Pharmaceutical composition for the treatment of chronic constipation

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for treating chronic constipation.[Background]

[0002] Constipation is a disorder accompanied with unpleasant symptoms such as dyschesia, feeling of incomplete evacuation, and abdominal pain due to decrease of stool frequency, decrease of quantity per bowel movement, and hardening of stool. Treatment has been conducted focusing on the improvement in diet and lifestyle, self-medication by commercial products, and drugs in a medical institution as countermeasures for constipation.

[0003] MOVICOL (Norgine Co., Ltd) has been known as a therapeutic drug for constipation. MOVICOL includes macrogol 3350 (European pharmacopoeia), sodium chloride, sodium bicarbonate, and potassium chloride and elicits an effect by increasing the stool volume through accumulating water in the colon and retaining the water of the colon. The administration period of MOVICOL is usually considered to be two weeks. Document CINCA R ET AL: "Randomised clinical trial: macrogol / PEG 3350+electrolytes versus prucalopride in the treatment of chronic constipation - a comparison in a controlled environment", ALIMENTARY PHARMACOLOGY & THERAPEUTICS, BLACKWELL SCIENTIFIC PUBLICATIONS LTD., CAMBRIDGE, GB, vol. 37, no. 9, 11 March 2013 (2013-03-11), pages 876-886, DOI: 10.1111 / APT.12278 discloses a study treatment with two sachets Movicol (PEG 3350+E, which means PEG3350 plus electrolytes, 13.13g), administered in a dosage adapted according to the aspect of the stool calculated based on the Bristol stool Chart: see page 878, left column, "study treatment".[Summary of Invention][Technical Problem]

[0004] The present invention is concerned with providing a pharmaceutical composition that can be used to treat chronic constipation even in long-term administration.[Means for Solving the Invention]

[0005] As a result of the investigation conducted by the inventors, they have found that using a pharmaceutical composition including polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride can show effectiveness for chronic constipation even in extremely long-term administration, and they have devised the present invention.

[0006] The present invention consists of the following embodiments. (1) In the first embodiment of the invention, there is provided a pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 2 sachets once a day; b) increasing or decreasing the dose by 2 sachets per day, after assessment of the stool; (i) wherein when the stool on the Scale is 1 or 2, or no defecation has occurred in a day then the dose is increased, every other day, up to a maximum of 6 sachets per day, wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); or wherein if 6 sachets the dose is administered as 2 sachets x 1 time and 4 sachets x 1 time (morning and evening); (ii) wherein when the stool on the Scale is 3, 4 or 5, the dose is not changed; and (iii) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued. (iv) wherein following discontinuation of the administration, if the stool on the Scale is 3 or more then the discontinuation is maintained or if the stool on the Scale is 1 or 2 or no defecation for 1 day, resume above administration regimen starting with 2 sachets per day. wherein the patient is aged 15 years or above, and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251g (2) In a second embodiment of the invention there is provided a pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 2 sachets once a day; b) increasing or decreasing the dose by 2 sachets per day, after assessment of the stool; i) wherein when the stool on the Scale is 1 or 2, then the dose is increased, every other day, up to a maximum of 6 sachets per day, wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); or wherein if 6 sachets the dose is administered as 2 sachets x 1 time and 4 sachets x 1 time (morning and evening); (ii) wherein when the stool on the Scale is 3, 4 or 5, the dose is not changed; and (iii) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued; wherein the patient is aged 12 to 14 years old and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251 g. (3) In a third embodiment of the invention there is provided a pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 1 sachet once a day (age 2 to 6 years) or 2 sachets per day (age 7 to 11 years); b) increasing or decreasing the dose by 1 sachet per day, after assessment of the stool; i) wherein when the stool on the Scale is 1 or 2, then the dose is increased, every other day, up to a maximum of 4 sachets per day, wherein if 1 sachet, the dose is 1 sachet once a day;] wherein if 2 sachets the dose is 2 sachets once a day wherein if 3 sachets, the dose is 1 sachet x 1 time and 2 sachets x 1 time (morning and evening; or wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); (ii) wherein when the stool on the Scale is 3 or 4, the dose is not changed or increased by 1 sachet if there is pain or anal bleeding during defecation; (iii) wherein when the stool on the Scale is 5, the dose is decreased by 1 sachet per day, and (iv) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued. wherein the patient is aged between 2 and 11 years, and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251 g. (4) A pharmaceutical composition, as defined above, for treating chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride and used to treat patients with chronic constipation over a long period of treatment including once or multiple administration periods. (5) The pharmaceutical composition according to any of (1) to (4), wherein the dosage is increased when the stool is separate hard lumps (stage 1), or is sausage-shaped, but lumpy (stage 2) (6) The pharmaceutical composition according to any of (1) to (5), wherein the dosage is decreased when the stool is a mushy stool (stage 6), or watery stool (stage 7). (7) The treatment period includes one or more discontinuation periods. The pharmaceutical composition according to any of (1) to (6), wherein each discontinuation period is set during each administration period. (8) The pharmaceutical composition according to (7), wherein the discontinuation period is started when the stool is a mushy stool (stage 6) or watery stool (stage 7). (9) The pharmaceutical composition according to (8), wherein the discontinuation period is ended when the stool is separate hard lumps (stage 1), or sausage-shaped, but lumpy (stage 2), or when there is no daily bowel movement. (10) The pharmaceutical composition according to (1) wherein the chronic constipation is functional chronic constipation. (11) The pharmaceutical composition according to (1), wherein the chronic constipation is not symptomatic chronic constipation, chemical chronic constipation, constipation-predominant irritable bowel syndrome, or organic chronic constipation. (12) The pharmaceutical composition according to (11), wherein the symptomatic chronic constipation is caused by Parkinson's disease or multiple sclerosis. (7) The pharmaceutical composition according to any of (1) to (9), wherein the chronic constipation is not constipation caused by organic disease.[Effect of the Invention]

[0007] According to the present invention, a pharmaceutical composition is provided that can be used to treat chronic constipation even in long-term administration. Moreover, a pharmaceutical composition is provided which is used to treat chronic constipation that can be stopped or prevented from reoccurring depending on the patient's symptoms.[Brief Description of Drawings]

[0008] [Fig. 1] Fig. 1 shows the transition of spontaneous bowel movement frequency. [Fig. 2] Fig. 2 shows the transition of complete spontaneous bowel movement frequency. [Fig. 3] Fig. 3 shows the transition of percentage of the responder in spontaneous stool frequency and complete spontaneous bowel movement frequency. [Fig. 4] Fig. 4 shows the number of days until the first manifestation of spontaneous bowel movement. [Fig. 5] Fig. 5 shows the transition of percentage of patients using relief drugs. [Fig. 6] Fig. 6 shows the transition of the median of stool hardness based on the Bristol Stool Scale. [Fig. 7] Fig. 7 shows the percentage when the stool hardness scale is divided into 3 classifications based on the Bristol Stool Scale. [Fig. 8] Fig. 8 shows the illustration describing the relationship with the condition of stool and the method of administration. [Mode for Implementing the Invention]

[0009] The first embodiment of the present invention relates to a pharmaceutical composition for treating chronic constipation containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride and is used to treat patients with chronic constipation over a long period of treatment including one or multiple administration periods.

[0010] So far, polyethylene glycol preparations have been used as a therapeutic drug for chronic constipation, but the administration period was basically two weeks. Consulting a doctor in long-term dosing has not been required and no specific examinations have been performed related to long-term dose. Note that long-term dose generally means taking for a long time continuously every day, and the setting of discontinuation period, resuming the treatment period after the discontinuation period, and also the obtaining of an equivalent effect have not been thought about at all until now.

[0011] Even if the pharmaceutical composition according to this embodiment is given for a long time (while repeating discontinuation and resumption), its effect is not attenuated. In addition, high safety is secured for long-term dosage. Furthermore, even if a discontinuation period is set during the treatment period, the adverse effects do not occur because of this, and the effect and safety can be maintained by restarting administration the same as before discontinuation.

[0012] The polyethylene glycol contained in the pharmaceutical composition according to the present embodiment is preferably macrogol, and more preferably macrogol 3350 (European Pharmacopoeia) or macrogol 4000 (Japanese Pharmacopoeia). But these can be changed and can be used because there is no basic difference between macrogol 3350 (European Pharmacopoeia) and macrogol 4000 (Japanese Pharmacopoeia).

[0013] It is preferable that the pharmaceutical composition according to the present embodiment be wrapped individually.

[0014] It is preferable that the pharmaceutical composition according to the present embodiment be dissolved in water before administering. The quantity of water to dissolve one sachet of the pharmaceutical composition is preferably 20-150 ml, more preferably 40-100 ml, and even more preferably 60-70 ml.

[0015] The pharmaceutical composition according to the present embodiment shows an effect depending on the quantity and not on the density of polyethylene glycol to be administered. Therefore, as for dosing method of the pharmaceutical composition according to the present embodiment can be indicated with, for example, "Administer by dissolving in approximately 1 / 3 cup of water (approximately 60 ml) per 1 sachet. Moreover, administer 2 sachets by dissolving in approximately 120 ml of water, and 180 ml of water in the case of 3 sachets." or "If administration is difficult due to taste, it can be administered by dissolving it in other drinks like apple juice or cold drinks." In addition, it is preferably indicated with "This medicine is administered by dissolving it in water but, the water at this time will become a stool without mostly being absorbed by the body. Therefore, it is vital to drink an adequate quantity of water other than this solution."

[0016] "Treatment" in the present specification means to suppress the symptoms of chronic constipation and / or to cure chronic constipation.

[0017] The pharmaceutical composition according to the present embodiment is used in treating patients with chronic constipation for over a long treatment period. "Treatment period" in the present specification is the period where the administration period is combined with discontinuation periods set as needed. When setting of a discontinuation period is not required, the treatment period corresponds to the administration period. The "Administration Period" in the present specification is the period when the pharmaceutical composition according to the present embodiment is administered. The "Discontinuation Period" in the present specification is the period when the pharmaceutical composition of this present embodiment is not administered.

[0018] The administration period includes one or multiple administration periods. On the other hand, the discontinuation period includes one or multiple discontinuation periods. It is preferable that the discontinuation period be set between each administration period. For example, when a discontinuation period is set once, it is preferable that the treatment period sequentially contain a first administration period, first discontinuation period, and second administration period. If two discontinuation periods are set, the treatment period shall preferably sequentially contain the first administration period, first discontinuation period, second administration period, second discontinuation period, and third discontinuation period.

[0019] The effect of the pharmaceutical composition according to the present embodiment is not attenuated even over a long administration period. In other words, a stable effect is shown over the long term. In addition, high safety is secured even if the administration period extends over the long term.

[0020] The pharmaceutical composition according to the embodiment can be administered until the chronic constipation is cured. Although there is no upper limit to the administration period, the upper limit may be set, for example, to 50 years, 40 years, 30 years, 20 years, 10 years, 8 years, 6 years, 4 years, 2 years, and 1 year because it is generally difficult to completely cure chronic constipation in adults.

[0021] It is preferable to adjust the dosage of the pharmaceutical composition according to the present embodiment depending on the state of the stool classified in 7 stages as shown below. Stage 1: Separate hard lumps Stage 2: Sausage-shaped, but lumpy Stage 3: Cracks on its surface Stage 4: Smooth and banana-shaped Stage 5: Soft semi-solid Stage 6: Mushy stool Stage 7: Watery stool

[0022] The dosage of the pharmaceutical composition according to the present embodiment is preferably increased in the case of stage 1 or stage 2 mentioned above. Preferably, the dosage of the pharmaceutical composition according to the present embodiment is reduced in the case of stage 6 or 7.

[0023] The discontinuation period is set appropriately depending on the patient's symptoms and the number of days are stipulated appropriately. No adverse effect occurs because of this even if the discontinuation period is set during the treatment period, and the effect and safety last by restarting administration the same as before discontinuation. It is preferable that the discontinuation period start when the stage is at stage 6 or 7. It is preferable to end the discontinuation period when the stage is at stage 1 or 2. In addition, it is preferable that the discontinuation period end when there's no daily bowel movement.

[0024] The dosage of the pharmaceutical composition according to the present embodiment can be adjusted depending on the Bristol stool scale. Preferably the dosage of the pharmaceutical composition according to the present embodiment is increased when the Bristol stool scale is 1 or 2, and preferably the dosage of the pharmaceutical composition according to the present embodiment is reduced when the Bristol stool scale is 5-7 (particularly, if 6 or 7).

[0025] It is preferable to start the discontinuation period when the Bristol stool scale is 6 or 7. Preferably, the discontinuation period is ended when the Bristol stool scale is 1 or 2. In addition, it is preferable to end the discontinuation period when there is no daily bowel movement.

[0026] The Bristol stool scale is an index to prescribe the state of the stool by its shape and hardness, and it is stipulated as follows. Scale 1: Separate hard lumps, like nuts (hard to pass) Scale 2: Sausage-shaped but lumpy (massive) Scale 3: Sausage-shaped but with cracks on the surface ____ Scale 4: Sausage or snake-like, smooth and soft Scale 5: Soft blobs with clear-cut edges (easy to pass) Scale 6: Fluffy pieces with ragged edges, mushy stool Scale 7: Watery, no solid pieces

[0027] For example, functional chronic constipation, symptomatic chronic constipation, chemical chronic constipation, and organic chronic constipation are cited as chronic constipation. Functional chronic constipation may be the subject of the pharmaceutical composition according to the present embodiment. Symptomatic chronic constipation, constipation-predominant irritable bowel syndrome, chemical chronic constipation, and organic constipation may be excluded as subjects of the pharmaceutical composition according to the present embodiment. For example, chronic constipation caused by Parkinson's disease and multiple sclerosis are cited as symptomatic chronic constipation. While on the other hand, chronic constipation caused by opioid and psychotropic drugs are cited as chemical constipation. Constipation caused by organic disease may also be excluded as subjects of the pharmaceutical composition according to the present embodiment.

[0028] The patient is preferably human. For example, patients ages 2-6 years old, 7-11 years old, 12 years and above, or 15 years and above. The human patients may be male or female.

[0029] The pharmaceutical composition according to the present invention is preferably taken orally.

[0030] In order to understand the usage of the pharmaceutical composition according to the present invention, it is convenient to have an illustration listing the relationship of the stool condition to the administration method. For example, the illustration mentioned in Fig. 8 classifies the condition of the stool into 7 stages with letters and drawings, and lists the administration methods at every stage. Such an illustration is convenient when the patient themselves take the medication and when the doctor is giving instruction. The illustration can be included in various things (for example, booklets, deskpads).[Examples]

[0031] Hereinafter, the present invention will be described in more detail by using examples.<Therapeutic Drug>

[0032] A therapeutic drug containing the following ingredients was prepared in one sachet. Macrogol 3350 (European Pharmacopoeia) (6.5625 g) Sodium chloride (0.1754 g) Sodium bicarbonate (0.0893 g) Potassium chloride (0.0251 g) Example 1<Subjects>

[0033] 153 patients with chronic constipation (15 years old and above).

[0034] About 85% of patients suffered from chronic functional constipation, and the rest suffered from constipation-predominant irritable bowel syndrome.<Dosage and Administration>

[0035] Starting with an administration of 2 sachets a day, depending on the condition of the subject, the dosage was adjusted based on the following Dosage Adjustment Standard. Dosage increases and decreases were carried out in units of 2 sachets, and the upper limit of dosing was set to 6 sachets per day. The timing of administration was once a day or twice a day according to the dosage below, and in the case of twice a day administration, it was in the morning and evening. If 2 sachets: 2 sachets once a day If 4 sachets: 2 sachets twice a day (morning and evening) If 6 sachets: (2 sachets × 1 time, 4 sachets × 1 time) a day (morning and evening) <Dosage Adjustment Standard>

[0036] If the Bristol stool scale is 1 or 2, or if there is no defecation in a day, increase the dosage every other day until it reaches a Bristol stool scale of 3 or 4.

[0037] If the Bristol stool scale is 3, 4 or 5, do not change the dosage.

[0038] If the Bristol stool scale is 6 or 7, reduce dose by 2 sachets or discontinue the administration. If there is no defecation for 1 day, or even if there was, if the Bristol stool scale is 1 or 2 after the discontinuation of administration, resume from 2 sachets once a day as starting dosage. If the Bristol stool shape scale is 3 or more, continue the suspension of the administration.<Clinical Trial Procedure (Drug discontinuation standard)>

[0039] If the frequency of complete spontaneous bowel movement (CSBM) 2 weeks prior to the hospital visit is 6 or more, reduce the dosage by 2 sachets or discontinue the administration. If the frequency of spontaneous bowel movement (SBM) in one week becomes less than three times after the suspension of administration, resume the administration at the dose before the suspension.<Results>

[0040] The results of the long-term administration of the therapeutic drug are shown on the table below. "Spontaneous bowel movement (SBM)" is defecation not induced by laxatives or due to enema or stool extraction. "Complete spontaneous bowel movement (CSBM)" refers to spontaneous bowel movement without the sensation of incomplete evacuation. "Responder" means a subject whose defecation frequency per week improved to more than once since before the drug administration, and defecates three times or more. "Rescue medication" means bisacodyl suppository (10 mg), and it is used when defecation is not observed for more than 72 consecutive hours.

[0041] As shown in Table 1, a stable SBM frequency was confirmed from Week 2 to Week 52.(Table 1)

[0042] Table 1Treatment PeriodNo. of Subjects (n)SBM Frequency (Average value ±Standard deviation)Week 11534.50±2.37Week 21535.86±2.88Week 41505.45±2.78Week 121476.04±2.48Week 241385.99±2.82Week 361326.05±3.45Week 481305.92±2.60Week 52815.78±2.42

[0043] As shown in Table 2, a stable total bowel movement frequency was confirmed from Week 2 to Week 52.(Table 2)

[0044] Table 2Treatment PeriodNo. of Subjects (n)Total Bowel Movement Frequency (Average value ± Standard deviation)Week 11534.58±2.31Week 21535.90±2.83Week 41505.48±2.74Week 121476.05±2.48Week 241386.00±2.81Week 361326.06±3.45Week 481305.92±2.60Week 52815.83±2.46

[0045] As shown in Table 3, it was confirmed that the proportion of SBM frequency of responders was kept high from Week 1 to Week 52.(Table 3)

[0046] Table 3Treatment PeriodPercentage of SBM Frequency of RespondersWeek 178.4%Week 288.9%Week 481.3%Week 1291.2%Week 2488.4%Week 3692.4%Week 4890.8%Week 5288.9%

[0047] As shown in Table 4, it was confirmed that the usage rate of rescue medication was kept low from Week 2 to Week 52.(Table 4)

[0048] Table 4Treatment PeriodUsage Status of Rescue MedicationWeek 16.5%Week 22.6%Week 43.3%Week 120.7%Week 240.7%Week 360.8%Week 480.8%Week 520.8%

[0049] As shown in Tables 5 and 6, it was confirmed that the improved stool hardness was stably maintained from Week 1 to Week 52.(Table 5)

[0050] Table 5Treatment PeriodNo. of Subjects (n)Bristol Stool Scale (Median ± Standard deviation)Week 11483.93±1.25Week 21524.36±1.06Week 41504.11±1.08Week 121474.12±0.95Week 241373.94±1.03Week 361314.07±0.81Week 481304.07±0.89Week 52814.11±0.91 (Table 6)

[0051] Table 6Treatment PeriodNo. of Subjects (n)Bristol Stool Scale (Average value ± Standard deviation)Week 11483.93±1.07Week 21524.40±0.94Week 41504.23±0.98Week 121474.24±0.82Week 241374.00±0.93Week 361314.11±0.74Week 481304.11±0.81Week 52814.15±0.81

[0052] As shown in Table 7, it was confirmed that the number of administered sachets of the therapeutic drug was stable from Week 1 to Week 52. Furthermore, the number of administered sachets at Week 52 is few compared to the other weeks, but this is due to the non-inclusion of the number post-hospital visit sachets with regard to subjects who came to the hospital before day 7 of week 52.(Table 7)

[0053] Table 7Treatment PeriodNo. of Subjects (n)No. of Administered Therapeutic Drug Sachets (Average value ± Standard deviation)Week 115321.5±7.3 sachetsWeek 215324.3±12.1 sachetsWeek 415221.7±13.4 sachetsWeek 1214722.6±13.3 sachetsWeek 2413922.0±13.9 sachetsWeek 3613320.9±13.2 sachetsWeek 4813020.8±13.3 sachetsWeek 5211815.7±13.4 sachets

[0054] As shown in Table 8, a discontinuation period was set during the treatment period as necessary.(Table 8)

[0055] Table 8No. of Subjects (n)Discontinuation Period (Average value ± Standard deviation)Discontinuation due to improvement in symptoms2360.2±84.1 daysDiscontinuation due to all reasons14355.2±80.4 days

[0056] Table 9 shows the No. of sachets used and the SBM frequency at -8 to -14 days (2 weeks before) and -1 to -7 days (1 week before) before the start of discontinuation period, as well as at 1 to 7 days (1 week after), 8 to 14 days (2 weeks after), and 15 to 21 days (3 weeks after) after the end of discontinuation period, and then Table 10 shows the SBM frequency per sachet of the drug. Table 11 shows the percentage of the SBM frequency per 1 sachet of the drug after 1 week, 2 weeks, and 3 weeks with regards to the average value of SBM frequency per 1 sachet of the drug at 1 week and 2 weeks before. If the percentage is close to 1, it indicates that there was no change in efficacy before and after the drug discontinuation period. As shown in Table 11, the percentages after 1 week, 2 weeks, and 3 weeks were 0.95, 1.08, and 1.21, respectively, which were values close to 1.(Table 9)

[0057] Table 9No. of Sachets UsedSBM FrequencyBefore discontinuationAfter resumptionBefore discontinuationAfter resumption2 weeks before1 week before1 week after2 weeks after3 weeks after2 weeks before1 week before1 week after2 weeks after3 weeks afterAverage value141314131266666Maximum value42384242421717121415Minimum value2222221111 (Table 10)

[0058] Table 10SBM Frequency per 1 sachetDiscontinuation PeriodBeforeAfter Resumption2 weeks before1 week before1 week after2 weeks after3 weeks afterAverage value0.630.580.540.620.64Maximum value3.002.752.004.004.00Minimum value0.070.100.070.130.14 (Table 11)

[0059] Table 11SBM Frequency After Resumption / SBM Frequency Before Discontinuation1 week after2 weeks after3 weeks afterAverage value0.951.081.21Maximum value4.575.766.83Minimum value0.200.210.19

[0060] As shown in Tables 12 to 14, the sodium (Na), potassium (K), and chloride (Cl) in the blood were stable from week 4 to week 52, no symptoms such as dehydration were observed, and it was confirmed that it was excellent in safety. The standard value for sodium concentration in blood is 136 to 147 mEq / L. The standard value for potassium concentration in blood is 3.6 to 5.0 mEq / L. The standard value for chloride concentration in blood is 98 to 109 mEq / L. (Table 12)Table 12: Sodium within the bloodTreatment PeriodBefore TreatmentLowWithin standardHighWeek 4After TreatmentLow000Within standard01350High000Week 12After TreatmentLow010Within standard01450High000Week 24After TreatmentLow000Within standard01380High000Week 36After TreatmentLow000Within standard01310High000Week 52After TreatmentLow010Within standard01260High000The numbers in the table indicate the number of subjects. (Table 13) Table 13: Potassium Concentration in BloodTreatment PeriodBefore TreatmentLowWithin standardHighWeek 4After TreatmentLow210Within standard11234High022Week 12After TreatmentLow000Within standard31355High030Week 24After TreatmentLow230Within standard11253High040Week 36After TreatmentLow030Within standard31193High030Week 52After TreatmentLow130Within standard21142High041 The numbers in the table indicate the number of subjects. (Table 14) Table 14: Chloride Concentration in BloodTreatment PeriodBefore TreatmentLowWithin standardHighWeek 4After TreatmentLow000Within standard11232High081Week 12After TreatmentLow000Within standard11403High020Week 24After TreatmentLow000Within standard11342High010Week 36After TreatmentLow100Within standard01272High010Week 52After TreatmentLow000Within standard11211High031 The numbers in the table indicate the number of subjects. Example 2<Subjects>

[0061] 39 patients (2 to 14 years old) with chronic constipation.<Dosage and Administration>(1) For 2 to 11 years old

[0062] The dose at the start was 1 sachet once a day for patients aged 2 to 6, and 2 sachets once a day for patients aged 7 to 11, and then the dose was adjusted according to the condition of the patient. Dose increases were made in units of 1 sachet a day, and the upper limit of dosage was set to 4 sachets per day. The timing of administration was once a day or twice a day according to the dosages below, and in the case of twice a day administration, it was in the morning and evening. If 1 sachet: 1 sachet once a day If 2 sachets: 2 sachets once a day If 3 sachets: (1 sachet × 1 time, 2 sachets × 1 time) / day (morning and evening) If 4 sachets: 2 sachets twice a day (morning and evening) (2) For 12 to 14 years old

[0063] Starting with administration of 2 sachets a day, the dosage was adjusted depending on the condition of the patient. Dose increases and decreases were made in units of 2 sachets a day, and the upper limit of dosage was set to 6 sachets per day. The timing of administration was once a day or twice a day according to the dosages below, and in the case of twice a day administration, it was in the morning and evening. If 2 sachets: 2 sachets once a day If 4 sachets: 2 sachets twice a day (morning and evening) If 6 sachets: (2 sachets × 1 time, 4 sachets × 1 time) a day (morning and evening) <Results>

[0064] Fig. 1 shows the transition of SBM Frequency.

[0065] Fig. 2 shows the transition of CSBM frequency.

[0066] Fig. 3 shows the transition of percentage of responders in the SBM Frequency and CSBM Frequency.

[0067] Fig. 4 shows the number of days until the first manifestation of SBM.

[0068] Fig. 5 shows the transition of the percentage of patients using rescue medication.

[0069] Fig. 6 shows the transition of the median of stool hardness based on Bristol stool scale.

[0070] Fig. 7 shows the percentage if the stool hardness scores are classified into three groups based on the Bristol stool scale.

Claims

1. A pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 2 sachets once a day; b) increasing or decreasing the dose by 2 sachets per day, after assessment of the stool; (i) wherein when the stool on the Scale is 1 or 2, or no defecation has occurred in a day then the dose is increased, every other day, up to a maximum of 6 sachets per day, • wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); or • wherein if 6 sachets the dose is administered as 2 sachets x 1 time and 4 sachets x 1 time (morning and evening); (ii) wherein when the stool on the Scale is 3, 4 or 5, the dose is not changed; and (iii) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued. (iv) wherein following discontinuation of the administration, if the stool on the Scale is 3 or more then the discontinuation is maintained or if the stool on the Scale is 1 or 2 or no defecation for 1 day, resume above administration regimen starting with 2 sachets per day. wherein the patient is aged 15 years or above, and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251g2. A pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 2 sachets once a day; b) increasing or decreasing the dose by 2 sachets per day, after assessment of the stool; (i) wherein when the stool on the Scale is 1 or 2, then the dose is increased, every other day, up to a maximum of 6 sachets per day, • wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); or • wherein if 6 sachets the dose is administered as 2 sachets x 1 time and 4 sachets x 1 time (morning and evening); (ii) wherein when the stool on the Scale is 3, 4 or 5, the dose is not changed; and (iii) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued; wherein the patient is aged 12 to 14 years old and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251 g.

3. A pharmaceutical composition for use in the treatment of chronic constipation characterized by containing polyethylene glycol, sodium chloride, sodium bicarbonate, and potassium chloride, wherein the composition is administered according to the following dosage adjustment regimen, wherein stool is assessed using the Bristol Stool Scale: a) a starting dose of 1 sachet once a day (age 2 to 6 years) or 2 sachets per day (age 7 to 11 years); b) increasing or decreasing the dose by 1 sachet per day, after assessment of the stool; (i) wherein when the stool on the Scale is 1 or 2, then the dose is increased, every other day, up to a maximum of 4 sachets per day, • wherein if 1 sachet, the dose is 1 sachet once a day; • wherein if 2 sachets the dose is 2 sachets once a day • wherein if 3 sachets, the dose is 1 sachet x 1 time and 2 sachets x 1 time (morning and evening; or • wherein if 4 sachets the dose is 2 sachets twice a day (morning and evening); (ii) wherein when the stool on the Scale is 3 or 4, the dose is not changed or increased by 1 sachet if there is pain or anal bleeding during defecation; (iii) wherein when the stool on the Scale is 5, the dose is decreased by 1 sachet per day, and (iv) wherein when the stool on the Scale is 6 or 7, the dose is reduced by 2 sachets or dosing is discontinued. wherein the patient is aged between 2 and 11 years, and wherein the composition of the sachet is the following: Macrogol6.5625 gSodium chloride0.1754 gSodium bicarbonate0.0893 gPotassium chloride0.0251 g.

4. The pharmaceutical composition for use according to Claim 3 wherein the patient is aged between 2 and 6 years.

5. The pharmaceutical composition for use according to Claim 3 wherein the patient is aged between 7 and 11 years.

6. The pharmaceutical composition for use according to Claim 1 wherein the chronic constipation is chronic functional constipation.

7. The pharmaceutical composition for use according to Claim 1 wherein the chronic constipation is constipation-predominant irritable bowel syndrome.