JP2509594B2 - Low sodium laxative and detergent formulation - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, and in particular to the treatment of constipation and the cleaning of the colon necessary for the treatment of diagnostics or pretreatment of surgery, for example.

Background Art Constipation is a common and often important problem, and numerous treatments have been developed to date. However, none of them prove to be quite sufficient, and many have serious limitations. For example, diets (eg, increasing dietary fiber content, switching to foods that are believed to be effective in constipation), laxatives and enemas are commonly used to solve problems. There are three methods. However, these methods have significant limitations in terms of user acceptance and acceptance and gas production (eg, as a result of the metabolism of carbohydrates such as fiber and lactulose by intestinal bacteria) in order to obtain the desired effects. is there. In addition, ingestion of substances that promote bowel movements can cause damage to the surface of the intestinal mucosa, and large amounts of ingestion can cause loss of body water and electrolytes (particularly potassium ions) and possibly renal failure.

Colon cleansing is very important as a pretreatment for many diagnostics or surgery. Thorough cleaning of the colon, for example,
It is said to be "indispensable for successful diagnostic barium enema" and "one of the most important stages in the diagnosis of early stage colon cancer". Davis, GR and HR, Smith, G
astrointestinal Radiology , 8 : 173-176 (1983). Colon cleansing is also required before colonoscopy or colon surgery.

Various methods can be used to cleanse the colon, but each has significant shortcomings, or none at all. Diets, laxatives and enemas are traditionally used to cleanse the colon. For example, Thomas and his co-workers used a combination of a laxative and an enema to clarify a clarified fluid.
It was shown to be relatively successful in producing a stool-free colon by time application. Thomas, G, Gastroente
Rology , 82 : 435-437 (1982). These methods are time consuming, inconvenient and uncomfortable for the patient. Use of laxatives and enemas may result in the loss of harmful salts and water. Davis, G. et al., Gastroenterology , 78 : 991
-995 (1980).

Another method of colonic cleansing is intestinal irrigation, which can be ingested with a large amount of electrolyte solution, either by drinking or by infusion by tube. The main component of the solution is typically sodium chloride. Ingestion of the solution results in large volume-induced diarrhea, which can result in colonic clearance. Although this method is generally faster than traditional methods, it is questionable both in terms of effectiveness and cleaning safety. A significant proportion of saline-based cleaning solutions are absorbed by the user, resulting in a sharp increase in intravascular volume. Therefore, this method is not recommended for people with heart or kidney disease who cannot excrete water or salt loads. Thomas, G et al., Gastroenterology , 82 : 435−437 (1
982), Goldman, J and M, Reichelderfer, Gastrointestinal Endoscopy , 28 :
9-11 (1982), Bacterial fermentation of mannitol, a component of certain wash solutions, may rapidly produce a gas mixture in the colon.

In 1980, Davis and co-workers reported the development of a wash solution described as being associated with minimal water or electrolyte absorption or secretion. Davis, GR, etc., Ga
stroenterology , 78 : 991-995 (1980), Davis GR
And HR Smith, Gastrointestinal Radiology , 8 : 1
73-176 (1983). The basic and essential component in this solution is sodium sulfate, which is poorly absorbed. Sodium uptake is significantly reduced when sulfate is the predominant anion in the tube over chloride and bicarbonate. In addition to sodium sulfate, the solution contains sodium chloride, potassium chloride, sodium hydrogen carbonate, polyethylene glycol or mannitol and water.
Although the resulting solution has been shown to be effective in clearing the gastrointestinal tract, it has the inconvenience of preventing its use. For example, patient acceptance can be problematic because the taste of the solution is so salty.

There is a need for an effective as well as acceptable method of treating constipation. There are many methods that can be used to cleanse the colon for diagnostic or surgical pretreatment, but none are without limitations. Thus, it's safer than the methods currently available,
There is a need for effective and user-acceptable methods of colon cleansing.

DISCLOSURE OF THE INVENTION The present invention relates to prescriptions for the treatment of constipation and colon cleansing. The formulation consists of polyethylene glycol (PEG) which can be administered either alone in the treatment of constipation or in combination with an electrolyte in the aqueous solution. In intestinal lavage, PEG is administered in combination with an electrolyte in an aqueous solution. In the treatment of constipation, the polyethylene glycol solution is administered in an amount sufficient to produce soft stools. In effective cleansing of the colon,
The polyethylene glycol / electrolyte solution is administered orally or nasozastrically in an amount sufficient for rapid and thorough excretion from the gastrointestinal tract. When the electrolyte is included in the solution, it contains an amount of electrolyte that prevents the net loss of electrolyte from the body as a result of consumption of the solution. The sodium concentration of the formulations of the present invention is significantly lower than the concentration of sodium sulphate-based wash liquors currently used. As a result, the wash liquor does not taste salty like solutions based on sodium sulphate.

There are at least three important advantages to using PEG for the treatment of constipation. First, PEG is poorly or not absorbed in the gastrointestinal tract. Furthermore, it is not fermented by colonic bacteria. Therefore, PEG is a gaseous product (eg hydrogen gas) that causes discomfort to the patient (eg flatulence),
It is not metabolized to a product that is absorbed. In contrast, mannitol, which is also poorly absorbed, is fermented by colonic bacteria, some of this fermentation product is absorbed in the colon and some are gaseous. Second PE
When G is used to treat constipation, the weight of the stool continues to increase even after using PEG for 3 consecutive days. This is apparently due to the fact that PEG is not metabolized by colonic bacteria so that the bacterial count does not adaptively increase over time. Thirdly, the use of PEG does not adversely affect the intestinal mucosa.

Similarly, the fact that PEG is poorly or not absorbed in the gastrointestinal tract and is not fermented by colonic bacteria is advantageous for its use as a lavage fluid for colon cleansing. As a result, there is no sudden increase in vascular volume or potential sudden gas production.

Brief Description of the Drawings The drawing shows equilibrium electrolyte solution (BES), Golyt
Fig. 3 is a graph showing the secretion and absorption of water and electrolyte after washing with ely) (GL) or the low sodium PEG washing solution of the present invention.

Detailed Description of the Invention A sufficient amount of aqueous PEG solution to produce soft stool can be used to treat constipation. Similarly, aqueous PEG solutions can be administered orally or nasally for effective and rapid defecation of the gastrointestinal tract. In the treatment of constipation
PEG can be administered alone or in combination with an electrolyte. For effective colon clearance, PEG is administered in combination with an electrolyte. In the PEG-electrolyte formulation, the electrolyte is present in an amount sufficient to prevent the net electrolyte loss from the body. The electrolyte contained in the solution of the present invention contains sodium ion, potassium ion, chlorine ion, and hydrogen carbonate ion alone or preferably in combination. The PEG solution of PEG-electrolyte solution is Crystal Light ( ^R ), aspartam (Aspartam)
e) or other flavoring agents such as suitable flavoring agents may be included.

The sodium concentration of the formulations of the present invention is less than 100 milliequivalents / l and usually less than 75 milliequivalents / l. In one preferred embodiment, the sodium concentration is about 65 milligram equivalents / l. This is well below the sodium concentration of the two sodium sulfate-based wash solutions available now (Golytely and Colyte) (sodium concentration of these two solutions is 125 mg eq / l). is there). Due to the low sodium concentration, the solutions of the present invention are not very salty, which makes users of the currently available solutions unhappy.

According to the invention, PEG is present in the solution at 75-300 g / l. In one preferred embodiment, PEG3350 is present in water at a concentration of 105 g / l solution. The concentration of each ion is 2-100 milligram equivalents. In one preferred embodiment, the concentration of sodium ions is 65 milliequivalents / l, the concentration of chloride ions is 53 milliequivalents / l, the concentration of bicarbonate ions is 17 milliequivalents (meq) / l, and potassium is The concentration of ions is 5 meq / l.

In another preferred embodiment, PEG3350 is 1 per solution 1.
Present in water at a concentration of 20 g. In another embodiment, solution 1
On the other hand, 120 g of PEG3350 is present together with sodium ion, potassium ion, chloride ion and bicarbonate ion. The concentration of each ion is 5.0 to 50 meq / l. In a preferred embodiment, it is present in one solution in the following concentrations: sodium ion 46.6 meq, potassium ion 9.0 meq, chloride ion 35.0 meq, bicarbonate ion 20.9 meq.

The PEG solution of the present invention is prepared by combining PEG3350 with water in an amount sufficient to bring the solution to one. For example, in one example, 105 g of PEG3350 is combined with sufficient water to form Solution 1. In another example, 120 g of PEG3350 is combined with enough water to make Solution 1. If the PEG solution also contains an electrolyte, combine the above ion source (in dry form) with PEG and mix in a standard mixer. P
The EG-electrolyte solution is prepared by combining the PEG-electrolyte mixture with a sufficient amount of water to make solution 1.

In the treatment of constipation, each person receives either a PEG solution or a PEG-electrolyte solution, usually once a day with a meal.
Ingest 50-500 ml. In one preferred example, each person is P
Ingest 250 ml of either EG solution or PEG-electrolyte solution. Particularly preferred is the ingestion of 250 ml of either a PEG solution having 105 g of PEG3350 in a sufficient amount of water to make solution 1 or a PEG-electrolyte solution containing PEG3350 at the same concentration. If the solution also has electrolytes, each electrolyte is at a concentration of 2 meq / l to 100 meq / l. Use of this amount
Increase stool weight from 100g to about 300g per day, thus relieving constipation.

Administration of this amount of PEG not only creates soft stools but also increases stool water. These two changes will contribute to the solution of the constipation problem. Furthermore, PEG
Is not fermented by colonic bacteria and does not produce gases such as hydrogen gas, which can cause flatus and discomfort to the user.
In particular, when the PEG solution contains an electrolyte as described above, it does not cause a significant loss of the electrolyte from the body.

For colon cleansing, each person usually has 20-30 ml / PEG solution.
Wash at a rate of minute (1.2 to 1.8 l / hour). That is,
The solution is administered orally or nasogastrically at this rate. In the PEG-electrolyte solution, the electrolyte is 2-100me
The concentration is q / l. The total amount of solution required for colon cleansing varies from individual to individual, may be small for some, and may be large for some, but is usually 3-4 liters.
Will. In one example, each person has 120 g of PEG3350, 1.46 g of sodium bicarbonate, 0.74 g of potassium chloride, 1.
It is washed with a PEG-electrolyte solution containing enough water to make 46 g of solution 1 at a rate of 20 ml / min. In a second embodiment, PEGs having the following composition, each expressed in g / l solution:
Washed with electrolyte solution: PEG3350 105, sodium chloride 2.80, sodium bicarbonate 1.43, potassium chloride 0.37 The invention is illustrated by the following examples, which are not intended to limit the invention in any way. .

Example 1 Osmolality of Polyethylene Glycol Solution Polyethylene glycol (PEG) was dissolved in water in an amount as shown in Table 1. The osmolality of each solution was measured by freezing point depression. As shown in Table 1, as the PEG concentration increases, the osmolality increases without being directly proportional. For example, a solution containing 60 mg of PEG is equivalent to an osmolality of 40 mOsm / kg. When the PEG concentration doubled to 120 mg / l, the osmolality was almost four times (156
mOsm / kg).

Example 2 Comparison of Effect of Ingestion of PEG on Stool Weight and Effect of Ingestion of Mannitol on Stool Weight Four test subjects consumed the mannitol aqueous solution and eight test subjects consumed the PEG aqueous solution for three consecutive days. Table 2 shows the amount of mannitol or PEG consumed by each subject.
Shown in 60g of PEG solution consumed by 8 subjects
Contains / l PEG. The stool weight (g / day) of each subject was measured in advance. The stool weight depends on the mannitol or PEG
Was measured daily for 3 days while consuming any of the above.
These weights are also shown in Table 2.

The stool weight was higher than the pre-treatment stool weight on the 1st and 2nd days even when mannitol was consumed. However, in all 4 subjects, the stool weight on the 3rd day was smaller than that on the 2nd day before, and up to 3 of the 4 cases were close to the weight before the treatment. In contrast, in the group that consumed the PEG solution,
The stool weight continued to increase for three days. This difference is believed to be due to the fact that colonic bacteria can ferment mannitol but not PEG. When the mannitol solution is consumed, colonic bacteria are adapted and proliferated during the first and second days, as a result, almost all of mannitol is fermented, and a bowel movement-promoting effect is exerted after the start of administration. Was disturbed. None of the PEG-consuming subjects complained of excessive flatus, which was a troublesome symptom in the mannitol intake group. Again, this is probably the result of the non-fermentable nature of PEG.

Example 3 Use of Low Sodium-PEG Solution for Colon Clearing Procedure Normal subjects were treated with a solution having the following composition at 30 ml /
It was washed at a rate of minute (1.8 l / hour).

PEG concentration 120 g / l (solution) ^* Measured sodium concentration 46.6 mEq / l (solution) Measured potassium concentration 9.0 mEq / l (solution) Measured chloride concentration 35.0 mEq / l (solution) Measured bicarbonate concentration 20.9 mEq / l ( Solution) Osmolality 293 mOs / kg (water) * Equivalent to 156 mOsm / kg when present as a solute The solution is PEG 120 g, sodium hydrogen carbonate (NaHCO ₃ ) 1.68
g, potassium chloride (KCl) 0.74 g and sodium chloride (Na
Cl) (1.46 g) was combined and water was added in an amount sufficient to give Solution 1.

The results of colonic cleansing with this solution were compared with those with equilibrium electrolyte solution (BES) and goriteri (GL). It is shown in the figure for reference. Golytely is the trade name for a cleaning solution and is essentially sodium sulfate based, disclosed by Davis and co-workers (see above). The results with the low sodium-PEG solution of the present invention are shown by the X plotted between the results of the other two solutions.

These results indicate that ingestion or loss of water, sodium, chloride, hydrogen carbonate and potassium into the body is negligible when using the low sodium-PEG solution.

Example 4 Use of Low Sodium PEG Solution in Perfusion Experiment Experimental Design After an overnight fast, the subject swallowed a single perforated mercury-tipped polyvinyl tube and placed its tip in the stomach. A solution having the following composition was used in the experiment.

 Composition Concentration (g / l) PEG3350 105.00 Sodium Chloride 2.80 Sodium Bicarbonate 1.43 Potassium Chloride 0.37 This solution had the following active ingredient concentrations.

 Composition Concentration (meq / l) Sodium 65 Chloride 53 Hydrogencarbonate 17 Potassium 5 The concentration of PEG-3350 in the solution was 31.30 mmol / l.

The solution was warmed to room temperature and infused into the stomach at a pump rate of 20 ml / min to 30 ml / min. Polyethylene glycol in solution, an integral component of the formulation, was also used as a non-absorbable label to assess water absorption or secretion (see below).

Twenty minutes after the start of gastric infusion, the infusion of the solution was interrupted for a while and 200 mg of sulfabromophthalein (BSP) was infused into the stomach through a polyvinyl tube. The infusion was then restarted at the same rate.

A stable state is reached when all BSPs are exhausted. Once this condition was reached, a rectal tube was inserted for rectal running water collection.

After reaching a stable state, perfusion was continued for 2 hours. The two hours were divided into two 60-minute periods, and PE
The G concentration was essentially the same, indicating that it was in a "stable state". Samples of rectal running water were analyzed for PEG and electrolyte concentrations by standard methods. Net water and electrolyte excretion is determined by standard nonabsorbable mar
ker equation) (see below). The results obtained from this experiment were carried out under similar conditions with a small amount of PEG,
The results were compared with those obtained from a second group of subjects infused with a sodium sulphate based solution also containing chloride, hydrogen carbonate and potassium. This solution is commercially available under the trade name Golytely ^R. The significance of the difference between both results was determined by t-analysis.

Data and Calculations Results of perfusion experiments are shown in Tables 3 and 4.

The results of the significance test are shown in Table 5.

Table 5 Independent average and t-test (n = 27) for comparison Measured substance S ^{2 t} 26 P Water 11111 0.6> 0.1 Sodium 145 2.2 <0.05 Potassium 5.4 2.2 <0.05 Chloride 207 1.2> 0.1 Bicarbonate 363 5.4 <0.001 where S ² is a pooled estimate of the common variance.

Among the measured parameters, sodium, potassium, and hydrogen carbonate had significant differences between the two formulations. The following null hypothesis was tested to determine if this difference was due to improvement. There is no significant difference between the results obtained when the low sodium-PEG solution was given and the results with no absorption / secretion.

Table 6 t-test measurement product ^St 13 P water 110 1.4> 0.1 Sodium 9.7 1.9> 0.05 Potassium 1.1 0.2> 0.1 Chloride 15.1 3.2 <0.01 Bicarbonate 4.4 0.4> 0.1 Where S is the standard deviation of the sample.

These results suggest that there was no significant difference between the data obtained by low sodium PEG solution administration and the nonabsorption / secretion data for all measured parameters except chloride. Chloride was not significantly different from the sodium sulfate based solution (Golytely). For sodium, potassium and bicarbonate there is a substantial improvement over the results obtained with sodium sulphate based solution administration.

Industrial Use The present invention has industrial use in the treatment of constipation, which is a common and often serious medical problem, and colonic cleansing, which is necessary, for example, as a diagnostic and surgical pretreatment. You can

Equivalents One of skill in the art would be able to understand or ascertain many equivalents to the specific materials and compositions described herein without undue experimentation. Such equivalents are included in the following claims.

Claims (13)

(57) [Claims] 1. A laxative containing a solution containing the following components. (A) An amount of polyethylene glycol that effectively relieves constipation. (B) Sodium, potassium, chloride and bicarbonate ions in an amount sufficient to prevent the net loss of electrolytes from the body of the person receiving the solution. 2. When administered orally or nasogastrically, it causes defecation from the gastrointestinal tract, (a) polyethylene glycol, (b) sodium ion, (c) potassium ion, (d) chloride ion, and ( e) The laxative according to claim 1, which contains hydrogen carbonate ion. 3. (a) 75 g to 300 g of polyethylene glycol, (b) 2 milliequivalent to 100 milliequivalent sodium ion, (c) 2 milliequivalent to 100 milliequivalent potassium ion per solution, (d) The laxative according to claim 1 or 2, which comprises 2 milligram equivalent to 100 milligram equivalent of chloride ion, and (e) 2 milligram equivalent to 100 milligram equivalent of bicarbonate ion. 4. The laxative according to any one of claims 1 to 3, wherein the polyethylene glycol is polyethylene glycol 3350. 5. The laxative according to any one of claims 1 to 4, which contains polyethylene glycol at a concentration of 105 g / l. 6. A solution containing (a) 120 g of polyethylene glycol 3350, (b) 46 mg of sodium ion, (c) 9 mg of potassium ion, (d) 35 mg of chloride ion, and e) A laxative as claimed in claim 1 which contains 21 milligram equivalents of bicarbonate. 7. (a) 105 g of polyethylene glycol 3350, (b) 65 mg of sodium ion, (c) 5 mg of potassium ion, (d) 53 mg of chloride ion, and (a) e) A laxative according to claim 1 which contains 17 milligrams of equivalent hydrogencarbonate. 8. A cleansing agent for gastrointestinal tract purification, which contains a solution containing the following components. (A) Polyethylene glycol in an amount sufficient to cause gastrointestinal clearance. (B) An electrolyte having an ion concentration sufficient to prevent net absorption or secretion of electrolyte ions in the gastrointestinal tract. 9. The cleaning agent for gastrointestinal tract purification according to claim 8, wherein the electrolyte produces sodium ions, potassium ions, chlorine ions and hydrogen carbonate ions. 10. A solution containing (a) 75 g to 300 g of polyethylene glycol, (b) 40 mg to 70 mg equivalent of sodium ion, (c) 2 mg to 15 mg equivalent of potassium ion, (d) The cleansing agent for gastrointestinal tract purification according to claim 8 or 9, comprising 30 milliequivalents to 60 milliequivalents of chlorine ions, and (e) 10 milliequivalents to 25 milliequivalents of hydrogen carbonate ions. 11. A solution containing (a) 105 g of polyethylene glycol 3350, (b) 65 mg of sodium ion, (c) 5 mg of potassium ion, (d) 53 mg of chloride ion, and ( e) The cleansing agent for gastrointestinal tract purification according to claim 10, which contains 17 mg of equivalent hydrogen carbonate ion. 12. The cleansing agent for gastrointestinal tract purification according to any one of claims 8 to 11, wherein the solution has a low sodium concentration. 13. The cleansing agent for gastrointestinal tract purification according to any one of claims 8 to 12, wherein the solution does not contain a sulfate salt.