JP3763360B2 - Antidiarrheal irritable bowel syndrome treatment - Google Patents

Description

  The present invention relates to a pharmaceutical, particularly a therapeutic agent for diarrhea-type irritable bowel syndrome or a diarrhea symptom improving agent for irritable bowel syndrome.

Ramosetron has the chemical name (-)-(R) -5-[(1-methyl-1H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole.
Ramosetron hydrochloride is sold as an ameliorating agent for digestive symptoms (nausea and vomiting) associated with the administration of antineoplastic agents (cisplatin, etc.). It is administered intravenously once a day. (For example, see Non-Patent Documents 1 and 2)
Patent Document 1 discloses that a series of tetrahydrobenzimidazole derivatives including ramosetron and a pharmaceutically acceptable salt thereof have 5HT ₃ receptor antagonistic activity. Based on this action, it is suggested that anti-cancer drugs such as cisplatin and radiation can be used to prevent vomiting, migraine, complex headache, trigeminal neuralgia, anxiety, gastrointestinal dysfunction, peptic ulcer, irritable bowel syndrome, etc. The clinical dosage is usually 0.1 to 10 mg intravenously per day for adults and 0.5 to 50 mg orally, and it is described that this is administered once or divided into several times.

On the other hand, Patent Document 2 describes that a 5HT ₃ receptor antagonist is useful for the treatment of female non-constipated irritable bowel syndrome patients, and the therapeutically effective amount is in the range of 0.01 to 500 mg per day, preferably It is described as 0.05 to 50 mg. Specifically, as a result of a clinical trial in which allosetron 1-8 mg was administered twice daily to patients with non-constipated irritable bowel syndrome, female patients alleviated pain and discomfort compared to placebo, stool consistency, Although there was a significant improvement in the frequency of defecation and the proportion of days requiring urgent, it was described that male patients showed no significant improvement over placebo except for stool firmness.
Furthermore, Patent Document 3 describes that a 5HT ₃ receptor antagonist is useful for treating male and female irritable bowel syndrome patients by administering 1 to 16 mg three times a day.

JP-A-3-223278 Special table 2001-518495 gazette International Publication No. 2002/007713 Pamphlet "Nazea OD Tablet 0.1mg package insert" revised in April 2003 "Nazea Injection 0.3mg package insert" revised in April 2003

  The present inventors have intensively studied for the purpose of creating a novel therapeutic agent for diarrhea-type irritable bowel syndrome without a sufficiently effective therapeutic agent. The present inventors once attempted a clinical trial in which ramosetron hydrochloride was administered twice daily to patients with irritable bowel syndrome, but could not confirm a significant therapeutic effect on placebo.

The inventors of the present invention found that the therapeutically effective amount of ramosetron hydrochloride for irritable bowel syndrome is far higher than the dose of 0.1 to 0.3 mg currently used as an ameliorating agent for digestive organ symptoms induced by administration of an antineoplastic agent. The idea was that it might be a low dose. Therefore, as a result of developing a stable preparation containing extremely low dose (0.001 to 0.01 mg) of ramosetron hydrochloride and conducting a 12-week clinical trial for patients with diarrhea-type irritable bowel syndrome using such preparation, The effectiveness was confirmed and the invention was completed.
That is, the present invention relates to a therapeutic agent for diarrhea-type irritable bowel syndrome comprising as an active ingredient 0.002-0.02 mg of ramosetron hydrochloride or an equimolar amount of ramosetron or a pharmaceutically acceptable salt thereof as a daily dose. Alternatively, the present invention relates to an agent for improving diarrheal symptoms of irritable bowel syndrome, which contains 0.002 to 0.02 mg of ramosetron hydrochloride or an equimolar amount of ramosetron or other pharmaceutically acceptable salt as an active ingredient.

The present invention can provide an excellent diarrhea-type irritable bowel syndrome therapeutic agent effective for both men and women or an ameliorating agent for diarrhea symptoms of irritable bowel syndrome.
As shown in Test Example 1 described later, ramosetron hydrochloride was effective for patients with diarrhea-type irritable bowel syndrome by oral administration of 0.005 mg or 0.01 mg once daily. Moreover, since the remarkable therapeutic effect which is not different from 0.01 mg administration was obtained by 0.005 mg administration, the effectiveness can be expected even at about half this amount. In addition, the subject of Test Example 1 is a Japanese adult patient, suggesting that the optimal dose for children may be even smaller, while the optimal dose for Westerners may be double that of Japanese. This is often the case. Therefore, the particularly preferred dose of ramosetron hydrochloride is in the range of 0.002 to 0.02 mg per day, but diarrhea-type irritable bowel syndrome or irritability in the range of 0.001 to 0.05 mg per day depending on the age and ethnicity of the patient. It is thought that the diarrhea symptom can be improved.

Hereinafter, the present invention will be described in more detail.
Ramosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 1 or according thereto.
Specific examples of pharmaceutically acceptable salts of ramosetron include mineral acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apples. Examples thereof include salts with acids, fumaric acid, tartaric acid, organic acids such as methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid. Of these, commercially available ramosetron hydrochloride is preferred.
The drug of the present invention should be prepared as an oral solid preparation, oral liquid preparation, or injection according to a conventional method using an organic or inorganic carrier, excipient, or other additive suitable for oral or parenteral administration. Can do. Preference is given to oral solid preparations that can be easily taken by the patient and are convenient to store and carry. Specifically, tablets, powders, granules, fine granules, capsules, pills and the like are preferred.

In such solid preparations, the active substance is mixed with at least one inert diluent such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The composition is prepared according to conventional methods with additives other than inert diluents, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, starch, talc, Disintegrants such as calcium calcium glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid, plasticizers such as Tween 80 and triacetin, coloring such as titanium oxide and iron sesquioxide An agent may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
Alternatively, an orally disintegrating tablet such as “Nazea OD Tablet 0.1 mg” commercially available may be used. For example, according to US Pat. No. 5,466,464, US Pat. No. 5,576,014, US Pat. No. 6,589,554, WO 03/009831, WO 02/092057, orally disintegrating tablets It can be.

Since the drug of the present invention contains a very low dose of ramosetron, a preparation subjected to stabilization technology against temperature and humidity is particularly preferred.
For example, by adding a specific compound having a carbonyl group, stabilization of ramosetron against temperature and humidity can be achieved. Specific compounds having a carbonyl group are specifically aliphatic carboxylic acids, in particular saturated or unsaturated, linear or branched aliphatic mono-, di- or tri-carboxylic acids. , Aliphatic carboxylic acids having 3 to 36 carbon atoms) or esters thereof, hydroxycarboxylic acids (specifically saturated or unsaturated, linear or branched aliphatic hydroxy mono-, di- or tri-). Carboxylic acids, especially hydroxycarboxylic acids having 3 to 36 carbon atoms) or esters thereof, acidic amino acids, enolic acids, aromatic carboxyl compounds (specifically, alkyl or hydroxy groups having 1 to 4 carbon atoms are substituted) Aromatic mono-, di- or tri-carboxylic acids, especially aromatic carboxylic acids having 7 to 20 carbon atoms) or esters thereof, Substances and the like, these compounds may be appropriately used in combination of two or more.

In particular, the specific compound having a carbonyl group is preferably a hydroxycarboxylic acid or an ester thereof, a polymer substance having a carboxyl group, an aromatic carboxyl compound or an ester thereof, or an enolic acid, particularly a hydroxycarboxylic acid or an ester thereof, a carboxyl A polymer substance having a group, an aromatic carboxyl compound or an ester thereof is preferred, and a hydroxycarboxylic acid or an ester thereof, or a polymer substance having a carboxyl group is more preferred.
The aliphatic carboxylic acid is preferably maleic acid, malonic acid, succinic acid, or fumaric acid. As the hydroxycarboxylic acid, tartaric acid, malic acid and citric acid are preferable, and tartaric acid and citric acid are more preferable. The acidic amino acid is preferably glutamic acid or aspartic acid. The aromatic carboxyl compound is preferably phthalic acid or propyl gallate, and more preferably propyl gallate. Preferred as the polymer substance having a carboxyl group is carboxymethyl cellulose or alginic acid, and more preferred is carboxymethyl cellulose. Further, enolic acid is preferably ascorbic acid or erythorbic acid, and more preferably ascorbic acid.

As for the above carbonyl compounds, it has been clarified that hydrates and anhydrides having no water of crystallization, such as citric acid hydrate or citric acid anhydride, also exhibit the stabilizing effect of the present invention. A hydrate, an anhydride, or a mixture thereof is included. Further, the degree of polymerization and the molecular weight of the polymer substance are not particularly limited, but in the case of carboxymethyl cellulose, a weight average molecular weight of about 110,000 is particularly preferable, and that of alginic acid is preferably about 200,000.
The compounding amount of the compound that stabilizes ramosetron or a pharmaceutically acceptable salt thereof is not particularly limited as long as the amount can achieve stabilization. For example, it is 0.01 to 90% by weight in the formulation, preferably 0.01 to 50% by weight, and more preferably 0.1 to 10% by weight in consideration of manufacturability.

  The dose of ramosetron or a pharmaceutically acceptable salt thereof is appropriately determined depending on the individual case in consideration of the administration route, disease symptoms, age, race, sex, etc. of the administration subject. Ramosetron hydrochloride is usually administered orally in an amount of about 0.001 to 0.05 mg per day for adults, most preferably 0.002 to 0.02 mg per day, which is orally administered once a day after meals.

Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples.
Example 1
Ramosetron hydrochloride 0.02 parts Lactose 86 parts Hydroxypropyl cellulose 3 parts Tartaric acid 1 part Yellow ferric oxide 0.2 parts Titanium oxide 10 parts Light anhydrous silicic acid 0.3 parts Hydroxypropyl cellulose 3 parts, Ramosetron hydrochloride 0.02 parts and Tartaric acid 1 part in 35 parts water After stirring and dissolving using a magnetic stirrer, 10 parts of titanium oxide and 0.2 part of yellow iron sesquioxide were kneaded using a Reika machine to prepare a spray solution (hydroxypropylcellulose, concentration 8% by weight). Next, 86 parts of lactose was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), and fluidized granulation was performed by spraying the spray liquid at a spraying rate of 5 g / min. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then mixed with 0.3 part of light anhydrous silicic acid to obtain a powder.

Example 2
Ramosetron hydrochloride 0.0008 parts Mannitol 89 parts Citric anhydride 0.1 parts Maltose 10 parts Red iron sesquioxide 1 part Magnesium stearate 1 part Maltose 10 parts, Ramosetron hydrochloride 0.0008 parts and citric anhydride 0.1 part, Red iron sesquioxide 1 part A spray solution (concentration of 15% by weight) was prepared by stirring and suspending in 67 parts of water using a magnetic stirrer. Next, 89 parts of mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), and fluidized granulation was performed by spraying the spray solution at a spraying rate of 10 g / min. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine to obtain tablets having an initial hardness of about 1 kp. This was stored at 25 ° C. and a relative humidity of 75% for 18 hours, and then stored at 30 ° C. and a relative humidity of 40% for 4 hours to obtain an orally disintegrating tablet.
Example 3
In the same manner as in Example 2, the amount of citric anhydride added was changed to 0.2 part to obtain an orally disintegrating tablet.
Example 4
In the same manner as in Example 2, the amount of citric anhydride added was changed to 0.5 part to obtain an orally disintegrating tablet.

Example 5
Ramosetron hydrochloride 0.0008 parts Mannitol 89 parts Ascorbic acid 0.2 parts Maltose 10 parts Red iron sesquioxide 1 part Magnesium stearate 1 part Maltose 10 parts, Ramosetron hydrochloride 0.0008 parts, Ascorbic acid 0.2 parts, Red iron sesquioxide 1 part to 67 parts water A spray liquid (concentration 15% by weight) was prepared by stirring and suspending using a magnetic stirrer. Next, 89 parts of mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), and fluidized granulation was performed by spraying the spray solution at a spraying rate of 10 g / min. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine to obtain tablets having an initial hardness of about 1 kp. This was stored at 25 ° C. and a relative humidity of 75% for 18 hours, and then stored at 30 ° C. and a relative humidity of 40% for 4 hours to obtain an orally disintegrating tablet.
Example 6
In the same manner as in Example 5, the ascorbic acid content was changed to 0.5 part to obtain an orally disintegrating tablet.

Example 7
Ramosetron hydrochloride 0.0008 parts Mannitol 88 parts Maltose 10 parts Yellow iron sesquioxide 1 part Citric acid anhydride 0.2 parts Magnesium stearate 1 part Maltose 10 parts, Ramosetron hydrochloride 0.0008 parts, Red iron sesquioxide 1 part and Citric acid anhydride 0.2 parts A spray solution (concentration of 15% by weight) was prepared by stirring and suspending in 67 parts of water using a magnetic stirrer. Next, 88 parts of mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), the intake air temperature was 50 ° C, the spray rate was 10 g / min, and the spray / dry / shaking cycle was 15 seconds / 15 seconds / Fluidized granulation was performed by spraying the spray solution in 10 seconds. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine to obtain tablets having an initial hardness of about 1 kp. This was stored at 25 ° C. and a relative humidity of 75% for 18 hours, and then stored at 30 ° C. and a relative humidity of 40% for 4 hours to obtain an orally disintegrating tablet.

Example 8
Ramosetron hydrochloride 0.01 parts Avicel 86 parts Low substituted hydroxypropyl cellulose 10 parts Citric acid hydrate 0.5 parts Hydroxypropyl cellulose 3 parts Magnesium stearate 0.5 parts Hydroxypropyl cellulose 3 parts, Citric acid hydrate 0.5 parts, Ramosetron hydrochloride 0.01 parts The solution was stirred and dissolved in 27 parts of water using a magnetic stirrer to prepare a spray solution (hydroxypropylcellulose concentration 10% by weight). Next, 86 parts of Avicel and 10 parts of low-substituted hydroxypropylcellulose are charged into a fluidized bed granulator (product name: GPCG-5, manufactured by Paulex) and sprayed at a spray rate of 100 g / min. Fluid granulation. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then mixed with 0.5 part of magnesium stearate. The mixed powder was tableted at 100 mg per tablet using a rotary tableting machine to obtain tablets.

Example 9
Ramosetron hydrochloride 0.1 part Lactose 77 parts Corn starch 19 parts Carboxymethyl cellulose (CMC) 5 parts Hydroxypropyl cellulose 3 parts Magnesium stearate 0.3 parts Hydroxypropyl cellulose 3 parts, Ramosetron hydrochloride 0.1 part in 35 parts of water using a magnetic stirrer A spray solution (hydroxypropylcellulose concentration 8% by weight) was prepared. Next, 77 parts of lactose, 19 parts of corn starch and 5 parts of CMC acid were charged into a fluidized bed granulator (product name: FLOW COATER, manufactured by Freund Corporation) and sprayed at a spray rate of 10 g / min. Fluid granulated. After granulation, the granulated product was dried at an intake air temperature of 40 ° C. for 5 minutes, and then mixed with 0.3 part of magnesium stearate. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine to obtain tablets.

Example 10
Ramosetron hydrochloride 0.0008 parts Mannitol 89 parts Propyl gallate 5 parts Maltose 10 parts Magnesium stearate 1 part Maltose 10 parts, Ramosetron hydrochloride 0.0008 parts and 5 parts propyl gallate in 67 parts of water using magnetic stirrer and suspended A liquid (concentration 15% by weight) was prepared. Next, 89 parts of mannitol was charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), and fluidized granulation was performed by spraying the spray solution. After granulation, the granulated product was dried at an intake temperature of 40 ° C. for 5 minutes, and then 1 part of magnesium stearate was mixed. The mixed powder was tableted at 120 mg per tablet using a rotary tableting machine to obtain tablets.

Test Example 1 Clinical test for patients with diarrhea-type irritable bowel syndrome A clinical test was conducted under the following conditions for patients with diarrhea-type irritable bowel syndrome (IBS).
Subjects: Number of diarrhea-type IBS patients according to the diagnostic criteria of RomeII (DA Drossman et al., P351-432, Degnon Associates, McLean, 2000): 418 cases Study drug and administration method: placebo, ramosetron hydrochloride 0.005mg and 0.01mg Test period of oral administration once a day for 12 weeks: Observation period 1 week, treatment period 12 weeks Observation items:
1.Main evaluation items
(1) Overall improvement of IBS symptoms (subject evaluation)
After entering the treatment period, the first day of study drug administration was the first day, and subjects evaluated the overall improvement effect of IBS symptoms by study drug compared to the state of the observation period by summing up all symptoms of IBS every week And filled out a patient diary. The scores for the overall improvement effect of IBS symptoms were as follows.
0 = no symptoms, 1 = considerably improved, 2 = slightly improved, 3 = unchanged, 4 = worsened Monthly responders who scored 0 or 1 in 2 or more of the 4 weeks As a result, the monthly responder rate for each month was calculated for each group of placebo and ramosetron hydrochloride 0.005 mg and 0.01 mg.

2. Secondary evaluation items
(1) Abdominal pain / abdominal discomfort improvement effect (evaluation by test subjects)
After entering the treatment period, the study drug was started on the first day, and subjects evaluated the abdominal pain and abdominal discomfort improvement effect of the study drug every week compared to the observation period, and entered the patient diary. In addition, the evaluation score of the abdominal pain / abdomen discomfort improvement effect was as follows.
0 = no symptoms, 1 = considerably improved, 2 = slightly improved, 3 = unchanged, 4 = worsened
(2) Effect of improving bowel movement (evaluation by test subjects)
After the transition to the treatment period, the first day of study drug administration was defined as the first day, and the subjects evaluated the effect of improving the bowel movements of the study drug every week compared to the observation period, and entered the patient diary. The evaluation scores for the effect of improving bowel movement were as follows.
0 = near normal, 1 = considerably improved, 2 = slightly improved, 3 = unchanged, 4 = worse
(3) Severity of abdominal pain / abdominal discomfort During the study period (observation period and treatment period), subjects evaluated the severity of abdominal pain / abdominal discomfort on the day and filled out a patient diary. The severity scores for abdominal pain and abdominal discomfort were as follows.
0 = none, 1 = weak, 2 = moderate, 3 = strong, 4 = very strong
(4) Stool shape (property)
During the study period, subjects entered daily stool shape (property) in the patient diary using the Bristol stool shape scale score (type). If the stool was defecation multiple times a day, or if there was a stool with different stool shape (characteristics) in one stool, the subject would be the most representative (feeling the most annoying) of the day Only one shape (characteristic) was entered.
(5) Defecation frequency During the study period, subjects entered the defecation frequency of the day in the patient diary every day.
(6) Feeling of urgency During the trial period, subjects entered the patient diary every day on the presence or absence of urgency.
(7) Feeling of residual stool During the study period, subjects entered the patient diary on the presence or absence of residual stool for the day.
For the secondary endpoints (1) to (3), the monthly responder rate was calculated in the same manner as the primary endpoint.

result:
The final monthly responder rate in the overall improvement effect of IBS symptoms was 26.9% in the placebo group. On the other hand, the monthly responder rates of the ramosetron hydrochloride 0.005 mg and 0.01 mg groups were 42.6% and 43.0%, respectively, exceeding the placebo responder rate by 15% or more. The p-values for the 0.005 mg and 0.01 mg placebo groups were 0.0273 and 0.0264, respectively. The difference in responder rate between the ramosetron hydrochloride 0.005 mg and 0.01 mg groups and the placebo group did not differ between male and female patients.
In addition, the final-point monthly responder rate in the effect of improving abdominal pain / abdominal discomfort and the effect of improving bowel movement exceeded the placebo group by 10% or more in the ramosetron hydrochloride 0.005 mg and 0.01 mg groups.
Based on the above, significant therapeutic effects were confirmed for patients with diarrhea-type irritable bowel syndrome of ramosetron hydrochloride 0.005 mg and 0.01 mg. In addition, ramosetron hydrochloride is effective for both male and female patients unlike Arosetron disclosed in Patent Document 2, and it is sufficiently effective once a day unlike the drug disclosed in Patent Document 3. It was confirmed that.

Claims (2)

As a once-daily dose for Japanese adult patients,
(a) 0.005 to 0.01 mg of ramosetron hydrochloride , or
(b) A therapeutic agent for diarrhea-type irritable bowel syndrome for oral administration containing 0.005-0.01 mg of ramosetron hydrochloride and equimolar amount of ramosetron or other pharmaceutically acceptable salt as an active ingredient. As a once-daily dose for Japanese adult patients,
(a) 0.005 to 0.01 mg of ramosetron hydrochloride , or
(b) A diarrhea symptom improving agent for irritable bowel syndrome for oral administration containing 0.005-0.01 mg of ramosetron hydrochloride and equimolar amount of ramosetron or other pharmaceutically acceptable salt as an active ingredient.