JPH04198126A - Solution for cleaning intestine - Google Patents

Abstract

PURPOSE:To obtain a solution for cleaning intestine, not producing formaldehyde during preservation at room temperature or during sterilization under heating by blending a cleaner for intestine consisting essentially of polyethylene glycol and an electrolyte with a fixed amount of an alpha-amino acid as a stabilizer. CONSTITUTION:Polyethylene glycol and an electrolyte as main components are blended with 0.005-0.2w/v% alpha-amino acid (e.g. L-tryptophan, L-histidine or L-arginine) to give a solution for cleaning intestine. The solution for cleaning intestine especially preferably contains a given amount of electrolytic ions shown by the table together with polyethylene glycol. The solution hardly evolves formaldehyde and formic acid during preservation and heating, has extremely slight variation of pH, is greatly stable and has high safety.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a liquid preparation for intestinal cleansing, specifically used for enema X-ray examination, colonoscopy, pretreatment for large intestine surgery, treatment of constipation, etc., and is stable in terms of formulation. Related to liquid preparations for intestinal cleansing.

Conventional technology Traditionally, pretreatment for enema X-ray examinations, colonoscopies, and large intestine surgeries has mainly been carried out using the Brown method, that is, low-residue, low-fat dietary restrictions and the use of salt laxatives and contact laxatives. The so-called dry method is used to administer the drug, but without enema.
Brown's method is difficult to swallow and causes sudden diarrhea, making it difficult for elderly and infirm people to tolerate, and the need to drink large amounts of water to make the salt laxative effective. Therefore, it has serious drawbacks, such as not being accepted by patients with heart failure or renal impairment, and radiologically it is difficult to clean the hemicolon, and residue tends to remain.

Recently, in place of the above-mentioned Brown method, a non-absorbable, non-secretory intestinal cleansing agent containing polyethylene glycol as a main component and electrolytes added thereto has been researched and developed, and is already commercially available in the United States and other countries. Research has also been done [Special Publications Show 6]
3-500523]. These cleaning agents can be formulated in both liquid form and powder form for dissolution before use, and commercially available products include liquid form (product name: OCL 5olut).
ion; manufactured by Abbott, etc.) and powder (product name: Go
(manufactured by Braintree, etc.) are known.

Among these, although powdered preparations are sold with containers for dissolving and measuring, it is inconvenient to dissolve them in water before use, and it takes a considerable amount of time and effort to completely dissolve polyethylene glycol in particular. Disadvantages include that maintaining hygiene during preparation and measuring the prescribed amount are complicated. On the other hand, liquid preparations have the disadvantage that they cannot be used immediately when needed or require measures to maintain stability and hygiene. Such liquid preparations are currently used as in-hospital preparations in Japan, and are prepared the day before administration and stored in a refrigerator until use.

Problems to be Solved by the Invention However, as we investigated the stability of the above-mentioned liquid in detail, we found that heat sterilization for maintaining hygiene was not effective.
In addition, increasing the concentration to prevent microbial growth (Japanese Patent Application Laid-Open No. 1999-1999,
＋-32529) or non-thermal preparation methods such as aseptic production and the addition of preservatives, there is a serious problem that polyethylene glycol, one of the main components, is oxidized and formaldehyde is generated during subsequent storage. A shortcoming was discovered. In particular, it has been reported that formaldehyde causes abdominal pain, hematemesis, hematuria, etc. when ingested, and is also carcinogenic. Therefore, the presence of such substances in intestinal cleansing agents, which must be taken several liters at a time, is extremely dangerous for patients.

In addition, formaldehyde is further oxidized to form formic acid,
It also has the disadvantage of lowering the pH of the formulation and reducing the bicarbonate ion content.

In order to solve the above problem, the present inventors have considered countermeasures such as, for example, filling gas barrier containers in a deoxidized state as much as possible, and storing them in a cool and dark place.
No satisfactory results were obtained. We also tried adding various antioxidants commonly used in the pharmaceutical and food fields, such as bisulfite, ascorbic acid, and tocopherol, but none of them were very effective, and as mentioned above, intestinal cleansing agents Since these drugs are taken in large quantities, there are quite a few antioxidants that are undesirable to add.

Thus, in order to ensure stability during heat sterilization and long-term storage and safety for patients in intestinal cleansing solutions containing polyethylene glycol, it is essential to suppress the generation of formaldehyde. Ta.

Means for Solving the Problems As a result of repeated research day and night in order to solve the above problems, the present inventors have found that α-amino acid acts as a stabilizer for the above polyethylene glycol, and the formulation obtained by its combination is We obtained a new finding that almost no formaldehyde is produced not only when stored at room temperature but also when sterilized by heat, and thus completed the present invention.

That is, according to the present invention, the main components are polyethylene glycol and an electrolyte, and 0.005 to 0.2 α-amino acids.
% (w/v%, the same hereinafter) is provided.

In the intestinal cleansing solution of the present invention, the compositions of polyethylene glycol and electrolyte ions are preferably selected from the following ranges.

Polyethylene glycol 40-160g/lNa+3
5-150 mEq/l1K” 5-20 mEq//CA
'-20~50 mEq//HCO3-10~30 mEq//SO42-0~
100 mEq// The intestinal cleansing liquid preparation of the present invention contains a predetermined amount of α-amino acid as a stabilizer as described above, thereby successfully preventing the generation of formaldehyde and ensuring safety without worrying about toxicity. It is very expensive. In addition, this liquid agent also eliminates the production of formic acid by preventing the production of formaldehyde.
Fluctuations in pH and decreases in bicarbonate ion content are also reliably prevented.

The α-amino acid used in the present invention can be appropriately selected from various essential and non-essential amino acids commonly used in ordinary infusions, nutritional supplements, etc., and one type thereof may be used alone or two or more types may be combined. . Among them, L-4 liptophan, L-histidine, and L-arginine are particularly suitable. Further, the α-amino acid can usually be used in the form of a free amino acid, but it is not particularly necessary to be in a free form, and it can also be used in various forms such as salts, esters, and peptides.

In this case, the amount to be used shall be determined in terms of free amino acid or within the above range, that is, 0.005 to 0.2%. In addition, considering the influence on the taste and coloring of the preparation, the above addition amount range is particularly about 0.01 to 0.1%.
Preferably, it is selected from the range of .

It is one of the main components of the liquid preparation for intestinal cleansing of the present invention, and the above α
- The type of polyethylene glycol whose oxidation is prevented by the addition of amino acids is not particularly limited as long as it has the effect of cleaning the intestinal lining, and in any case, the present invention prevents its oxidation and makes it a stable preparation. Become. Among them, pharmacopeias such as polyethylene glycol 4000 and polyethylene glycol 6000, which are commonly used as carriers for pharmaceuticals, are suitable.

The intestinal cleansing solution of the present invention must contain a predetermined amount of the specific electrolyte ion having the above-mentioned composition together with the above-mentioned polyethylene glycol.

The source of such electrolyte ions is not particularly limited, and various compounds used in general infusions may be used. Usually these are preferably selected from sodium sulfate, potassium chloride, sodium chloride and sodium bicarbonate. These formulations, when the liquid preparation of the present invention is applied to a patient, sufficiently replenish the net electrolytes lost from the patient's body, substantially preventing loss of electrolytes from the body, and thereby reducing tissue electrolytes. Maintains balance and maintains a normal state. More preferable composition ranges of each component (including polyethylene glycol) of the liquid preparation of the present invention to ensure the above-mentioned effects are as follows.

Polyethylene glycol 48-144g/lNa+
40-135mEq/lK+7-13m
Eq/A' C12-24~46 mEq/A' HCO3-14~26 mEq/l SO4' 0~85 mEq/V Each of the above components is used to prevent the permeation of the entire liquid in order to minimize the change in the water content of living tissues. It is preferable to mix so that the pressure is approximately isotonic.

In addition, the liquid preparation of the present invention may contain, for example, a flavoring agent such as saccharin sodium, a flavoring agent such as fruit essence, etc., as appropriate, in order to improve the ease of drinking.
The stability of the liquid formulation is not affected at all by these formulations.

The method for producing the liquid preparation of the present invention is no different from the method for producing a commercially available liquid form of this type of intestinal cleansing agent, in which polyethylene glycol, electrolyte, and αT amino acid are dissolved in water, and each component is adjusted to a predetermined concentration. This is then filled into a suitable container made of glass or synthetic resin, preferably a container with high gas barrier properties, after purging with nitrogen if necessary.
It may be a product.

The intestinal cleansing liquid preparation of the present invention thus prepared can be used in the same manner as conventional liquid preparations of this kind. The amount is generally 1
A rough guideline is approximately 1,000 to 30,007 times, and this can be increased or decreased as appropriate depending on the age, weight, etc. of the patient to whom it is applied. In addition, the dosing rate should normally be about 15 to 25 ivA'/min (about 0.9 to 1.51/hour), and the dosing is usually orally, but is not limited to this, for example, nasally. etc. may be used.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the liquid preparation for intestinal cleansing of the present invention will be given as examples, and then test examples will be given to clarify its effects.

Example 1 Ingredients Amount (g/A') Polyethylene glycol 4000
6 0Na2 304
5. 69NaCI
1. 46KCI
0.
75NaHCO31,68 L~Histidine 0. 2 Each of the above components was dissolved in purified water in the amounts shown above, filled into a container, sealed, and sterilized by heating at 105° C. for 40 minutes to prepare a liquid preparation for intestinal cleansing of the present invention.

Example 2 Ingredients Amount (g//) Polyethylene glycol 4000
6 ONa 2 SO45,69 NaCl
1. 46KCI
0. 75NaHCO31
,68 L,-)Liptophan 0. 1 In the same manner as in Example 1, a liquid preparation for intestinal cleansing of the present invention having the composition shown above was prepared.

Example 3 Ingredients Amount (g/l) Polyethylene glycol 400 []
6 ONa 2 SO45,69 NaC/
1. 46KCI
0. 75NaHCO3
1-, 68 L-) Liptophan 0. LL-arginine 0. 5 In the same manner as in Example 1,
A liquid preparation for intestinal cleansing of the present invention having the composition shown above was prepared.

Example 4 Ingredients Amount (g/A') Polyethylene glycol 4000
6 0Na2 SO45,69 NaCA'
1. 46KC/
0. 75NaHCO
31,68 L-Histidine 0. 5 In the same manner as in Example 1, a liquid preparation for intestinal cleansing of the present invention having the composition shown above was prepared.

Example 5 Ingredients Amount (g/l) Polyethylene glycol 4000 1
20NaCl
1. 46KCI
0. 75N
aHCO31,68 L-cysteine 0.2 In the same manner as in Example 1, a liquid preparation for intestinal cleansing of the present invention having the composition shown above was prepared.

Example 6 Ingredients Amount (g/A'
) Polyethylene glycol 4000
6 ONa 2 SO45,69 NaC11,46 KCI 0.75Na
HCO31,68 L-Histidine 1.0 In the same manner as in Example 1, a liquid preparation for intestinal cleansing of the present invention having the composition shown above was prepared.

Test Example 1 Each of the liquid samples for intestinal cleansing of the present invention obtained in Examples 1 to 4 was filled into glass bottles and aluminum laminated film bags with a capacity of II, and then heat sterilized at 105°C for 40 minutes. .

When using a glass bottle, the liquid agent was prepared in a nitrogen atmosphere and filled with nitrogen. In the case of aluminum laminated film bags, they were prepared and filled in an air atmosphere.

Each filled liquid sample prepared above was stored at 40° C. for 3 months and at room temperature for 1 year, and the formaldehyde concentration, formic acid concentration, and pH of the sample solution after storage were measured. Moreover, the same measurement was also performed at the start of the above-mentioned storage.

The above formaldehyde concentration is based on the Sanitary Testing Method (1990).
It was quantified based on the AHMT method. Further, the formic acid concentration was determined by ion chromatography. The column used was TSK gel 5CX()l+) [manufactured by Tosoh Corporation], and the eluent was 1.2 mM hebutafluoro-n-butyric acid.

On the other hand, as a comparative example, amino acids (L
- Histidine) was prepared in the same manner, and the same test as above was conducted with or without heat sterilization.

The results obtained are shown in Table 1.

Table 1 GV: Glass bottle, A1: Aluminum laminate film bag Table 1 (Continued) GV: Glass bottle, A l: Aluminum laminate film bag In Table 1 above, the units for the measured values of formaldehyde concentration and formic acid concentration are: ppm, and N and D indicate the detection limit (0.5 ppm or less).

As is clear from Table 1, the samples shown in Comparative Examples 1 and 2 (
Comparative intestinal cleansing liquid sample with no α-amino acid added was 4
Under both storage conditions of 3 months at 0°C and 1 year at room temperature,
A significant increase in formaldehyde generation and formic acid generation was observed, and a decrease in pH was also confirmed.

In contrast, the liquid samples for intestinal cleansing of the present invention generate almost no formaldehyde and formic acid under the same storage conditions, have very little pH fluctuation, are extremely stable, and are highly safe. It was confirmed that

(that's all)

Claims (2)

[Claims] (1) A liquid preparation for intestinal cleansing which is characterized by containing polyethylene glycol and electrolyte as main components and 0.005 to 0.2% (w/v) of α-amino acids. (2) The liquid preparation for intestinal cleansing according to claim (1), wherein the compositions of polyethylene glycol and electrolyte ions are selected from the following ranges. Polyethylene glycol 40-160g/lNa^+
35-150mEq/l K^+ 5-20mEq/l Cl^- 20-50mEq/l HCO_3^- 10-30mEq/l SO_4^2^- 0-100mEq/l