Magnesium oxide-containing pharmaceutical composition for treating pediatric chronic functional constipation

Abstract

To provide a pharmaceutical composition with which an adequate constipation treatment success rate is achieved in pediatric constipation patients aged 1 to 5.SOLUTION: A pharmaceutical composition is for treating constipation and contains magnesium oxide as an active ingredient, the pharmaceutical composition being characterized in being orally administered twice a day to pediatric patients aged 1 to 5 and having a body weight of 7.5 kg or above, so that the daily dose of magnesium oxide is 25 to 45 mg / kg.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for treating chronic functional constipation in children, which contains magnesium oxide as an active ingredient. [Background technology]

[0002] Chronic functional constipation in children is said to be "high in frequency, and does not necessarily have a good prognosis if appropriate treatment is not given early." Because the continuation of chronic functional constipation is accompanied by pain and distress, children hold in their bowels to avoid the pain and distress they feel when defecating. This leads to the formation of hard stools and loss of the urge to defecate, further worsening chronic constipation. For the above reasons, it is desirable to relieve chronic functional constipation as soon as possible.

[0003] The periods and triggers when children are susceptible to developing constipation include weaning, toilet training, and school age, with the peak incidence occurring during the toilet training period between the ages of 2 and 4. It has been pointed out that repeated unpleasant bowel movements during this period may lead to children avoiding bowel movements, whether consciously or unconsciously.

[0004] According to the Guidelines for the Treatment of Chronic Functional Constipation in Children compiled by the Japanese Society of Pediatric Gastroenterology and Hepatology and the Japanese Society for Pediatric Gastrointestinal Function, more than 40% of children diagnosed with constipation at age four or younger continue to experience symptoms of constipation even when they reach school age, despite treatment with fecal block removal, laxatives, and dietary fiber intake.

[0005] The prognosis for pediatric chronic functional constipation is significantly worse when the patient is older than 2 years old at the first visit, and about 25% of children with constipation who visit the hospital at age 5 or older progress to adult constipation.Furthermore, factors that contribute to a poor prognosis include a long period from onset to the first visit and a low number of bowel movements at the time of the first visit.

[0006] According to the above guidelines, malt extract, lactulose, sodium picosulfate, bisacodyl, and glycerin are used as drugs for chronic functional constipation in children in Japan. Of these, malt extract, lactulose, and sodium picosulfate can be administered orally. Overseas, polyethylene glycol has been found to be an oral drug, and in recent years, drugs containing polyethylene glycol have been approved in Japan (Non-Patent Document 1).

[0007] In Japan, the drug therapy for pediatric chronic functional constipation is generally started with an osmotic laxative. Of lactulose, sodium picosulfate, and polyethylene glycol, which are approved as oral medical drugs, lactulose and polyethylene glycol can be selected. The dosage forms of these drugs are syrup and powder for lactulose and powder for oral liquid for polyethylene glycol, and lactulose powder is the only medical drug that can be orally administered as a solid preparation.

[0008] The approved dosage of lactulose powder is 0.33-1.30g / kg per day, orally administered in three divided doses. The single dose for children aged 1 year or older and weighing 10kg or more is high, at 1.1-4.3g, and younger children often complain of difficulty in taking the dose due to the large dose, and it is not easy to increase or decrease the dose depending on symptoms.

[0009] Meanwhile, the most frequently used constipation medication in Japan is magnesium oxide powder. Although there is little evidence among various constipation medications, its effectiveness and safety are considered clear when administered in appropriate amounts. The Guidelines for the Treatment of Chronic Functional Constipation in Children also list magnesium oxide powder as a frequently used constipation medication.

[0010] Magnesium oxide is available for medical and general use, but both are used mainly by adults, especially the elderly. The medical version is not suitable for children, but the general version can be taken from the age of 5, with 0.33 to 0.66 g orally taken once a day before bedtime. For medical use to treat constipation, adults should take 2 g per day in magnesium oxide equivalent, orally in three divided doses before or after each meal, or once before bedtime. However, the dosage and administration for children has not been approved.

[0011] A document comparing the effectiveness of approved lactulose and unapproved magnesium oxide (Non-Patent Document 2) discloses the success rate of constipation treatment for children aged 15 years or younger who were diagnosed with chronic constipation, particularly for children with a median age of 2 years and 11 months who were analyzed. The success rate of constipation treatment was reported to be significantly higher in the unapproved magnesium oxide group, at 41% (20 out of 49 cases) in the magnesium oxide group and 18% (9 out of 50 cases) in the lactulose group. However, it cannot be said that either of these drugs provides sufficient treatment for chronic functional constipation in children.

[0012] The dosage of magnesium oxide for infants aged 1 year and over has not been determined, but in the above-mentioned document (Non-Patent Document 2) which compared its effectiveness with lactulose, magnesium oxide was administered at a dose of 50.0 mg / kg per day. The number of times it is divided is also unclear, but the dosage for adults is generally followed, and the above-mentioned document (Non-Patent Document 2) also divides it into two doses per day, just like adults. Since the treatment subjects are children aged 1 to 5 years, it is rarely administered in a form that is difficult to take, and powders or liquids are generally prescribed (Non-Patent Document 3), and the above-mentioned document (Non-Patent Document 2) also administers magnesium oxide bulk powder.

[0013] On the other hand, in patients who have used medical magnesium oxide, there have been reports of hypermagnesemia in which serum magnesium levels are abnormally high after oral administration of magnesium oxide, and in severe cases, hypermagnesemia can lead to death, and caution is advised when using it. In general, impaired renal function is pointed out as the reason for abnormal elevation of serum magnesium levels. It has been suggested that in children with normal renal function, elevation of serum magnesium levels is minor and does not pose a clinical problem. However, because treatment of children with chronic functional constipation is long-term (Non-Patent Document 4), attention is paid to the dosage of magnesium oxide powder. Therefore, the treatment provided by magnesium oxide must be effective in a short period of time.

[0014] In order to prevent abnormally high serum magnesium levels, it is recommended to reduce the dosage of magnesium oxide powder. However, by reducing the dosage, the powder becomes difficult to handle, and the therapeutic effect on children with chronic functional constipation is significantly reduced, resulting in a longer treatment period. As a result, in order to improve the pain and distress during defecation, difficulty in defecation, and irregular defecation habits that are the causes of constipation, drug therapy must be continued for at least several months (Non-Patent Document 5).

[0015] Although it has been suggested that increasing the dosage of magnesium oxide powder may have a therapeutic effect, the increased dosage may lead to medication aversion and abnormally high serum magnesium levels, and there may be a risk of diarrhea.

[0016] It has been shown that children aged 1 to 2 years do not take tablets, and powders also have problems when taken (Non-Patent Document 6). Therefore, in the treatment of children with constipation aged 1 to 5 years, if a dosage form and an appropriate dosage that allow continued appropriate medication can be determined, it will be possible to enjoy the maximum therapeutic effect without worrying about hypermagnesemia. As a result, children with constipation will be relieved from pain and distress during defecation as quickly as possible, and early relief will lead to a good prognosis and prevent the transition to adult constipation.

[0017] The present applicant has conducted various studies on magnesium oxide preparations for treating chronic functional constipation. For example, as magnesium oxide preparations with high disintegrating properties for improving the ease of administration, they have developed a tablet in which water-suspended particles are made fine by adjusting the type, blending ratio, and manufacturing method of a disintegrant (Patent Document 1), a tablet in which the average secondary particle size of magnesium oxide particles and the types and amounts of binder and disintegrant added are adjusted to improve tableting properties and disintegration properties (Patent Document 2), and a fine granule preparation in which the average secondary particle size and apparent specific volume of magnesium oxide particles are adjusted and the solubility and texture are improved by granulating with a sugar alcohol and a disintegrant (Patent Document 3). [Prior art documents] [Patent documents]

[0018] [Patent Document 1] International Publication No. 2020 / 101016 [Patent Document 2] Patent No. 4015485 [Patent Document 3] International Publication No. 2010 / 098417 [Non-patent literature]

[0019] [Non-Patent Document 1] Guidelines for the Treatment of Chronic Functional Constipation in Children, 2013 Edition [Non-Patent Document 2] Outpatient Pediatrics, 19(2), 141-148, 2016 [Non-Patent Document 3] YAKUGAKU ZASSHI, 135(2), 2015, 245-247 [Non-Patent Document 4] Journal of the Japanese Society of Pediatric Gastroenterology and Hepatology, 29, Suppl., 2015, 126 [Non-Patent Document 5] Journal of the Japanese Society of Pediatric Surgeons, 49(3), 2013, 835 [Non-Patent Document 6] Reflection Paper, Formulations of choice for the Pediatric Population, EMA, 28 July 2006 Summary of the Invention [Problem to be solved by the invention]

[0020] An object of the present invention is to provide a pharmaceutical composition that achieves a sufficient success rate in treating constipation in children aged 1 to 5 years old suffering from constipation. [Means for solving the problem]

[0021] The present inventors have intensively studied the appropriate dosage form in order to explore the possibility of using magnesium oxide preparations for the treatment of chronic functional constipation in pediatric patients. As a result, they have found that by lowering the daily dosage of magnesium oxide from the conventionally known 50.0 mg / kg (Non-Patent Document 2), not only the risk of side effects can be reduced, but also, unexpectedly, the success rate of treatment can be significantly improved. Furthermore, as a result of examining the preferable dosage form, etc., they have found that by making the magnesium oxide into tablets or fine granules, which are generally not suitable for children, instead of the conventionally known magnesium oxide bulk powder (Non-Patent Document 2), it is possible to improve the compliance rate and further improve the success rate of treatment. Based on the above findings, the present inventors have completed the present invention.

[0022] That is, the gist of the present invention relates to, for example, the following. [Item 1] A pharmaceutical composition for treating constipation, comprising magnesium oxide as an active ingredient, the pharmaceutical composition being orally administered twice daily to a pediatric patient weighing 7.5 kg or more and aged 1 to 5 years, so that the daily dosage of magnesium oxide is 25 to 45 mg / kg. [Item 2] The pharmaceutical composition according to Item 1, which is in the form of a tablet or fine granules. [Item 3] The pharmaceutical composition according to Item 1 or 2, wherein the twice-daily administration is after breakfast and after dinner. [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, wherein the number of units administered per day is 2n units, and the composition is administered in divided doses of n units after breakfast and n units after dinner. [Item 5] The pharmaceutical composition according to any one of Items 1 to 3, wherein the number of units administered per day is 2n+1 units, and the composition is orally administered in a divided dose of n units after breakfast and n+1 units after dinner. [Item 6] The pharmaceutical composition according to any one of Items 1 to 5, wherein the constipation is chronic functional constipation. [Item 7] Use of magnesium oxide for preparing the pharmaceutical composition according to any one of items 1 to 6. [Item 8] A method for treating constipation in a patient, the method comprising administering to a patient in need thereof a pharmaceutical composition containing magnesium oxide as an active ingredient, the patient being a pediatric patient weighing 7.5 kg or more and aged 1 to 5 years, and the pharmaceutical composition being orally administered twice a day so that the daily dosage of magnesium oxide is 25 to 45 mg / kg. [Item 9] The method according to Item 8, wherein the pharmaceutical composition is in the form of a tablet or fine granules. [Item 10] The method according to Item 8 or 9, wherein the pharmaceutical composition is administered twice a day, after breakfast and after dinner. [Item 11] The method according to any one of Items 8 to 10, wherein the number of units of the pharmaceutical composition administered per day is 2n units, and the composition is administered in divided doses, that is, n units after breakfast and n units after dinner. [Item 12] The method according to any one of Items 8 to 11, wherein the number of units of the pharmaceutical composition administered per day is 2n+1 units, and the composition is orally administered in a divided form into n units after breakfast and n+1 units after dinner. [Item 13] The method according to any one of Items 8 to 12, wherein the constipation is chronic functional constipation. Effect of the Invention

[0023] According to the present invention, there is provided a pharmaceutical composition that realizes a sufficient success rate of treating constipation in children aged 1 to 5 years old suffering from constipation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments, and can be implemented in any form within the scope of the present invention. In addition, the various aspects of the present invention described below are not alternative or exclusive, and can be implemented by appropriately combining any two or more aspects, except in cases where there is a clear logical contradiction. In addition, an aspect in which any two or more aspects are appropriately combined is naturally included in the scope of the present invention. In addition, when multiple upper limits and / or multiple lower limits are indicated for a numerical range, all numerical ranges obtained by combining any upper limit among the upper limits and any lower limit among the lower limits are included in the scope of the present invention.

[0025] [Pharmaceutical composition] In one aspect, the present invention provides a pharmaceutical composition containing magnesium oxide as an active ingredient for treating pediatric patients with constipation. According to one aspect, the constipation to be treated by the pharmaceutical composition of the present invention is preferably chronic constipation, more preferably chronic functional constipation. As mentioned above, the use of magnesium oxide preparations has not been approved for the treatment of children who have developed chronic constipation. On the other hand, there are clinical cases in which magnesium oxide powder is prescribed based on the doctor's judgment for off-label use. However, it is presumed that from the viewpoint of cost-effectiveness, no pharmaceutical manufacturer would have chosen to go to the trouble of conducting clinical trials to obtain the indication of magnesium oxide tablets. The present inventors have first found the findings of the present invention, which examine specific aspects of magnesium oxide in the treatment of pediatric chronic functional constipation and provide various preferred aspects. These findings are of great significance in the treatment of pediatric patients with constipation, preferably pediatric patients with chronic functional constipation.

[0026] The pharmaceutical composition of the present invention is administered to a pediatric patient weighing 7.5 kg or more and aged 1 to 5 years at a daily dose of 25 to 45 mg / kg of magnesium oxide. The above-mentioned Non-Patent Document 2 is the only known report on the measurement of the effect of administration of magnesium oxide to a pediatric patient with chronic functional constipation. The above-mentioned Non-Patent Document 2 shows a 41% success rate of treatment when pediatric patients with chronic functional constipation are administered magnesium oxide powder at a dose of 50 mg / kg of body weight per day. Usually, in order to increase the success rate of treatment, an increase in the daily dose is attempted. In the present invention, it has been found that by significantly reducing the daily dose (from 50 mg / kg body weight per day to 25 to 45 mg / kg body weight), not only the risk of side effects is reduced, but also the success rate of treatment can be significantly improved from an early stage. Such an effect is a surprising finding that far exceeds the level that a person skilled in the art would expect based on common sense.

[0027] According to one embodiment, the pharmaceutical composition of the present invention is preferably in the form of a tablet or fine granules containing magnesium oxide. Usually, for the treatment of children aged 1 to 5 years, tablets or fine granules that are difficult to take are not selected, and powders or liquids are prescribed (Non-Patent Document 6). In the only known report, Non-Patent Document 2, mentioned above, bulk magnesium oxide powder is also used. However, in the present invention, in addition to the reduction in the daily dose mentioned above, the use of tablets or fine granules as the dosage form can improve the compliance rate. This enables continuous compliance with medication, and thus a high treatment success rate can be achieved even with short-term administration. In this way, by adopting tablets or fine granules, a compliance rate similar to or higher than that of conventional powders or liquids can be achieved, which is a surprising finding that far exceeds the level that a person skilled in the art can expect based on common sense. The present invention provides a pharmaceutical composition having excellent therapeutic effect and compliance.

[0028] As mentioned above, the present applicant has been conducting various studies on magnesium oxide preparations for treating chronic functional constipation, and has developed a tablet containing 100 mg per tablet (Patent Document 1), a tablet containing 200 mg per tablet (Patent Document 2), and a fine granule containing 83% per gram (Patent Document 3) as magnesium oxide preparations with high disintegrability to improve ingestibility. By utilizing the knowledge of these tablets and fine granules, it is possible to prepare tablets and fine granules that are easy to take even for children aged 1 to 5 years. In addition, for children who have particular difficulty in swallowing due to illness, a method of disintegrating and suspending tablets in water and administering the dispersion through a feeding tube is considered. Specific examples of such tablets and fine granules will be described later.

[0029] According to one embodiment, the pharmaceutical composition of the present invention is orally administered in two divided doses per day. According to one embodiment, the two doses per day are preferably administered after breakfast and after dinner. According to one embodiment, the number of units administered per day of the pharmaceutical composition of the present invention is 2n units, and it is preferably divided into n units administered after breakfast and n units administered after dinner. According to one embodiment, the number of units administered per day of the pharmaceutical composition of the present invention is 2n+1 units, and it is preferably divided into n units administered after breakfast and n+1 units administered after dinner. In this way, when the number of units administered per day is an odd number (2n+1), allocating the number of units administered after dinner to be greater provides the effect of magnesium oxide, which has a medicinal effect time of 6 to 8 hours, after waking up, which is advantageous in that more appropriate bowel habits can be obtained. It is considered desirable to have a bowel habit in the morning.

[0030] [Childhood chronic functional constipation] As mentioned above, the subject of treatment with the pharmaceutical composition of the present invention is constipation in pediatric patients, and it is particularly preferable to treat chronic functional constipation. Chronic functional constipation in children is constipation or its symptoms caused by stool retention or difficulty in passing stool in children, and is not organic constipation, but requires medical examination and treatment. The internationally used diagnostic criteria for chronic functional constipation in children are the ROMEIV criteria. The ROMEIV criteria are diagnostic criteria for chronic functional constipation used internationally, and chronic functional constipation is suspected when the following criteria are met.

[0031] <Infants / Toddlers> For children under 4 years of age (infants or toddlers), at least two of the following must be met for a period of at least one month. 1: Fewer than two bowel movements per week 2: History of excessive stool retention 3. History of painful or hard bowel movements 4. History of giant stools 5: Presence of a large stool mass in the rectum Toilet trained children add to above 6: After acquiring toilet skills, fecal incontinence occurs at least once a week 7. History of stools large enough to clog the toilet

[0032] <School children / youth> Children (school children) and adolescents aged 4 years or older must have at least two of the following symptoms at least once a week for a minimum of one month, but must not meet the diagnostic criteria for irritable bowel syndrome. 1: Defecating in the toilet less than twice a week 2: Fecal incontinence at least once a week 3: History of stool holding or excessive spontaneous stool retention 4. History of painful or hard bowel movements 5: Presence of a large stool mass in the rectum 6. History of stools large enough to clog the toilet 7: After appropriate evaluation, the symptoms cannot be explained by another medical condition.

[0033] In addition, the condition of the stool is evaluated when determining whether or not the patient has chronic functional constipation according to the Bristol Fecal Scale, which is an index used to evaluate the condition of the stool and classifies the stool into the following seven stages based on its shape and hardness. 1: Hard stool (rabbit droppings-like stool) 2: Hard stool (sausage-like hard stool) 3: Slightly hard stool (sausage-like stool with cracks on the surface) 4: Normal stool (smooth, soft, semi-solid stool) 5: Slightly soft stool (soft, wrinkled, semi-solid stool) 6: Muddy stool (irregularly shaped pieces or muddy stool) 7: Watery stool (liquid stool containing no solid matter)

[0034] Diagnosis of constipation involves asking each item in the ROMEIV criteria to confirm whether or not the patient is constipated.

[0035] The goal of treatment for chronic functional constipation in children is to achieve or return to a state free of constipation and to maintain it, preferably as diagnosed by the ROME IV criteria.

[0036] The effectiveness of treatment is determined when the patient and their caregivers understand the pathology of constipation, desirable dietary habits and bowel movements, and are unable to achieve or maintain a constipation-free state even with drug treatment. Treatment is deemed ineffective.

[0037] [Composition and manufacturing method of the formulation] The dosage form of the pharmaceutical composition of the present invention is not limited, but as described above, it is preferably a tablet or fine granules. As described above, the present applicant has conducted various studies on magnesium oxide preparations for treating chronic functional constipation, and has developed, as magnesium oxide preparations with high disintegrability for improving ingestibility, a tablet in which water-suspended particles are refined by adjusting the type, blending ratio, and manufacturing method of disintegrant (Patent Document 1), a tablet in which the average secondary particle size of magnesium oxide particles and the type and amount of binder and disintegrant are adjusted to improve tableting and disintegration properties (Patent Document 2), and a fine granule in which the average secondary particle size and apparent specific volume of magnesium oxide particles are adjusted and granulated with sugar alcohol and disintegrant to improve solubility and texture (Patent Document 3). By utilizing the knowledge of these tablets and fine granules, it is possible to prepare tablets and fine granules that are easy to take even for children aged 1 to 5 years.

[0038] Hereinafter, various dosage forms of the pharmaceutical composition of the present invention will be described, mainly in the case of tablets and fine granules, but the dosage form of the pharmaceutical composition of the present invention is not limited to these specific dosage forms. In the following description, any dosage form of the pharmaceutical composition of the present invention will be collectively referred to as the "preparation of the present invention", and among them, the tablet or fine granule formulation may be individually referred to as the "tablet of the present invention" and the "fine granule of the present invention", respectively.

[0039] Magnesium oxide: The magnesium oxide particles contained in the preparation of the present invention have, for example, an elemental composition represented by the following composition formula (1), but are not limited thereto. Also, for example, the magnesium oxide is specified in the Japanese Pharmacopoeia, but are not limited thereto. (Mg 2+ 1-X Zinc 2+ X )O (1)

[0040] In the above formula, X is usually a number from 0 to 0.02. Magnesium oxide particles with X exceeding 0 are not a mixture of magnesium oxide and zinc, but have zinc atoms inserted into the crystal structure of magnesium oxide, and have the same crystal structure as magnesium oxide. These magnesium oxide particles show the same diffraction pattern as magnesium oxide according to powder X-ray diffraction. X is usually a number of 0 or more, or 0.001 or more, or 0.005 or more, and usually 0.02 or less, or 0.015 or less, or 0.01 or less. If X is large, it may exceed the required amount as an essential mineral, together with Zn ingested from food.

[0041] The volume-based 50% particle diameter (D 50 ) is not limited, but may be, for example, usually 0.1 μm or more, or 0.5 μm or more, or 1 μm or more, and usually 25 μm or less, or 20 μm or less, or 18 μm or less, or 15 μm or less, or 10 μm or less. In particular, in the case of fine granules, if the particle size of the magnesium oxide particles is too large, the disintegration time becomes long and the particles may not disperse quickly in the oral cavity.

[0042] Magnesium oxide volumetric 50% particle size (D 50 ) is measured by the following method. 0.7 g of magnesium oxide and 70 mL of 0.2% sodium hexametaphosphate aqueous solution are added to a beaker, and a dispersion process is performed using an ultrasonic homogenizer (US-300, manufactured by Nippon Seiki Co., Ltd.). The volume-based 50% particle diameter (D 50 ) is measured.

[0043] The apparent specific volume of the magnesium oxide particles contained in the formulation of the present invention is not limited, but can be, for example, usually 3 mL / g or more, or 4 mL / g or more, and usually 20 mL / g or less, or 15 mL / g or less, particularly in the case of fine granules. If the apparent specific volume of the magnesium oxide particles is too small, particularly in the case of fine granules, the dissolution may be poor. On the other hand, if the apparent specific volume of the magnesium oxide particles is too large, the bulk may increase and granulation may be difficult.

[0044] The magnesium oxide particles contained in the preparation of the present invention can be produced, for example, by calcining magnesium hydroxide particles. The specific procedure is, for example, as follows, for example, but is not limited to the following. The magnesium hydroxide particles as the raw material can be produced, for example, by precipitating magnesium ions in seawater or bittern as magnesium hydroxide using an alkali source, for example, but is not limited to the above. Examples of such alkali sources include, but are not limited to, calcium hydroxide, caustic soda, potassium hydroxide, lithium hydroxide, and aqueous ammonia. Of these, caustic soda or calcium hydroxide is preferred. The precipitated magnesium hydroxide is subjected to a heat treatment, for example, at 100 to 120°C, and then subjected to calcination. The calcination conditions are, for example, but are not limited to, a temperature of usually 500°C or higher, or 600°C or higher, and usually 1,000°C or lower, and especially 900°C or lower, for example, usually for 0.1 to 10 hours. If the calcination temperature is too high or the calcination time is too long, the magnesium oxide particles may become hard and may have poor disintegrability.

[0045] Magnesium oxide particles in which zinc (Zn) is dissolved in magnesium oxide can be produced by adding an alkaline substance in an amount approximately equal to or less than the total equivalent of these cations to an aqueous solution containing magnesium ions and zinc (Zn) ions, and reacting them under stirring. If necessary, the reaction product may be further subjected to hydrothermal treatment using an autoclave at 100 to 200°C. Thereafter, like magnesium oxide, it can be adjusted by washing with water, dehydrating, drying, and then calcining, and by appropriately carrying out conventional means such as pulverization and classification. The supply source of magnesium ions is not limited, but for example, magnesium nitrate, magnesium chloride, etc. can be used. The supply source of zinc (Zn) ions is not limited, but for example, zinc nitrate, zinc chloride, etc. can be used. The alkaline substance is not limited, but for example, sodium hydroxide, etc. can be used.

[0046] Binder: The formulation of the present invention may contain a binder. The binder is not limited to, but may be, for example, crystalline cellulose, sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, starch (e.g., corn starch), sugar alcohol, etc. Any one of these may be used alone, or two or more may be used in any combination and ratio. The timing of addition is not important. The content of the binder in the formulation of the present invention is not limited to, but may be, for example, in the case of tablets, usually 1% by mass or more, or 3% by mass or more, and usually 15% by mass or less, or 13% by mass or less.

[0047] Disintegrants: The formulation of the present invention may contain a disintegrant. The disintegrant is not limited to, but may be, for example, starch, croscarmellose sodium, crospovidone low-substituted hydroxypropylcellulose, carmellose calcium, carmellose, sodium carboxystarch, insoluble polyvinylpyrrolidone, etc. Any one of these may be used alone, or two or more may be used in any combination and ratio. The content of the disintegrant in the formulation of the present invention is not limited to, but may be, for example, usually 0.5% by mass or more, or 1% by mass or more, and usually 10% by mass or less, or 7% by mass or less.

[0048] The volume-based 50% particle size (D 50 ) is not limited to, but may be, for example, typically 0.1 μm or more, or 0.5 μm or more, or 1 μm or more, and typically 150 μm or less, or 100 μm or less, or 25 μm or less, or 15 μm or less, or 10 μm or less.

[0049] The volume-based 50% particle size (D 50 ) is measured using a laser diffraction scattering type particle size distribution measuring device (Seishin Enterprise, LMS-2000e). No dispersion medium is used for particle size distribution measurement, and the volume-based 50% particle diameter (D 50 ) is measured.

[0050] ·lubricant: The preparation of the present invention may contain a lubricant, particularly in the case of tablets. The lubricant is not limited to, but may be, for example, stearic acid and its salts (Na, Mg, Ca salts). Among them, calcium stearate is preferred. Any one of these may be used alone, or two or more may be used in any combination and ratio. The content of the lubricant in the tablet of the present invention is not limited to, but may be, for example, usually 0.2% by mass or more, or 0.5% by mass or more, or 0.7% by mass or more, and usually 3% by mass or less, or 2% by mass or less, or 1.5% by mass or less.

[0051] Sugar alcohols: The preparation of the present invention, particularly in the case of fine granules, may contain a sugar alcohol. Examples of sugar alcohols that can be used include, but are not limited to, xylitol, erythritol, sorbitol, mannitol, etc. Among these, mannitol is preferred. Any one of these may be used alone, or two or more may be used in any combination and ratio. The content of sugar alcohol in the fine granules of the present invention is not limited, but may be, for example, usually 2% by mass or more, 5% by mass or more, or 6% by mass or more, and usually 15% by mass or less, 10% by mass or less, or 9% by mass or less.

[0052] Other Ingredients: The formulation of the present invention may contain other additional components depending on the dosage form. These additional components may be used alone or in any combination and ratio of two or more. Examples include sweeteners, flavoring powders, and flavoring agents. Examples of sweeteners include, but are not limited to, aspartame, acesulfame potassium, sucralose, and the like. Examples of flavoring powders include, but are not limited to, peppermints, L-menthol, orange powder, strawberry essence, and the like. Examples of flavoring agents include, but are not limited to, sucrose, mannitol, sorbitol, and the like. The content of other components in the formulation of the present invention is, but is not limited to, for example, usually 0.05% by mass or more, or 0.1% by mass or more, or 0.2% by mass or more, and usually 2% by mass or less, or 1% by mass or less, or 0.5% by mass or less.

[0053] Manufacturing method for tablets and granules: The preparation of the present invention may be produced by any method, and an appropriate method may be selected according to the dosage form. The following mainly describes the case of tablets and fine granules, but the method of producing the preparation of the present invention is not limited to these.

[0054] When the preparation of the present invention is made into a tablet, a raw material mixture for tableting is first prepared. The raw material mixture can be prepared by appropriately mixing, in addition to magnesium oxide particles, which is an active pharmaceutical ingredient, for example, a part or all of the binder and disintegrant, and optionally other additional ingredients. For mixing, a mixer such as a container type, V type, or W type can be used. Then, the raw material mixture is granulated into granular particles. Such granulation can be carried out, for example, using a dry granulator. An example of a dry granulator is a roll molding type dry granulator. In this case, the roll pressure can be, for example, usually 3 MPa or more, particularly 4 MPa or more, and usually 12 MPa or less, or 8 MPa or less. The granulated sheet-like molded product is then pulverized to obtain granular particles. For pulverization, for example, an oscillator type pulverizer can be used. The screen attached to the oscillator is not limited, but can have an opening of, for example, usually 0.7 mm or more, or 0.8 mm or more, and usually 1.2 mm or less, or 1.0 mm or less. The size of the granular particles is not limited, but may be, for example, an average particle size of 0.25 to 0.4 mm, an apparent density of 0.5 to 0.7 g / mL, and an angle of repose of 35 to 43°.

[0055] The granular particles can be mixed with a lubricant, optionally with the remainder of the binder and disintegrant, and optionally with other additional components, as necessary, and then compressed into tablets. The punch pressure per tablet can be, for example, usually 5 kN or more, or 6 kN or more, and usually 12 kN or less, or 10 kN or less. Any punch pressure can be selected according to the shape of the punch and die and the unit mass of one tablet. The shape of the tableting punch can be any of R-face, R-corner, flat corner, round corner, and the like. The diameter of the tablet is not limited, but can be, for example, usually 4 mm or more, or 5 mm or more, and usually 12 mm or less, or 10 mm or less, or 8 mm or less. The thickness of the tablet is not limited, but can be, for example, usually 2 mm or more, or 2.5 mm or more, and usually 6 mm or less, or 5 mm or less, or 4.5 mm or less. The mass of each tablet is not limited, but can be, for example, usually 50 mg or more, 70 mg or more, or 90 mg or more, and usually 300 mg or less, 280 mg or less, or 250 mg or less. By setting the size and mass of the tablet within the above ranges, the tablet can be made easy for children to swallow.

[0056] On the other hand, when the preparation of the present invention is to be a fine granule preparation, a raw material mixture for granulation is first prepared. The raw material mixture can be prepared by appropriately mixing, in addition to magnesium oxide particles, which is an active pharmaceutical ingredient, for example, the above-mentioned binder and disintegrant, and optionally sugar alcohol and other additional ingredients. For mixing, a mixer such as a container type, V type, or W type can be used. Then, the raw material mixture is granulated into granular particles. Such granulation can be carried out, for example, using a dry granulator. An example of a dry granulator is a roll molding type dry granulator. In this case, the roll pressure is not limited, but can be, for example, usually 3 MPa or more, particularly 4 MPa or more, and usually 12 MPa or less, or 8 MPa or less. The granulated sheet-like molded product is then pulverized to obtain granular particles. For pulverization, for example, an oscillator type pulverizer can be used. The screen attached to the oscillator is not limited, but may have an opening of, for example, typically 0.7 mm or more, or 0.8 mm or more, and typically 1.2 mm or less, or 1.0 mm or less. The size of the granular particles is not limited, but may have an average particle size of, for example, 0.25 to 0.4 mm, an apparent density of, for example, 0.5 to 0.7 g / mL, and an angle of repose of, for example, 35 to 43°.

[0057] The granular particles are classified, for example, using a vibrating sieve (for example, 0.15 mm or 0.5 mm) to obtain an average particle size (X 50) is, for example, 0.2 mm to 0.4 mm, or 0.25 mm to 0.35 mm. The bulk density of the fine granules is not limited, but can be, for example, usually 0.4 g / mL or more, or 0.5 g / mL or more, and usually 0.7 g / mL or less, or 0.65 g / mL or less, or 0.6 g / mL or less. The particle size distribution of the fine granules is not limited, but, for example, the ratio of particles having a particle diameter of 355 μm or more and less than 500 μm can be usually 30 mass% or more, or 32 mass% or more, and usually 45 mass% or less, or 42 mass% or less, the ratio of particles having a particle diameter of 180 μm or more and less than 355 μm can be usually 40 mass% or more, or usually 50 mass% or less, or 49 mass% or less, and the ratio of particles having a particle diameter of 150 μm or more and less than 180 μm can be usually 10 mass% or more, and usually 28 mass% or more, or 27 mass% or more. The resulting granules can be mixed with other ingredients in a container or mixer, if desired. Among them, a small amount of peppermint cortone or L-menthol adsorbed on hydrous silicon dioxide is used as a flavoring powder to improve the taste.

[0058] When the formulation of the present invention is made into a tablet or fine granules, for children who have difficulty swallowing due to illness, the formulation of the present invention may be suspended in water and administered through a feeding tube. For feeding tube administration to children, it is preferable to use a 3 Fr (outer diameter 1.0 mm) or 4 Fr (outer diameter 1.3 mm) feeding tube depending on the body weight. The average particle size generated when the formulation of the present invention is suspended in water is not limited, but can be, for example, as follows. The volume-based 50% particle size (D 50 The volume-based 90% particle diameter (D) of the formulation of the present invention measured by a laser diffraction method can be, for example, 70 μm or less, or 60 μm or less, or 50 μm or less, and can be, for example, 20 μm or more, or 30 μm or more, or 40 μm or more. 90) can be, for example, 130 μm or less, 120 μm or less, or 110 μm or less, or, for example, 50 μm or more, 60 μm or more, or 70 μm or more. By setting the suspension particle size of the formulation within the above range, tube administration using a tube feeding tube becomes possible even for children who have difficulty swallowing, and a higher intake rate can be achieved.

[0059] When the preparation of the present invention is made into a tablet or fine granule, the volume-based 50% particle size (D 50 ) and volume-based 90% particle size (D 90 ) is measured by the following method. Ten tablets of the formulation and 40 mL of ion-exchanged water are added to a beaker, and the tablets are disintegrated and suspended using a glass rod. The volume-based 50% particle diameter (D 50 ) and the volume-based 90% particle size after suspension in water (D 90 ) is measured.

[0060] ·others: The composition and manufacturing method of the preparation of the present invention have been described above mainly using tablets and fine granules as examples, but for further details, reference can be made to the descriptions in, for example, the above-mentioned Patent Documents 1 to 3. However, the preparation of the present invention is not limited to the above explanations or the descriptions in these patent documents, and can be carried out by appropriately changing the conditions.

[0061] Moreover, the various aspects of the present invention are not limited to the above-mentioned pharmaceutical composition of the present invention and its preparation, and include various inventions that can be understood by a person skilled in the art. For example, one aspect of the present invention relates to the use of magnesium oxide in the manufacture of the above-mentioned pharmaceutical composition of the present invention for treating constipation. Another aspect of the present invention relates to a method for treating constipation, which comprises administering the pharmaceutical composition of the present invention containing magnesium oxide to a patient in need thereof. In these aspects of the present invention, the details of the composition, dosage form, physical properties, manufacturing method, etc. of the pharmaceutical composition of the present invention, the shape, physical properties, etc. of magnesium oxide as an active ingredient, the age, symptoms, weight, etc. of the patient to be administered, the patient to be treated, the dosage and administration method (dosage and method) of the pharmaceutical composition of the present invention to the patient, etc. are all as described above in detail in relation to the pharmaceutical composition of the present invention. EXAMPLES

[0062] The present invention will be described in more detail below with reference to examples. However, these examples are merely illustrative and are not intended to limit the present invention in any way.

[0063] [Example 1] In this example, the effectiveness of a tablet containing 100 mg of magnesium oxide was examined in pediatric patients aged 1 to 5 years who suffered from chronic functional constipation.

[0064] Dosage Formulation: Magnesium oxide (100 mg tablet). Prepared according to paragraphs

[0019] to

[0026] and Example 3 of Patent Document 1.

[0065] Eligible patients: 26 cases. Usage / Dosage:The number of tablets to be administered per day and the starting dose were determined according to Table 1 below, based on the patient's weight at the start of administration, so that the daily dose would be approximately 40 mg / kg as magnesium oxide. If the number of tablets to be administered per day was 2n, then n tablets would be administered after breakfast and n tablets after dinner, and if the number of tablets to be administered per day was 2n+1, then n tablets would be administered after breakfast and n+1 tablets after dinner, i.e., the tablets were to be orally administered in divided doses as shown in Table 1 below.

[0066] [Table 1]

[0067] Dose adjustment: Starting from the initial dose, the dose can be increased or decreased until an appropriate bowel movement state is achieved (spontaneous solid stool frequency of 3 or more times per week, with no persistent hard or mushy stools, and no muddy or watery stools). For patients in whom a stool mass was found before administration, administration was started after the stool mass was removed.

[0068] Treatment duration: The treatment was continued for 4 weeks. How to consider this: The frequency and nature of spontaneous bowel movements were collected using electronic or non-electronic patient diaries during the final week of treatment, and the frequency and nature of spontaneous bowel movements per week were evaluated according to the ROMEIV criteria. Four weeks later, blood samples were taken to measure serum magnesium concentrations.

[0069] Evaluation method: Summary statistics were calculated for the frequency and condition of spontaneous bowel movements during the final week (values ​​according to the Bristol Fecal Scale), the proportion of patients who did not meet the ROMEIV criteria for constipation during the final week, medication compliance rate, changes in serum magnesium concentration, and the dosage per body weight during the final week, and a statistical analysis was performed to determine the success rate of treatment. If no bowel movements were observed for 2 days, the use of bisacodyl suppositories or glycerin enemas (rescue medication) was permitted, and in order to distinguish spontaneous bowel movements, the 24 hours after using rescue medication were not counted as spontaneous bowel movements.

[0070] Table 2 shows the patient characteristics of the magnesium oxide (100 mg tablet) group.

[0071] [Table 2]

[0072] When the drug was administered continuously for 4 weeks, the number of spontaneous bowel movements during the final week was 5.0±2.8 times (95% confidence interval: 3.81 to 6.11 times), with a minimum of 1 time and a maximum of 15 times.

[0073] Table 3 shows the number of spontaneous bowel movements during the last week of each age group.

[0074] [Table 3]

[0075] When the drug was administered continuously for 4 weeks, the median stool condition (value according to the Bristol Fecal Scale) in the final week was 5.0, the minimum was 3, and the maximum was 6.

[0076] Table 4 shows the stool characteristics for the last week of each age group.

[0077] [Table 4]

[0078] During the final week of four consecutive weeks of treatment, 21 out of 26 patients (81%) did not meet the ROME IV criteria for diagnosing constipation.

[0079] The mean compliance rate over four consecutive weeks of treatment was 99%.

[0080] The serum magnesium concentration was 2.3mg / dL before the start of treatment, 2.4mg / dL after 2 weeks of treatment, and 2.4mg / dL after 4 weeks of treatment. None of the patients showed hypermagnesemia.

[0081] The dose administered during the final week of 4-week continuous administration was 32.97±7.4 mg / kg / day (maximum: 45.1 mg / kg / day, minimum: 17.1 mg / kg / day, 95% confidence interval: 30.11-35.83 mg / kg / day).

[0082] Table 5 shows the dosage administered for the final week of treatment for each age group.

[0083] [Table 5]

[0084] When patients were defined as having a bowel movement frequency of 3 or more times per week, stool quality ranging from 2 to 7, and no symptoms of encopresis, abdominal pain, pain during defecation, or bleeding during defecation, the rate of successful constipation treatment was 73% (19 out of 26 cases).

[0085] The posterior distribution of the treatment success probability can be calculated from the proportion of successful treatment cases (19 out of 26 cases were successful treatment). The posterior distribution is a distribution derived from a probability distribution (beta distribution) in Bayesian statistics by adding data to a prior distribution that represents the uncertainty of parameters. Analysis using this distribution is a scientifically valid method of combining current data with a prior distribution obtained based on previous test data. The posterior distribution makes it possible to derive the probability of future observed results. The probability that the posterior distribution of the treatment success probability would be 70% or higher was calculated using the statistical analysis software R (R version 3.4.2).

[0086] As 19 out of 26 cases were successful treatments, the prior distribution had 19 successes and 7 failures, and by combining the prior distribution and likelihood, a posterior distribution was obtained with 20 successes and 8 failures. From this posterior distribution, the probability that the posterior distribution treatment success rate was 0.7 or less was calculated to be 0.411. In other words, the probability that the treatment success rate was 70% or more was 58.9%.

[0087] Similarly, in the results of two weeks of continuous administration, the weekly spontaneous bowel movement frequency was 5.5 ± 3.3 times (95% confidence interval: 4.20 to 6.88 times), and the weekly stool condition (value according to the Bristol Fecal Scale) median was 5.2. In addition, when patients who had a bowel movement frequency of 3 times or more per week, a stool condition of 2 to 7, and no symptoms of encopresis, abdominal pain, pain during defecation, or bleeding during defecation were considered successful constipation treatment cases, the rate of successful constipation treatment cases was 73% (19 out of 26 cases). Since 19 out of 26 cases were successful treatment cases, the probability that the posterior distribution treatment success rate was 0.7 or less was 0.411, that is, the probability that the treatment success rate was 70% or more was 58.9%, and the effect was confirmed from the early stage of treatment initiation.

[0088] [Example 2] In this example, equivalence was examined in pediatric patients aged 1 to 5 years who showed efficacy in terms of bowel movements of 4 or more times per week after continuous administration of tablets containing magnesium oxide (100 mg tablets) for 8 weeks in an open-label, group-by-group comparative study in which the patients were switched to tablets containing magnesium oxide (200 mg tablets) or fine granules (83% fine granules).

[0089] Dosage Formulation: Magnesium oxide (100 mg tablet). As in Example 1 above, this was prepared according to the description in paragraphs

[0019] to

[0026] and Example 3 of Patent Document 1.

[0090] Magnesium oxide (200 mg tablet). Prepared according to the description in

[0024] to

[0029] of Patent Document 2.

[0091] Magnesium oxide (83% fine granules). Prepared according to the description in paragraph

[0005] of Patent Document 3.

[0092] Eligible patients: Magnesium oxide (100 mg tablets): 29 people Magnesium oxide (200 mg tablets): 8 people Magnesium oxide (83% granules): 21 people

[0093] Dosage and Administration: [Example 1] Similarly, the number of tablets to be administered per day and the initial dose were determined according to Table 2 above, based on the patient's weight at the start of administration, so that the daily dose would be approximately 40 mg / kg as magnesium oxide. If the daily dose of 100 mg tablets after 8 weeks of continuous administration was 4 n tablets, 2 n tablets of 200 mg tablets were administered per day, and if the daily dose of 100 mg tablets was anything other than 4 n tablets, 83% fine granules were orally administered twice a day, after breakfast and dinner, in the same amount as the 100 mg tablets (as magnesium oxide).

[0094] Treatment duration: Both the 200 mg tablet and the 83% fine granules were administered continuously for two weeks. Method of study: For the final week of the study, Spontaneous bowel movement frequency and stool characteristics were collected using electronic or non-electronic patient diaries, and the weekly number of bowel movements and stool characteristics listed in the ROMEIV criteria were evaluated.

[0095] Evaluation method: Summary statistics were calculated for the change in spontaneous bowel movements from the week before switching to the last week after switching to 100mg tablets, stool characteristics (values ​​according to the Bristol Fecal Scale), the proportion of patients who did not meet the ROMEIV criteria for constipation in the last week, and medication compliance rate, and statistical analysis was performed on the treatment success rate. As in [Example 1], if no bowel movements were observed for 2 days, the use of bisacodyl suppositories or glycerin enemas (rescue drugs) was permitted, and in order to distinguish the number of spontaneous bowel movements, the 24 hours after using rescue drugs was not counted as the number of spontaneous bowel movements.

[0096] Table 6 shows the patient characteristics of each administration group when receiving 200 mg tablets or 83% fine granules.

[0097] [Table 6]

[0098] When the drug was administered continuously for 2 weeks after switching, the frequency of spontaneous bowel movements in the final week was 5.5 ± 2.9 times (95% confidence interval: 3.05 to 7.95 times) in the 200 mg tablet group and 5.8 ± 2.3 times (95% confidence interval: 4.76 to 6.86 times) in the 83% fine granule group. The change from the frequency of spontaneous bowel movements in the week before switching to the 100 mg tablet group was 0 ± 2.2 times, and The result was -1.1±2.2 times.

[0099] Table 7 shows the number of spontaneous bowel movements during the final week for each age group in each treatment group.

[0100] [Table 7]

[0101] The median stool profile (values ​​according to the Bristol Fecal Scale) per week in the final week of treatment after switching was 4.8 in the 200 mg tablet group and 4.3 in the 83% fine granule group.

[0102] Table 8 shows the stool characteristics for the final week of each treatment period for each age group.

[0103] [Table 8]

[0104] The mean compliance rate during the two-week period following the switch was 100% in the 200 mg tablet group and 99.8% in the 83% fine granule group.

[0105] Table 9 shows the change in spontaneous bowel movement frequency during the final week after switching from the spontaneous bowel movement frequency during the week prior to switching to the spontaneous bowel movement frequency during the final week after two weeks of continuous administration, with a 95% confidence interval that meets the equivalence margin of ±2 times.

[0106] [Table 9]

[0107] The equivalence margin is a range that is considered to be equivalent in order to verify the equivalence of the effectiveness of different therapeutic drugs. In Example 2, the subjects were patients who achieved the efficacy of "four or more bowel movements per week" by administration of the 100 mg tablet, and since "two or fewer bowel movements per week" is considered to be ongoing constipation according to the ROME IV criteria, the equivalence margin was set at 2 to prevent the number of bowel movements from becoming 4 or more times per week and less than 2 times per week, and equivalence was evaluated.

[0108] Comparability evaluation showed that the 100mg tablet, 200mg tablet, and 83% fine granules had the same therapeutic effect in terms of the number of defecations. They could be taken continuously in the same dose as the 100mg tablet, and the therapeutic effect obtained was as follows: spontaneous defecation frequency of 5.5±2.9 times (95% confidence interval: 3.05-7.95 times) and median stool condition (value according to the Bristol Fecal Scale) of 4.8 in the 200mg tablet group, and spontaneous defecation frequency of 5.8±2.3 times (95% confidence interval: 4.76-6.86 times) and median stool condition (value according to the Bristol Fecal Scale) of 4.3 in the 83% fine granules group. In other words, it means that chronic functional constipation in children aged 1 to 5 years could be treated with either the tablet or fine granule form.

[0109] When constipation was considered to be successfully treated in patients who met the following criteria: bowel movements 3 or more times a week, stool quality between 2 and 7, and no symptoms of encopresis, abdominal pain, pain during defecation, or bleeding during defecation, the rates of successful constipation treatment in the 200 mg tablet group and the 83% fine granule group were 88% (7 out of 8 cases) and 95% (20 out of 21 cases), respectively.

[0110] In the 200 mg tablet group, seven out of eight cases were successful, so the prior distribution had seven successful treatments and one failure. The prior distribution and likelihood were combined to obtain a posterior distribution with eight successful treatments and two failures. From this posterior distribution, the probability that the posterior distribution probability of treatment success was 0.7 or less was calculated to be 0.196. In other words, the probability that the treatment success rate was 70% or more was 80.4%.

[0111] In the 83% fine granule group, 20 out of 21 cases were successful, so the prior distribution had 20 successful treatments and 1 failure. The prior distribution and likelihood were combined to obtain a posterior distribution with 21 successful treatments and 2 failures. From this posterior distribution, the probability that the posterior distribution probability of treatment success was 0.7 or less was calculated to be 0.004. In other words, the probability that the treatment success rate was 70% or more was 99.6%.

[0112] [Comparative Example 1] This Comparative Example shows the results of a known report evaluating the effectiveness of magnesium oxide powder in 52 children aged 15 years or younger who were diagnosed with chronic constipation according to the ROME III criteria (Non-Patent Document 2).

[0113] Magnesium oxide dosage: 49 cases Usage / Dosage: Magnesium oxide powder was orally administered at 50 mg / kg per day (maximum dose 2000 mg / day) in two divided doses.

[0114] Treatment duration: The treatment was continued for three weeks. How to consider this: The treatment was started after 3 days of fecal mass removal using glycerin enemas, and if no bowel movements were observed for 4 days, a glycerin enema was used on the 5th day. During the treatment, bowel movements frequency, stool characteristics (values ​​according to the Bristol Fecal Scale), medication compliance, and side effects were recorded using a bowel diary.

[0115] Evaluation method: The frequency and condition of bowel movements were evaluated for the second and third two weeks after administration. Bowel movements using glycerin enemas were not counted. The primary evaluations were that the frequency of bowel movements in the third week was 3 or more times per week, that the condition of the stool was 2 to 7, and that there were no symptoms of encopresis, abdominal pain, pain during defecation, or bleeding during defecation. The proportion of successful cases was evaluated.

[0116] Table 10 shows the patient characteristics of those administered magnesium oxide.

[0117] [Table 10]

[0118] When the drug was administered continuously for 3 weeks, the average number of defecations during the 2nd and 3rd two weeks after administration was 5.5±3.15 times.

[0119] When the drug was administered continuously for 3 weeks, the average stool condition (value according to the Bristol Fecal Scale) for the 2 weeks after the second and third weeks of administration was 4.90±0.91.

[0120] The compliance rate when administered continuously for three weeks was evaluated based on cases in which the patient was able to take the medication for 75% or more of the target period.

[0121] The serum magnesium concentrations of the 32 patients tested were 2.1-2.8 mg / dL at least one week after administration. None of them had hypermagnesemia.

[0122] When patients were defined as having a bowel movement frequency of 3 or more times per week, stool quality ranging from 2 to 7, and no symptoms of encopresis, abdominal pain, pain during defecation, or bleeding during defecation, the rate of successful constipation treatment was 41% (20 out of 49 cases).

[0123] As 20 out of 49 cases were successful treatments, the prior distribution had a number of successful treatments of 20 and a number of failures of 29. By combining the prior distribution with the likelihood, a posterior distribution was obtained with a number of successful treatments of 21 and a number of failures of 30. From this posterior distribution, the probability that the posterior distribution probability of treatment success is 0.7 or less is calculated to be 0.9999894. In other words, the probability that the treatment success rate is 70% or more is 0.001%. [Industrial Applicability]

[0124] INDUSTRIAL APPLICABILITY The present invention can be widely used in the treatment of pediatric constipation patients, for which effective treatments have been limited until now, and its industrial value is extremely high.

Claims

[Claim 1] A pharmaceutical composition for treating constipation, comprising magnesium oxide as an active ingredient, the pharmaceutical composition being orally administered twice a day to a pediatric patient weighing 7.5 kg or more and aged 1 to 5 years, so that the daily dosage of magnesium oxide is 25 to 45 mg / kg.

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