JPH1053530A - Sennoside calcium aqueous solution preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject stable solution preparation from which no insoluble products deposit and no precipitates form by containing calcium salts of sennoside A and B. SOLUTION: This drug contains at least one of calcium salts of sennoside A and B useful as a mild cathartic and carboxylic acids or their salts. Further, a preservative agent and an auxiliary are formulated thereto when necessary to adjust an aqueous solution at pH5-8. The salts of sennoside A and B are contained in an amount of 0.2-55mg/ml as the sennoside A and B. The carboxylic acids or their salts are contained in an amount of 1-80mg/ml. An aqueous solution preparation containing 12-24mg as calcium salts of sennoside A and B is taken once a day for adult. It is a preparation capable of easily administrating to young children and aged men.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an aqueous solution of calcium sennoside containing a calcium salt of sennoside A or B useful as a laxative as an active ingredient.

[0002]

2. Description of the Related Art Sennosides A and B are main active ingredients having a laxative effect contained in senna and rhubarb, which have been widely used as laxatives since ancient times. Senna has the comprehensive action of natural herbal medicine, but it is thought that a considerable amount of resin components may be mixed therein, which may cause irritating abdominal pain, diarrhea, nausea and the like. Senna extract is sennosides contained in senna, sennoside analog, aloe-emodin,
It contains an active ingredient such as rain and can be expected to exert the comprehensive action of natural herbal medicine, and is highly useful because it removes resin components and reduces side effects. (Pharmaceutical Daily, No. 8582, 1
995)

[0003] According to the Japanese Pharmaceutical Non-Pharmaceutical Standards, the sennoside A and B contents of the senna extract are 15 to 25%. In clinical practice, tablets using a drug substance containing calcium salts of sennosides A and B as a main component of the active ingredient and having a content of about 55 to 95% are widely used. By increasing the content of sennosides, the dosage of the laxative active ingredient becomes accurate,
Reliable laxative effects and reduction of side effects have been achieved. However, sennosides A and B have a strong laxative effect,
With tablets, it is difficult to set an appropriate dose for each patient. In addition, children and the elderly have problems such as difficulty in taking tablets. Therefore, development of a solution preparation containing sennosides A and B as active ingredients has been desired.

[0004] Regarding an aqueous solution preparation using a senna extract or a senna extract granule having a low sennoside content, Japanese Patent Publication No. 7-5470 discloses that a solution containing sennosides is filtered through a porous filter medium in a state where no precipitate is formed, and is stabilized. A production method for obtaining a suitable liquid medicine for internal use is disclosed.

On the other hand, as for an aqueous solution using high-purity sennosides A and B, Rainonen et al. (Pharm)
acology & Toxicology, 63, 37
P. 1988) report its stability, with pH 6.5 being the most stable using a citrate-phosphate buffer.

Next, JP-A-49-118820 discloses that
Powders stabilized as crystals of the calcium salts of sennosides A and B have been disclosed and used in the manufacture of tablets. However, nothing is known about the solution preparation of this calcium salt.

[0007]

The calcium salts of sennosides A and B are highly purified salts. Therefore, the solubility in water is good, but a mere aqueous solution has a defect that insolubles are precipitated due to decomposition during storage, and a long-term stable water-soluble preparation has not been obtained.

The aqueous solution of the calcium salt of sennosides A and B was filtered through a cellulose filter according to the method described in JP-B-7-5470, but the stability was not changed before and after filtration. This is thought to be because the calcium salts of sennosides A and B before filtration were highly purified and did not contain components such as β-glucosidase that inactivate sennosides, and stabilization of calcium salt solution preparations was considered. On the other hand, the filtration method described in JP-B-7-5470 is not a sufficient method.

In the case of calcium salts of sennosides A and B, calcium phosphate precipitates in a buffer containing phosphoric acid as described in the report of Rainonen et al. The precipitated calcium phosphate is a fine crystal and hardly sedimented, so that it is difficult to decant, and there is a problem that the filtration medium is clogged by filtration and requires a long time, and is difficult to remove. As described above, in order to obtain a stable solution preparation of a calcium salt of sennoside having a high content, it is necessary to solve stabilization of sennoside and prevention of precipitation of insolubles.

[0010]

Means for Solving the Problems As a result of various studies, the present inventors have found a stable aqueous solution of sennoside calcium which does not cause precipitation of insoluble matter or precipitation during storage and completed the present invention. That is, the present invention provides: (1) an aqueous solution of calcium sennoside, comprising: (1) at least one of calcium salts of sennosides A and B; and (2) a carboxylic acid or a pharmaceutically acceptable salt thereof.

2. The content of the calcium salt of sennosides A and B is 0.2 to 55 mg as sennosides A and B.
2. The aqueous solution preparation according to claim 1, which is / ml. 3. The aqueous solution preparation according to the above 1, wherein the carboxylic acids are water-soluble di- to tetra-basic acids. 4. The aqueous solution preparation according to the above 1, wherein the pH of the aqueous solution is 5 to 8, 5. The aqueous solution preparation according to the above item 1, which contains a preservative and an auxiliary agent as necessary, that is, a sweetener as a flavoring agent, a flavoring agent as a flavoring agent, and a consistency modifier. An aqueous solution containing calcium salts of sennosides A and B, carboxylic acids or pharmacologically acceptable salts thereof, water, and if necessary, preservatives and auxiliaries. Formulation, calcium salt of sennosides A and B as sennosides A and B 0.2 to 55 mg / ml carboxylic acids or pharmaceutically acceptable salts thereof 1 to 80 mg / ml preservatives 0 to 8 mg / ml auxiliaries 0 to 700 mg / Ml pH of aqueous solution pH5-8 water balance

7. Based on the whole preparation, calcium salts of sennosides A and B as sennosides A and B 12 to 40 mg / ml citric acid or an alkali metal salt thereof 5 to 30 mg / ml preservative 0.2 to 5 mg / ml auxiliary agent 3 to 300 mg 7. The preparation according to the above item 6, wherein the pH of the aqueous solution is 6 to 7.5, and the remaining amount of water is pH. A sennoside calcium aqueous solution preparation containing at least one of the calcium salts of sennosides A and B, and which does not precipitate insolubles or precipitates even after storage at 40 ° C. for 2 weeks;

9. 9. an aqueous solution of calcium sennoside which contains at least one of calcium salts of sennosides A and B and does not precipitate insolubles or precipitates even after storage at 25 ° C. for 13 weeks; 10. The preparation according to the above item 8 or 9, wherein the pH of the aqueous solution is 5 to 8, 11. The preparation according to claim 8 or 9, further comprising a carboxylic acid or a pharmaceutically acceptable salt thereof. The calcium salt of sennoside A and B was 0.2 to 55 mg /
12. the preparation according to the above item 8 or 9, wherein the preparation comprises 13. The preparation according to the above-mentioned 12, further comprising 1 to 80 mg / ml of a carboxylic acid or a pharmaceutically acceptable salt thereof, based on the whole preparation.

14. With respect to 1 part by weight of the calcium salt of sennosides A and B as sennosides A and B, a carboxylic acid or a pharmacologically acceptable salt thereof is used in an amount of 0.02 to 2.0 parts by weight.
120 parts by weight, preferably 0.1 to 60 parts by weight,
14. the preparation according to the above item; 2. The preparation according to the above item 1, wherein the preparation is substantially free of orthophosphoric acid or a pharmaceutically acceptable salt thereof. The phrase "substantially free of orthophosphoric acid or its salt" means that it does not contain an amount of orthophosphoric acid that causes an insoluble precipitate during storage.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The sennosides A and B are erythro and threo stereoisomers of reindiathrone glucoside present in senna, rhubarb and the like. As the high-content products of sennosides A and B, products converted into calcium salts are commercially available and can be used as drug substances. The content of the calcium salt of sennoside A or B of the product of the present invention in the aqueous preparation is generally 0.2 mg / ml or more, preferably 5 mg / ml or more, more preferably 10 mg / ml as sennoside A and B.
mg / ml or more, and the upper limit is generally 55 mg
/ Ml, preferably 50 mg / ml, more preferably 4 mg / ml.
0 mg / ml. Therefore, the content of aqueous formulations of calcium salts of sennosides A and B is generally 0.2
-55 mg / ml, preferably 5-50 mg / ml, more preferably 12-40 mg / ml.

In the present invention, examples of the solubilizer include water-soluble carboxylic acids. These carboxylic acids may be used as salts with alkalis. Examples of the alkali salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and organic alkali metal salts such as pyridine and triethylamine. Preferably, alkali metal salts such as sodium and potassium are preferred. Examples of the carboxylic acids include polybasic acids. For example, succinic acid, glutaric acid, maleic acid, malic acid, dibasic acids such as tartaric acid, tribasic acids such as citric acid, tetrabasic acids such as edetic acid and alkali metal salts thereof, and citric acid and The alkali metal salts are particularly preferred. The content of the solubilizer is generally 1 mg / ml or more, preferably 3 mg / ml.
ml or more, more preferably 5 mg / ml or more, and the upper limit is generally 80 mg / ml, preferably 50 m / ml.
g / ml, more preferably 30 mg / ml. Therefore, the content of the solubilizer is generally 1 to 80 mg /
ml, preferably 3 to 50 mg / ml, more preferably 5 to 30 mg / ml.

Examples of the pH adjuster of the aqueous solution include acids and bases usually used in medicine, and hydrochloric acid and sodium hydroxide are preferred. Further, it may be adjusted by using a carboxylic acid as a solubilizer and an alkali metal salt thereof. The pH of the aqueous solution is 5 or more, preferably 6 or more, and the upper limit is 8 or less,
Preferably it is 7.5 or less. Therefore, the pH of the aqueous solution
Is 5 to 8, preferably 6 to 7.5.

Examples of the preservative include paraoxybenzoic acid esters (eg, methyl paraben), benzoic acid, sorbic acid, dehydroacetic acid, and salts thereof. The amount of the preservative added may not be added, but is generally 8 mg / ml or less, preferably 5 mg / ml or less, for example, 0 to 8 mg / ml.
ml, preferably 0.2-5 mg / ml. The preservative may be added after being dissolved in a water-soluble solvent such as ethanol.

The aqueous solution preparation of the present invention may contain, if necessary, auxiliaries usually used in pharmaceutical preparations, in addition to solubilizers, pH adjusters and preservatives. Examples of the auxiliary include a flavoring agent, a flavoring agent, and a consistency adjusting agent. The flavoring agent is
Sweeteners such as sucrose, mannitol, sorbitol, xylitol, saccharin sodium, aspartame and the like. Flavoring agents include flavorants such as cauliflower oil, peppermint oil and menthol. Ethanol, as a consistency adjusting agent,
Solvents such as propylene glycol and glycerin, grape and the like, sugars such as lactose, macrogol, hydroxypropyl cellulose, polymers such as polyvinyl pyrrolidone, polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyethylene polyoxypropylene glycol and the like Surfactants and the like. Since the amount of the auxiliary agent varies depending on the type of the auxiliary agent, it cannot be unconditionally determined.
ml or less, preferably 300 mg / ml or less, for example, 0
-700 mg / ml, preferably 3-300 mg / ml
It is.

In the aqueous sennoside calcium preparation of the present invention, the amounts of the calcium salts of sennosides A and B, a solubilizer, water, optional preservatives and auxiliaries are preferably as follows with respect to the whole aqueous preparation. It is. Sennoside A is generally 0.2 mg / ml or more, preferably 5 mg / ml or more, and more preferably 10 mg / ml or more on the calcium of B, the upper limit of which is that of a monosium salt, generally 55 mg / ml. , Preferably 50 mg / ml, more preferably sennoside A, preferably 40 mg / ml. Therefore, generally 0.2 to 55 mg / ml as B and preferably 5 to 50 mg / ml, more preferably 12 to 40 mg / ml. Solubilizer In general, it is 1 mg / ml or more, preferably 3 mg / ml or more, more preferably 5 mg / ml or more, and the upper limit is generally 80 mg / ml, preferably 50 mg / ml, more preferably 30 mg / ml. / Ml. Therefore, the content of the solubilizer is generally 1 to 80 mg / ml, preferably 3 to 50 mg / ml, more preferably 5 to 30 mg / ml. Although no preservative may be added, it is 8 mg / ml or less, preferably 5 mg / ml or less, for example, 0 to 8 mg / ml, and preferably 0.2 to 5 mg / ml. Although no auxiliary agent may be added, 700 mg / ml or less, preferably 300 mg / ml or less, for example, 0 to 700 mg / ml, preferably 3 to 300 mg / ml. Water

The aqueous solution preparation of the present invention contains 0.02 to 120 parts by weight of a carboxylic acid or a pharmaceutically acceptable salt thereof per 1 part by weight of the calcium salt of sennosides A and B as sennosides A and B. , Preferably 0.1 to 60
It is preferably in parts by weight. The aqueous sennoside calcium preparation of the present invention is prepared according to a conventional method. That is, calcium salts of sennosides A and B, a solubilizing agent, and if necessary, a preservative and an auxiliary agent are dissolved in water. After adjusting the pH, adjust the volume. To remove insolubles and foreign matter,
Perform filtration, decantation and / or centrifugation to obtain a clear aqueous solution. This aqueous solution is filled in a glass container, a plastic container, or the like, and provided as a preparation. The dose is determined according to the age, body weight, symptoms, treatment purpose, etc. of the patient, but usually an adult is taken once daily with an aqueous preparation containing 12 to 24 mg of sennoside AB calcium salt. It may not increase or decrease depending on the symptoms. In the present invention, the aqueous solution preparation may be taken as a stock solution,
It is desirable to dilute the waste liquid with water or the like and take it.

[0022]

The operation and effect of the present invention will be specifically shown by test examples. Test example. Aqueous solution stability test Sample Inventive product: Aqueous solution of calcium salt of sennoside A and B of Examples 1-4 Control: Aqueous solution of calcium salt of sennoside A and B of control example 1

2. Test 2 ml of the sample aqueous solution was placed in a 10 ml vial, sealed, stored at 40 ° C. for 2 weeks, and measured for appearance, content and pH. The content was determined by high performance liquid chromatography (detection wavelength 2
70 nm), and the residual ratio at the start of storage was determined.

3. Test Results The results of the appearance test are shown in Table 1. The aqueous solution preparation of the product of the present invention was a stable aqueous solution without insolubles or precipitates.
On the other hand, in the control example, insolubles were precipitated and the stability was lacking. The insolubles in Control Example 1 (containing no solubilizer) were presumed to be degradants derived from commercially available sennoside A and B drug substance. In the product of the present invention, no precipitation or the like occurred due to the fact that calcium sennoside and citric acid had a special dissolved structure.

[0025]

Table 1 Formulation Appearance Inventive product: Aqueous solution preparation of Example 1 No change Inventive product: Aqueous solution formulation of Example 2 No change Inventive product: Aqueous solution formulation of Example 3 No change Inventive product: Example 4 Aqueous solution formulation No change Control: Aqueous solution formulation of control example 1 Brown insoluble precipitate

The content is from 91% to 96% in the examples,
In the control example, it was 86% to 93%. There was almost no change in pH. The aqueous solution of sennoside calcium of the product of the present invention has a content of 95 when stored at 25 ° C for 13 weeks.
% Or more, and has sufficient stability for practical use if stored at low temperatures.

[0027]

【Example】

Example 1 Calcium salts of sennosides A and B (Sennoside-7
0, Nippon Powder Chemical, content is 5 as sennoside A and B
(5.1%) 3.0m g in 50mM citrate buffer pH 6.0 (adjusted with citric acid and sodium hydroxide) 140m
l. An aqueous sodium hydroxide solution was added to adjust the pH to 7.0. The insolubles were removed with a 0.22 μm pore size membrane filter, and the sennoside A and B
mg / ml, about 10 mg / ml citric acid, pH 6.0, resulting in a clear, dark brown aqueous solution.

Example 2 Calcium salts of sennosides A and B (Sennoside-7
0, Nippon Powder Chemical, content is 5 as sennoside A and B
(5.1%) 3.07 g was dissolved in 140 ml of 50 mM citrate buffer pH 6.0. An aqueous sodium hydroxide solution was added to adjust the pH to 7.0. Insoluble materials were removed with a 0.22 μm pore size membrane filter, and sennoside A was removed.
And B concentration 12 mg / ml, citric acid about 10 mg / m
1, a dark brown clear aqueous solution of pH 7.0 was obtained.

Example 3 Calcium salts of sennosides A and B (Sennoside-9
0, Nippon Powder Chemical, content is 8 as sennoside A and B
(6.9%) 0.35 g, citric anhydride 0.25 g, and methyl paraben 7.5 mg were dissolved in purified water. An aqueous sodium hydroxide solution was added to adjust the pH to 7.0, and purified water was added to 25 ml. The insolubles were removed with a 0.45 μm pore size membrane filter, and the sennoside A and B concentrations were 1
A dark brown clear aqueous solution of 2 mg / ml, citric acid 10 mg / ml, methyl paraben 0.3 mg / ml, pH 7.0 was obtained.

Example 4 Calcium salts of sennosides A and B (Sennoside-7
0, Nippon Powder Chemical, content is 5 as sennoside A and B
5.1%) 1.64 g, citric acid 0.5 g, sucrose 12.
5 g and 7.5 mg of methyl paraben were dissolved in purified water.
An aqueous sodium hydroxide solution was added to adjust the pH to 7.0, and purified water was added to 25 ml. 0.4 pore size for insoluble matter
After removing with a 5 μm membrane filter, sennoside A
And B concentration about 36 mg / ml, citric acid about 20 mg / m
l, white sugar 500mg / ml, methyl paraben 0.3mg
/ Ml, pH 7.0, resulting in a clear dark brown aqueous solution.

Example 5 Calcium salt of sennoside A and B (Sennoside, Nippon Powder Chemical Co., Ltd., content is 64.9 as sennoside A and B
%) 22 g, sorbitol 100 g, citric acid 1.5
g, 8.6 g of sodium citrate dihydrate, 0.5 g of methyl paraben, and 0.25 g of benzoic acid were dissolved in purified water. An aqueous sodium hydroxide solution was added to adjust the pH to 7.0, and purified water was added to 500 ml. The mixture was treated with a high-speed centrifuge at 10,000 rpm for 30 minutes to precipitate insolubles, and sennoside A and B concentrations were about 28 mg / ml, citric acid was about 14 mg / ml, sorbitol 200 mg / ml,
Methyl paraben 1 mg / ml, benzoic acid 0.5 mg / m
1, a dark brown clear aqueous solution of pH 7.0 was obtained.

Control Example 1 Calcium salt of sennoside A and B (Sennoside-7
0, Nippon Powder Chemical, content is 5 as sennoside A and B
8.8%) was dissolved in purified water. The pore size is 0.
The solution was removed with a 45 μm membrane filter to obtain a dark brown clear aqueous solution having sennoside A and B concentrations of 12 mg / ml and pH 7.0.

[0033]

The aqueous sennoside preparation of the present invention contains calcium salts of sennosides A and B, which are highly effective, and is stable without precipitation of insolubles and formation of precipitates. In addition, it is easy to set an appropriate dose for each patient, and the preparation is easy to take even for children and the elderly.

Claims (15)

[Claims] 1. A sennoside calcium aqueous solution preparation comprising (1) at least one of calcium salts of sennosides A and B, and (2) carboxylic acids or a pharmaceutically acceptable salt thereof. 2. The calcium salt content of sennosides A and B is 0.2 to 55 mg / m 2 as sennosides A and B.
The aqueous solution preparation according to claim 1, which is 1. 3. The aqueous solution preparation according to claim 1, wherein the carboxylic acids are water-soluble di- to tetra-basic acids. 4. The aqueous solution preparation according to claim 1, wherein the pH of the aqueous solution is 5 to 8. 5. The aqueous solution preparation according to claim 1, which further comprises a preservative and an auxiliary agent as required, that is, a sweetener as a flavoring agent, a flavor as a flavoring agent, and a consistency regulator. 6. A calcium salt of sennosides A and B, a carboxylic acid or a pharmaceutically acceptable salt thereof, water, and if necessary, a preservative and an auxiliary agent. An aqueous solution formulation as described below. Calcium salts of sennosides A and B as sennosides A and B 0.2 to 55 mg / ml Carboxylic acids or pharmaceutically acceptable salts thereof 1 to 80 mg / ml Preservatives 0 to 8 mg / ml Auxiliaries 0 to 700 mg / ml PH of aqueous solution pH5-8 Water balance 7. A calcium salt of sennosides A and B as sennosides A and B in an amount of 12 to 40 mg / ml citric acid or an alkali metal salt thereof in an amount of 5 to 30 mg / ml preservative 0.2 to 5 mg / ml The formulation according to claim 6, wherein the pH of the aqueous solution is 3 to 300 mg / ml. 8. An aqueous solution of calcium sennoside which contains at least one of calcium salts of sennosides A and B and does not precipitate insolubles or precipitates even after storage at 40 ° C. for 2 weeks. 9. An aqueous solution of calcium sennoside which contains at least one of calcium salts of sennosides A and B and which does not precipitate insolubles or precipitates even after storage at 25 ° C. for 13 weeks. 10. The preparation according to claim 8, wherein the pH of the aqueous solution is from 5 to 8. 11. The preparation according to claim 8, further comprising a carboxylic acid or a pharmaceutically acceptable salt thereof. (12) Sennosides A and B relative to the whole preparation
Sennosides A and B in the range of 0.2 to 5
The formulation according to claim 8 or 9, which comprises 5 mg / ml. 13. A carboxylic acid or a pharmacologically acceptable salt thereof in an amount of 1 to 80 mg / ml based on the whole preparation.
The formulation of claim 12, comprising: 14. A carboxylic acid or a pharmaceutically acceptable salt thereof is used in an amount of 0.02 to 12 based on 1 part by weight of the calcium salt of sennoside A or B as sennoside A or B.
2. The preparation according to claim 1, comprising 0 parts by weight. 15. The preparation according to claim 1, which is substantially free of orthophosphoric acid or a pharmaceutically acceptable salt thereof.