JP2014091740A - Glycerol enema - Google Patents

Abstract

PROBLEM TO BE SOLVED: To accomplish development of a new glycerol enema in which stimulating effect by glycerol is alleviated unlike a conventional commercial glycerol enema and severe defecation facilitating effect is improved, and to provide a product having reduced physical and mental burden on a patient and excellent usability for medical institutions.SOLUTION: The above mentioned problem solved with a glycerol enema of the present invention having the following property: comprised therein is glycerol, water and salt consisting of alginic acid and cation; adhesion of the alginic acid salt on rectal mucosa is moderated and defecation effect of glycerol is moderated by tissue protection effect; and viscosity at 36°C is 1000 mPa/s or less, pH is 7±2, and glycerol concentration is 50±5 mass%.

Description

Detailed Description of the Invention

  The present invention relates to a glycerin enema.

  The present invention relates to a glycerin enema that can promote a physiologically comfortable defecation to a patient at the time of administration by slowly exerting a defecation promoting action based on stimulation and permeation of rectal mucosa of glycerin as a main drug. About.

  It is said that the bowel movement of normal people is at least three times a week. On the other hand, stool is a condition in which feces stay in the intestine for 3 to 4 days or longer and the stool is absorbed into the intestine for a long time and moisture is absorbed, that is, the intestinal defecation mechanism is impaired. Symptoms caused by constipation may include abdominal pain, fullness of the abdomen, indirectly uncomfortable or severe findings such as low back pain, headache, loss of appetite, and glycerin enema for the treatment of severe symptoms Is applied preferentially. Currently marketed glycerin enemas (aqueous solution containing 30 g of JP glycerin (glycerin concentration 84-87%) in a total volume of 60 mL) is peristalized by intestinal peristalsis by injecting into the rectal mucosa by injection into the rectum. It is a formulation that improves various symptoms caused by constipation by the action of excretion of stool by softening and lubricating stool by osmotic action.

  The glycerin enema currently available on the market varies from patient to stool after injection into the rectum, although the effect of promoting defecation is excellent, but the enema is based on the fact that the rectal mucosa irritation is too strong. Rapid abdominal pain, belly, abdominal fullness, rectal discomfort, rapid constipation, short time required from infusion to defecation, etc. In many cases, it imposes a burden on the patient's mind and body, such as when the drug solution is excreted due to inability to hold for a while, the sensation after defecation is not clear, or unpleasant symptoms such as abdominal pain occur.

Therefore, in order to reduce the mental and physical burden on patients during administration of such glycerin enemas, physiologically comfortable by slowly exerting the stimulating effect on the rectal mucosa of glycerin, the main drug for constipation treatment Some attempts have been made so far to obtain a glycerin enema that can exert a defecation promoting effect on a patient.
For example, a gel enema composition containing glycerin, a carboxyvinyl polymer and a basic substance at the same time can be mentioned. However, in this example, the effect is not so remarkable and the viscosity of the composition itself is so high that it cannot be easily injected into the rectum and the practicality is poor (Patent Document 1). Further, a gelled rectal injection in which a drug is blended with a gel composed of various water-soluble polymers (gelling base) for the purpose of rectal absorption or enema has been devised (Patent Document 2). In addition, as a past finding that showed the possibility of covering and protecting the gastrointestinal mucosa clinically, for example, sodium alginate, which is the main agent of Alloid G internal solution 5%, adheres to the gastrointestinal mucosa and covers the mucosal surface Based on the knowledge that it has an effect of protecting mucosal tissue, the clinical effects of the improvement of subjective symptoms in gastric / duodenal ulcer, erosive gastritis and reflux esophagitis and hemostasis at bleeding of gastric biopsy are currently It is seen that it is used in the field (Non-patent Documents 1 and 2 and 3), and since calcium ions are contained in, for example, about 0.1 to 3 mM in the local secretions, etc., sodium alginate , A sustained ophthalmic preparation has been devised that slows down its efficacy based on the fact that a gel is locally formed when it comes into contact with tears at the time of instillation (Non-Patent Document 4, ) Furthermore, a method of enhancing the viscosity increase by calcium ions when a liquid composition containing an alginic acid derivative and boric acid or a salt thereof comes into contact with a fluid derived from a living body and its application to a living body have been devised. (Patent Document 3). On the other hand, a method in which a water-soluble polymer solution itself is administered alone to the rectum for purposes such as enema has also been studied. For example, a novel constipation preventive and ameliorating agent (Patent Document 4) having no side effects at all comprising a gel containing alginate polyvalent metal salt obtained by dripping a polymer sodium alginate aqueous solution into a polyvalent metal salt aqueous solution, drugs such as enema Of an aqueous gel prepared using a water-soluble polymer such as carboxyvinyl polymer or sodium alginate to a rectal preparation for the purpose of rectal absorption (Patent Document 5), prednin powder and alloid G internal solution (sodium alginate 5% aqueous solution) is prepared as an enema solution and administered in clinical settings (Non-patent Document 6). Betamethasone sodium phosphate ester is formulated in a gel composed of carboxyvinyl polymer and sodium hydroxide. Practical examples such as intestinal agents (Non-patent Document 7) were observed.

JP-A-7-291855 JP-A-56-25109 JP-A-14-332249 Japanese Patent Application No. 2005-505861 WO2004 / 096243, Japanese Patent Application No. 2005-505861 Drug interview form of Alloy G internal solution 5% Michio Hongo; Basic and Clinical, 16 (10), 5259-5262 (1982) Manabu Yamaji et al, Pharmaceutical Journal, 101 (5), 452-457 (1981) FRAGRANCE JOURNAL 1999-4, 76-84 journal of controlled release 44 (1997) 201-208 Hospital Pharmacy Formulation III, Yakuji Nipposha, 1990, page 270 Attached document "Steronema enema"

  Accordingly, the present inventors have overcome the above-mentioned drawbacks of glycerin enemas currently on the market, and reduce the burden on the patient's mind and body at the time of administration. In order to obtain a novel glycerin enema that can exert a stimulating action and an osmotic action of the patient slowly and exert a physiologically comfortable defecation-promoting action on the patient, a trial production and evaluation were conducted.

  First of all, in glycerin enemas, the combination of glycerin and the rectal mucosa coating protective agent is effective in the formulation as a means that the irritant action of glycerin on the rectal mucosa is slow and the action as a laxative can be demonstrated reliably. The present inventors thought whether there was.

  As an appropriate main component that is considered to exhibit an appropriate performance to be included in the glycerin enema preparation having the performance intended by the present invention, as a result of considering with reference to various findings found in the above prior art documents, alginic acid Alternatively, the present inventor considered that a salt of alginic acid and a cation is desirable. That is, when an aqueous solution containing alginic acid or a salt of alginic acid and a cation at the same time as glycerin is administered to the rectum, the alginic acid or a salt of alginic acid and a cation first adheres to the rectal mucosa, and then covers the rectum. It reacts with calcium ions contained in the mucous secretion of the mucous membrane and hydrogels to enhance the protective coating of the rectal mucosal surface. As a result, the stimulating action of glycerin becomes indirect and does not occur rapidly, It is expected that a mild laxative effect can be expected.

  Thus, the present inventors have conducted diligent research on the past findings supporting the hypothesis of the present inventor. However, enemas or constipation preventive agents containing a combination of alginic acid, which is a kind of water-soluble polymer, or a salt of alginic acid and a cation together with glycerin. Has not been studied at all in the past, and it has been found that there are no commercially available products.

  Based on the above considerations and investigation results, the present inventors made an enema preparation containing alginic acid or a salt of alginic acid and a cation together with glycerin and administered it to an adult male as a subject. Awareness such as time to start defecation, leakage of chemicals during infusion, feeling after defecation, presence or absence of abdominal pain in time from infusion to defecation, and ease of infusion with enema tool The target findings were compared with commercially available glycerin enemas.

  As a result, it was confirmed that the product of the present invention had a longer time than the commercial product after the infusion, until the defecation was started. Also, the leakage of the drug solution during the injection is not observed in the present product unlike the commercially available products, and the present invention also relates to the degree of patience, the feeling after defecation, and the presence or absence of abdominal pain in the time from injection to defecation. The product was better than the commercial product. Further, in terms of the ease of injection by the enema tool felt by the administration operator, the product of the present invention and Comparative Example 1 could be easily injected into the rectum, whereas in contrast to this, the example of JP-A-7-291855 The glycerin enema preparation with a viscosity of about 60,000 mPa · s prepared according to the description in 1 required a considerable gripping force at the time of injection because the viscosity was too high.

  As described above, the combined use of glycerin, alginic acid, and metal ion salt alleviated the rapid irritation of glycerin to the rectal mucosa, and a glycerin enema was obtained that facilitated enema using an enema device. . The present invention has been completed by the above process. That is, the present invention contains a glycerin enema containing glycerin and alginic acid or a salt of alginic acid and cation at the same time, more specifically, glycerin, a salt of alginic acid and metal ion, and water, and has a viscosity at 36 ° C. The present invention relates to a glycerin enema that has a viscosity of 1000 mPa · s or less, a pH of 7 ± 2, and a glycerin concentration of 50 ± 5 W / V%.

  The glycerin used in the glycerin enema of the present invention is prepared by diluting Japanese Pharmacopoeia glycerin or Japanese Pharmacopoeia concentrated glycerin with water. This glycerin is an active ingredient which stimulates the rectal mucosa and has a defecation promoting action, and is blended in the composition at 50 ± 5% by mass.

In the present invention, a salt of alginic acid and a metal ion is gelled by contact with a bodily fluid containing calcium ions secreted from the rectal tube by the osmotic pressure of glycerin, and protects the mucosal surface by adhering to the rectal mucosa. Mild irritation to rectal mucosa. At this time, as the chemical species, commercially available alginic acid of various viscosities, sodium alginate, ammonium alginate, potassium alginate, such as sodium alginate, the viscosity of an aqueous solution having a concentration of 1% by mass is 30, 60, 70, 120, 300. , 400, 500, 800 and 1000 mPa · s. When alginic acid is used, a salt is formed by mixing an inorganic basic substance such as sodium hydroxide, ammonium hydroxide, potassium hydroxide or calcium hydroxide, and an organic basic substance such as diethylamine, ethanolamine or diethanolamine. Use. Moreover, the compounding quantity of the salt of alginic acid and a metal ion mix | blends the quantity which ensures the value of the viscosity in 36 degreeC of the glycerol enema of Claim 1. Therefore, the blending amount is adjusted depending on what commercial grade viscosity of alginic acid and metal ion salt is used.

  Since the gelation reaction of alginic acid and calcium ions on the rectal mucosa surface proceeds stably when the pH is neutral or higher, the pH of the glycerin enema of the present invention is 7 ± 2, and sodium hydroxide or Adjust with aqueous hydrochloric acid.

  The viscosity at 36 ° C. of the glycerin enema of the present invention is 1000 mPa · s or less at 36 ° C. in order to exhibit the effect of slowing the irritation of glycerin to the rectal mucosa.

  In order for the gelation reaction between alginic acid and calcium ions on the rectal mucosa surface to proceed stably, it is effective to maintain the pH so as not to fluctuate. Therefore, a buffering agent such as a phosphate buffer, Tris-HCl buffer, acetate buffer, carbonate buffer, or citrate buffer may be added to the liquid composition of the present invention as necessary.

  As described above, the glycerin enema of the present invention is used, for example, by using a salt of alginic acid and a metal ion in combination with glycerin. Moreover, it is used by injecting into the rectum with a normal enema tool or a disposable enema tool.

  Hereinafter, the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples.

Example 1
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 120 mPa · s grade sodium alginate, methyl parahydroxybenzoate 0.1 w / v%, and citric acid 1 w / v Adjust the pH to 7 with a 5 w / v% aqueous sodium hydroxide solution for the mixed solution consisting of v%, add an appropriate amount of water to prepare an aqueous solution with a viscosity at 36 ° C. of 300 mPa · s and a total amount of 100 w / v%, Fill enema equipment.

Example 2
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 60 mPa · s, suitable amount of sodium alginate, methyl paraoxybenzoate 0.1 w / v%, propyl paraoxybenzoate 0 0.020.1 w / v% and boric acid 1.5 w / v% mixed solution was adjusted to pH 8 with 5 w / v% sodium hydroxide aqueous solution, and an appropriate amount of water was added, and the viscosity at 36 ° C. was 100 mPa Prepare an aqueous solution of s, 100% w / v% in total and fill the enema device.

Example 3
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 300 mPa · s grade sodium alginate and methyl paraoxybenzoate 0.1 w / v%, propyl paraoxybenzoate 0 0.020.1 w / v%, mixed liquid consisting of sodium dihydrogen phosphate 1 w / v% Adjust pH to 7.5 with 5 w / v% sodium hydroxide aqueous solution, add appropriate amount of water, viscosity at 36 ° C. Prepare an aqueous solution of 500 mPa · s, 100% w / v% in total, and fill the enema device.

Example 4
Japanese Pharmacopoeia Glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 1000 mPa · s grade sodium alginate and methyl paraoxybenzoate 0.1 w / v%, propyl paraoxybenzoate 0 .020.1 w / v%, boric acid 1 w / v% mixed solution, adjusted to pH 8 with 5 w / v% aqueous sodium hydroxide solution, added with an appropriate amount of water, the viscosity at 36 ° C. is 1000 mPa · s, An aqueous solution with a total amount of 100 w / v% is prepared and filled into an enema device.

Example 5
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 70 mPa · s grade ammonium alginate and methyl paraoxybenzoate 0.1 w / v%, propyl paraoxybenzoate 0 .020.1 w / v%, tartaric acid 1 w / v% mixed solution, adjust pH to 8 with 5 w / v% sodium hydroxide aqueous solution, add appropriate amount of water, viscosity at 36 ° C. is 150 mPa · s, total amount A 100 w / v% aqueous solution is prepared and filled into an enema device.

Example 6
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 800 mPa · s grade of potassium alginate and methyl paraoxybenzoate 0.1 w / v%, propyl paraoxybenzoate 0 0.020.1 w / v%, boric acid 2 w / v% mixed solution, adjusted to pH 7 with 5 w / v% sodium hydroxide aqueous solution, added with a suitable amount of water, the viscosity at 36 ° C. is 100 mPa · s, An aqueous solution with a total amount of 100 w / v% is prepared and filled into an enema container.

Example 7
Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / v%, 1 w / v% aqueous solution with a viscosity of 300 mPa · s, suitable amount of alginic acid, diethylamine equivalent to carboxyl group in alginic acid, methyl paraoxybenzoate 0.1 w / A mixture of v%, propyl paraoxybenzoate 0.020.1 w / v% and boric acid 1 w / v% was adjusted to pH 7 with a 5 w / v% aqueous sodium hydroxide solution and added with an appropriate amount of water 36 An aqueous solution having a viscosity at 100 ° C. of 100 mPa · s and a total amount of 100 w / v% is prepared and filled into an enema container.

[Test example]
1. Sample product of the present invention; glycerin enema prepared according to Examples 1, 2 and 3.
Comparative Example 1: An aqueous solution (commercial glycerin enema) containing 30 g of JP glycerin (glycerin 84 to 87%) in a total volume of 60 mL.
Comparative Example 2; [Patent Document 1] Preparation method of glycerin enema having a viscosity of about 60000 mPa · s prepared according to Example 1 of JP-A-7-291855; Japanese Pharmacopoeia glycerin 50 w / v%, water 40 w / About a mixed solution consisting of v% and an appropriate amount of Carbopol 934P, adjust the pH to 7 with a 5 w / v% aqueous sodium hydroxide solution, add an appropriate amount of water, the viscosity at 36 ° C. is 60000 mPa · s, and the total amount is 100 w / v% Prepare an aqueous solution and fill it into an enema container.
2. Administration conditions: Men in their 50s to 70s who have defecation once a day.
3. Number of cases: 5 for each 1 type of test drug Observation items: Samples were injected into the rectum at 7 am before meals, the time from the start of the injection until the start of defecation, the leakage of liquid during the injection, the degree of patience, the feeling after defecation, the injection We observed the presence or absence of abdominal pain in the time from defecation to the defecation, and the ease of injection with the enema tool felt by the administration workers.
5. Results It was confirmed that the time from the injection to the start of defecation after the infusion was extended in the case of the present invention product (Examples 1, 2 and 3) as compared with Comparative Examples 1 and 2. Further, unlike the comparative examples 1 and 2, the leakage of the drug solution during the injection is not observed in the present invention product. About the degree of patience, the feeling after defecation, the presence or absence of abdominal pain in the time from the infusion to the defecation The product of the present invention was slower than Comparative Examples 1 and 2. Further, in terms of the ease of injection by the enema tool felt by the administration worker, the product of the present invention and Comparative Example 1 could be easily injected into the rectum, but Comparative Example 2 had a high gripping force during injection because of its high viscosity. Cost.

(1) Time (seconds) from infusion to start of defecation after defecation

(2) Drug leakage during injection

(3) Degree of patience

(4) Sensation after defecation

(5) Absence of abdominal pain during the period from injection to defecation

(6) Ease of injection with enema tool felt by the administration worker

Glycerin enemas based on the combination of salts of glycerin, alginic acid and metal ions according to the present invention relieve the stimulating action of glycerin unlike conventional commercially available glycerin enemas because of adhesion of alginates to the rectal mucosa and tissue protection effect. In addition, since the effect of promoting rapid defecation is improved, the burden on the mind and body for the patient is small, and the usability is excellent for medical institutions.

Claims (6)

  A glycerin enema comprising glycerin, alginic acid or a salt of alginic acid and a cation, and water.   The glycerin enema of claim 1, wherein the cation is sodium ion, ammonium ion, potassium ion or organic basic substance. The glycerin enema of claim 1, having a viscosity at 36 ° C of 1000 mPa · s or less. The glycerin enema of claim 1 having a pH of 7 ± 2. The glycerin enema of claim 1, wherein the concentration of glycerin is 50 ± 5% by mass.   The glycerin enema according to claim 1, comprising a buffer derived from phosphoric acid, acetic acid, citric acid, boric acid and carbonic acid.