preferred that average molecular mass is respectively about 110,000 or about 200,000 carboxymethyl cellulose and alginic acid.
Consumption about the chemical compound that is used for stablizing ramosetron or its pharmaceutically-acceptable salts can reach stablizing effect as long as there is no particular limitation.For example, account for 0.01% to 90% of said preparation weight, preferably account for 0.01% to 50%, perhaps be more preferably at when considering preparation factor, account for 0.1% to 10% of said preparation weight.
The dosage of ramosetron or its pharmaceutically-acceptable salts can take in and determine the suitable amounts of each case according to the age that gives object, race, sex etc.With regard to common oral hydrochloride ramosetron, be approximately every day 0.001 to 0.05mg, the most preferred adult is once a day oral after the meal 0.002 to 0.02mg.
As indicated above, for comprising American or European given patient colony, in order to treatment large intesitine irritation syndrome (comprising that diarrhoea is main large intesitine irritation syndrome) or can be in 0.0025mg to 0.05mg scope in order to optimal dose every day (according to the free alkali form metering) of the ramosetron of the symptom of diarrhea that improves large intesitine irritation syndrome, perhaps more suitably every day dosage in 0.0025mg to 0.02mg scope, the perhaps ramosetron pharmaceutically acceptable salt of equimolar amounts.
Be understandable that, the ramosetron that reference dose refers to or the administration total amount of its pharmaceutically-acceptable salts in 24 hours every day of the ramosetron that this paper lists or its pharmaceutically-acceptable salts, wherein this total amount can once give (being potion every day) or repeatedly give (divide in promptly 24 hours 2 times or repeatedly give this dosage, and the dosage summation that this repeatedly gives is in every day described herein dosage range).As mentioned above, administration once a day may be fit at least some schemes.Therapeutic Method of the present invention also can comprise an authentication step, promptly identifies the symptom of diarrhea whether object needs to treat large intesitine irritation syndrome and/or alleviation or improve large intesitine irritation syndrome.Suitable evaluation can be judged or be judged by the medical professionalism personage by patient, can be subjective (for example, individual opinion) or objective (for example, measuring by test or diagnostic method).
Can adopt multiple therapeutic scheme.For example, can adopt intermittent treatment to patient, for example, when the outbreak of acute large intesitine irritation syndrome, can give ramosetron or its pharmaceutically acceptable salt by daily dose as described herein, the persistent period of administration should be enough to alleviate the symptom of large intesitine irritation syndrome, as give ramosetron or its pharmaceutically-acceptable salts 7 days, 14,21,28,6 weeks, 8 weeks, 12 weeks, 16 weeks or longer time with daily dose as herein described, stop administration then and experience the large intesitine irritation syndrome again until patient.Perhaps, patient can continue medication the longer time treatment, for example, give between daily dose variable interval described herein or give ramosetron for a long time or its pharmaceutically-acceptable salts (for example, at least 6,9,12 or 15 months), administration every day as prophylactic treatment with the generation of avoiding the large intesitine irritation syndrome or reduce to its incidence rate minimum.Also can adopt other therapeutic scheme.
According to the defined diarrhoea of Rome II diagnostic criteria is that the patient of main IBS comprises and is in the alternately patient in property large intesitine irritation syndrome diarrhoea stage.(D.A.Drossman, etc., 351 to 432 pages, Degnon Associates, McLean, 2000)
Implement optimal mode of the present invention
Now the present invention is set forth in more detail, but the present invention is not limited in these embodiment by following embodiment and test implementation example.
Embodiment 1
0.02 part of Ramosetron HCl
86 parts of lactose
3 parts of hydroxypropyl celluloses
1 part in tartaric acid
0.2 part of yellow iron sesquioxide
10 parts of titanium oxides
0.3 part of light silicic acid anhydride
Hydroxypropyl cellulose (3 parts), 0.02 part of Ramosetron HCl and 1 part of tartaric acid are dissolved in 35 parts of water, use magnetic stirrer, and use device for grinding to grind with 10 parts of titanium oxides and 0.2 part of yellow iron sesquioxide and rub, preparation spraying liquid (hydroxypropyl cellulose concentration: 8 weight %).After this, 86 parts lactose is added liquid level granulating machine (Flow Coater; Produce by Freund), with 5g/ minute the spray velocity above-mentioned spraying liquid of spraying, carry out the liquid granulating.Granule placed under 40 ℃ the intake air temperature dry 5 minutes, then the powder formulation that mixes to obtain diluting with 0.3 part of light silicic acid anhydride.
Embodiment 2
0.0008 part of Ramosetron HCl
89 parts in mannitol
0.1 part of Citric anhydride
10 parts of maltose
1 part of red iron sesquioxide
1 part of magnesium stearate
Maltose (10 parts), 0.0008 part of Ramosetron HCl, 0.1 part of Citric anhydride and 1 part of red iron sesquioxide are suspended in 67 parts of water, prepare spraying liquid (concentration: 15 weight %) with magnetic stirrer.After this, 89 portions of mannitol are added fluidized bed formula fluidized bed formula granulating machine (Flow Coater; Produce by Freund) in, with 10g/ minute the spray velocity above-mentioned spraying liquid of spraying, carry out the liquid granulating.Behind the granulating, granule was placed under 40 ℃ of intake air temperature dry 5 minutes, mix with 1 part of magnesium stearate then.With the speed of 120mg/ sheet mixed-powder is made tablet with the rotation pelleter, obtain having the tablet of about 1kp initial hardness.These tablets were preserved 18 hours under the condition of relative humidity 75%, under the condition of relative humidity 40%, preserved 4 hours then, obtain the tablet of good to eat interior disintegrate.
Embodiment 3
Implement the production method identical,, obtain the tablet of good to eat interior disintegrate except the amount with added Citric anhydride makes 0.2 part into embodiment 2.
Embodiment 4
Implement the production method identical,, obtain the tablet of good to eat interior disintegrate except the amount with added Citric anhydride makes 0.5 part into embodiment 2.
Embodiment 5
0.0008 part of Ramosetron HCl
89 parts in mannitol
0.2 part in ascorbic acid
10 parts of maltose
1 part of red iron sesquioxide
1 part of magnesium stearate
Maltose (10 parts), 0.0008 part of Ramosetron HCl, 0.2 part of ascorbic acid and 1 part of red iron sesquioxide are suspended in 67 parts of water, use magnetic stirrer, preparation spraying liquid (concentration: 15 weight %).After this, 89 portions of mannitol are added fluidized bed formula fluidized bed formula granulating machine (Flow Coater; Produce by Freund) in 10g/ minute the spray velocity above-mentioned spraying liquid of spraying, carry out the liquid granulating.Behind the granulating, granule was placed under 40 ℃ of intake air temperature dry 5 minutes, mix with 1 part of magnesium stearate then.With the speed of 120mg/ sheet mixed-powder is made tablet with the rotation pelleter, obtain having the tablet of about 1kp initial hardness.These tablets were preserved 18 hours under the condition of relative humidity 75%, under the condition of relative humidity 40%, preserved 4 hours then, obtain the tablet of good to eat interior disintegrate.
Embodiment 6
Implement the production method identical,, obtain the tablet of good to eat interior disintegrate except making added ascorbic acid amount into 0.5 part with embodiment 5.
Embodiment 7
0.0008 part of Ramosetron HCl
88 parts in mannitol
10 parts of maltose
1 part of yellow iron sesquioxide
0.2 part of Citric anhydride
1 part of magnesium stearate
Maltose (10 parts), 0.0008 part of Ramosetron HCl, 1 part of red iron sesquioxide and 0.2 part of Citric anhydride are suspended in 67 parts of water, use magnetic stirrer, preparation spraying liquid (concentration: 15 weight %).After this, 88 portions of mannitol are added fluidized bed formula fluidized bed formula granulating machine (Flow Coater; Produce by Freund) under the air of 50 ℃ of temperature the above-mentioned spraying liquid of spraying, spray velocity 10g/ minute, spraying/drying/shake circulation time was 15 seconds/15 seconds/10 seconds, carries out the liquid granulating.Behind the granulating, granule was placed under 40 ℃ of intake air temperature dry 5 minutes, mix with 1 part magnesium stearate then.With the speed of every of 120mg/ mixed-powder is made tablet with the rotation pelleter, obtain having the tablet of about 1kp initial hardness.These tablets were preserved 18 hours under the condition of relative humidity 75%, under the condition of relative humidity 40%, preserved 4 hours then, obtain the tablet of good to eat interior disintegrate.
Embodiment 8
0.01 part of Ramosetron HCl
86 parts of microcrystalline Cellulose (Avicel)
10 parts of the low hydroxypropyl celluloses that replaces
0.5 part of Citric anhydride
3 parts of hydroxypropyl celluloses
0.5 part of magnesium stearate
Hydroxypropyl cellulose (3 parts), 0.5 part of Citric anhydride and 0.01 part of Ramosetron HCl are dissolved in 27 parts of water, use magnetic stirrer, the preparation spraying liquid (concentration of hydroxypropyl cellulose: 10 weight %).Then; 86 parts of microcrystalline Cellulose and the 10 parts low hydroxypropyl celluloses that replace are added fluidized bed formula fluidized bed formula granulating machine (trade name: GPCG-5; produce by Powlex) in, with 100g/ minute the spray velocity above-mentioned spraying liquid of spraying, carry out the liquid granulating.Behind the granulating, granule was placed 40 ℃ of following dryings 5 minutes, mix with the 0.5g magnesium stearate then.With the speed of 100mg/ sheet mixed-powder is made tablet with the rotation pelleter.
Embodiment 9
0.1 part of Ramosetron HCl
77 parts of lactose
19 parts of corn starchs
5 parts of carboxymethyl celluloses (CMC)
3 parts of hydroxypropyl celluloses
0.3 part of magnesium stearate
Hydroxypropyl cellulose (3 parts) and 0.1 part of Ramosetron HCl are dissolved in 35 parts of water, use magnetic stirrer, the preparation spraying liquid (concentration of hydroxypropyl cellulose: 8 weight %).Then, 77 parts of lactose, 19 parts of corn starchs and 5 parts of CMC are added in the fluidized bed formula granulating machine (trade name: Flow Coater, produced by Freund),, carry out the liquid granulating with 10g/ minute the spray velocity above-mentioned spraying liquid of spraying.Behind the granulating, granule was placed under 40 ℃ of intake air temperature dry 5 minutes, mix with 0.3 part magnesium stearate then.With the speed of 120mg/ sheet mixed-powder is made tablet with the rotation pelleter.
Embodiment 10
0.0008 part of Ramosetron HCl
89 parts in mannitol
5 parts of propyl gallates
10 parts of maltose
1 part of magnesium stearate
Maltose (10 parts), 0.0008 part of Ramosetron HCl and 5 portions of propyl gallates are dissolved in 67 parts of water, use magnetic stirrer, preparation spraying liquid (concentration: 15 weight %).Then, 89 portions of mannitol are added in the fluidized bed formula fluidized bed formula granulating machine (Flow Coater is produced by Freund), the above-mentioned spraying liquid of spraying carries out the liquid granulating.Behind the granulating, granule was placed under 40 ℃ of intake air temperature dry 5 minutes, mix with 1 part magnesium stearate then.With the speed of 120mg/ sheet mixed-powder is made tablet with the rotation pelleter.
Test implementation example 1
To suffering from the clinical research that diarrhoea is master's large intesitine irritation syndrome patient
Carrying out under the following conditions, is that the male and female patient of main large intesitine irritation syndrome (IBS) carries out clinical research as object to suffer from diarrhoea.
Object:, suffering from the patient that diarrhoea is main IBS (D.A.Drossman, etc., 351 to 432 pages, Degnon Associates, McLean, 2000) according to the RomeII diagnostic criteria.
Case number: 418 examples
Testing drug and medication: the placebo of orally give 0.005mg or 0.01mg and Ramosetron HCl once a day continued for 12 weeks.
Test period: the treatment phase in the observation period in a week and 12 weeks
Observation item:
1, main evaluation item
(1) the alleviation situation of whole IBS symptoms is carried out net assessment (by the object assessment)
Changing the treatment after date over to, be defined as first day Start Date that gives testing drug.Weekly the alleviation situation of whole IBS symptoms is carried out net assessment, consider all IBS symptoms of object, their situation was compared with the observation period, in these evaluate recorded patients' Yu the diary.By way of parenthesis, it is as follows the alleviation situation of whole IBS symptoms to be carried out the standards of grading of net assessment.
0=is alleviated fully
1=is alleviated to a great extent
2=is alleviated a little
3=is constant
4=worsens
It is that 0 or 1 object is just done to become the every month person of responding that the scoring of 2 weeks or more time was arranged in 4 weeks, calculates the placebo of 0.005mg and 0.01mg and every month moon responder ratio of each group of Ramosetron HCl.
2, auxiliary evaluation item
(1) net assessment of abdominal discomfort/pain relief situation (by the object assessment)
Changing the treatment after date over to, be defined as first day Start Date that gives testing drug.The alleviation situation of abdominal discomfort/pain that testing drug is caused is carried out net assessment weekly, compares with the observation period, in these evaluate recorded patients' Yu the diary.By way of parenthesis, it is as follows the alleviation situation of abdominal discomfort/pain to be carried out the standards of grading of net assessment.
0=is alleviated fully
1=is alleviated to a great extent
2=is alleviated a little
3=is constant
4=worsens
(2) net assessment that unusual intestinal custom is improved (by the object assessment)
Changing the treatment after date over to, be defined as first day Start Date that gives testing drug.Weekly unusual intestinal custom was compared with the observation period, net assessment is carried out in the improvement of unusual intestinal custom, in these evaluate recorded patients' Yu the diary.By way of parenthesis, it is as follows the improvement situation of unusual intestinal custom to be carried out the standards of grading of net assessment.
0=is alleviated fully
1=is alleviated to a great extent
2=is alleviated a little
3=is constant
4=worsens
(3) order of severity of abdominal discomfort/pain
During clinical research (observation period and treatment phase), object was all assessed and was recorded in patient's diary the order of severity of abdominal discomfort/pain every day.Severity scale standard to abdominal discomfort/pain is as follows.
0=does not have discomfort/pain
Slight discomfort/the pain of 1=
2=moderate discomfort/pain
Serious discomfort/the pain of 3=
Intolerable discomfort/the pain of 4=
(4) feces type (outward appearance)
During clinical research, object all writes down its feces type (outward appearance) according to Bristol ' s feces type rank scores (type) every day in patient's diary.When defecation being arranged repeatedly or in a defecation, observe different feces types (outward appearance) in one day, only need record same day the most representative (or object sensation disagreeable) one type (outward appearance).
(5) bowel movement frequency
During clinical research, object writes down its bowel movement frequency every day in patient's diary.
(6) sense of urgency
During clinical research, object writes down in patient's diary whether sense of urgency is arranged every day.
(7) not exclusively bowel movement is felt
During clinical research, object writes down the sensation whether incomplete bowel movement is arranged every day in patient's diary.
For auxiliary evaluation item (1) to (3) item,, calculate the ratio of month responder also as main evaluation item.The result:
For the net assessment of the alleviation situation of whole IBS symptoms, a final moon responder ratio placebo group is 26.9%.On the other hand, in 0.005mg and the 0.01mg Ramosetron HCl group, the ratio of month responder is respectively 42.6% and 43.0%, and is higher more than 15% than the responder ratio of placebo group.0.005mg and the p value that 0.01mg organizes placebo group is respectively 0.0273 and 0.0264.With regard to the responder rate variance between placebo group and 0.005mg and the 0.01mg Ramosetron HCl group, between male and female patient, do not find to have any different.
For the net assessment of abdominal discomfort/pain relief situation and the net assessment that unusual intestinal custom is alleviated, 0.005mg and 0.01mg Ramosetron HCl group are better than placebo group more than 10% equally.
It seems that from The above results 0.005mg and 0.01mg Ramosetron HCl are that main large intesitine irritation syndrome patient's therapeutic effect obtains confirming for suffering from diarrhoea.What determine equally is that unlike the alosetron described in the WO99/17755, Ramosetron HCl is all effective for the men and women, and unlike the medicine described in the WO2002/007713, Ramosetron HCl is as long as administration once a day is promptly effective.
Industrial usability
According to the present invention, can provide a kind of good treatment diarrhoea to be main large intesitine irritation syndrome or to improve large intestine The syndromic preparation of excitation, said preparation is all effective for the men and women.
Claims (6)
1. pharmaceutical composition, it contains 0.001 to 0.01mg Ramosetron HCl, and perhaps the ramosetron of equimolar amounts or its pharmaceutically acceptable other salt are as active component.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, described pharmaceutical composition also comprises and is applicable to oral or through the organic or inorganic carrier and the excipient of gastrointestinal administration.
3. the described pharmaceutical composition of claim 1 is a purposes in the medicine of main large intesitine irritation syndrome in production for treating male and female patient diarrhoea.
4. the purposes of the described pharmaceutical composition of claim 1 in the medicine of the symptom of diarrhea of the male and female patient of produce to improve suffering from large intesitine irritation syndrome.
5.0.001 to the Ramosetron HCl of 0.01mg, the perhaps ramosetron of equimolar amounts or its pharmaceutically acceptable other salt are purposes in the medicine of main large intesitine irritation syndrome in production for treating male and female patient diarrhoea.
6.0.001 to the Ramosetron HCl of 0.01mg, the perhaps ramosetron of equimolar amounts or its pharmaceutically acceptable other salt, the purposes in the medicine of producing the symptom of diarrhea that improves the male and female patient of suffering from large intesitine irritation syndrome.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPPCT/JP2004/000896 | 2004-01-30 | ||
| PCT/JP2004/000896 WO2004066998A1 (en) | 2003-01-31 | 2004-01-30 | Stable solid medicinal composition for oral administration |
| JPPCT/JP2004/006657 | 2004-05-12 | ||
| PCT/JP2004/006657 WO2005073220A1 (en) | 2004-01-30 | 2004-05-12 | Remedy for irritable bowel syndrome with diarrhea |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1764453A CN1764453A (en) | 2006-04-26 |
| CN100372533C true CN100372533C (en) | 2008-03-05 |
Family
ID=34650735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005800000636A Expired - Fee Related CN100372533C (en) | 2004-01-30 | 2005-01-27 | Therapeutic formulation for mainly of diarrhea large intesitine irritation syndrome |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1559446B1 (en) |
| JP (1) | JP3763360B2 (en) |
| KR (1) | KR100746444B1 (en) |
| CN (1) | CN100372533C (en) |
| ES (1) | ES2367896T3 (en) |
| RU (1) | RU2351327C2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4632204B2 (en) * | 2005-09-21 | 2011-02-16 | アステラス製薬株式会社 | Antidiarrheal irritable bowel syndrome treatment |
| KR20110045027A (en) * | 2008-08-28 | 2011-05-03 | 아스텔라스세이야쿠 가부시키가이샤 | How to treat irritable bowel syndrome |
| KR20120111954A (en) * | 2009-06-30 | 2012-10-11 | 아스텔라스세이야쿠 가부시키가이샤 | Therapeutic agent for abnormal defecation in inflammatory bowel disease patient who is in remission phase |
| JP5938886B2 (en) * | 2010-12-14 | 2016-06-22 | アステラス製薬株式会社 | Defecation disorder therapeutic agent in active inflammatory bowel disease patients |
| JP5365949B2 (en) * | 2011-10-28 | 2013-12-11 | アステラス製薬株式会社 | Orally disintegrating tablets containing low-dose ramosetron |
| JP6355806B1 (en) * | 2017-09-04 | 2018-07-11 | 株式会社三和化学研究所 | A therapeutic agent for constipation containing lactulose as an active ingredient |
| CA3189029A1 (en) | 2020-07-21 | 2022-01-27 | Teijin Pharma Limited | Light beam irradiation apparatus |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9721139D0 (en) * | 1997-10-07 | 1997-12-03 | Glaxo Group Ltd | Medicaments |
| US6566369B2 (en) * | 2000-07-26 | 2003-05-20 | Solvay Pharmaceuticals Gmbh | Medicament containing cilansetron for the treatment of non-obstipative male irritable bowel syndrome patients |
-
2004
- 2004-05-12 JP JP2004141975A patent/JP3763360B2/en not_active Expired - Lifetime
-
2005
- 2005-01-27 KR KR1020057016208A patent/KR100746444B1/en active Protection Beyond IP Right Term
- 2005-01-27 CN CNB2005800000636A patent/CN100372533C/en not_active Expired - Fee Related
- 2005-01-31 EP EP05001928A patent/EP1559446B1/en not_active Not-in-force
- 2005-01-31 ES ES05001928T patent/ES2367896T3/en active Active
-
2007
- 2007-05-22 RU RU2007119067/15A patent/RU2351327C2/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| Usefulness of 5-HT3 receptor antagonists in irritablebowelsyndrome -Pharmacological profile oframosetronhydrochloride-. 平田等.细胞，第35卷第10期. 2003 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2367896T3 (en) | 2011-11-10 |
| KR20060052661A (en) | 2006-05-19 |
| JP3763360B2 (en) | 2006-04-05 |
| RU2007119067A (en) | 2008-11-27 |
| EP1559446A1 (en) | 2005-08-03 |
| JP2005213244A (en) | 2005-08-11 |
| RU2351327C2 (en) | 2009-04-10 |
| CN1764453A (en) | 2006-04-26 |
| KR100746444B1 (en) | 2007-08-03 |
| EP1559446B1 (en) | 2011-07-13 |
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