JP3422656B2 - Sennoside calcium aqueous solution preparation - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous sennoside calcium preparation containing calcium salts of sennosides A and B useful as laxatives as an active ingredient.

[0002]

2. Description of the Related Art Sennosides A and B are major medicinal components having a laxative effect contained in senna and rhubarb, which have been used as laxatives since ancient times. Although senna has a general action of a natural crude drug, it is considered that a considerable amount of a resin component is mixed therein, which may cause irritating abdominal pain, diarrhea, nausea and the like. Senna extract is a sennoside contained in senna, a sennoside-like compound, aloe-emodin,
It contains an active ingredient such as rhein and can be expected to have a general action of natural herbal medicines, and it is highly useful because the resin component is removed to reduce side effects. (Yakuji Nippo, No. 8582, 1
995)

According to the Japanese Pharmacopoeia specification, the senna extract has a sennoside A and B content of 15 to 25%. In clinical practice, tablets using a calcium salt of sennosides A and B as a main component of the active ingredient and a drug substance having a content of about 55 to 95% are widely used. By increasing the content of sennoside, the dose of laxative ingredients becomes more accurate,
Reliable laxative action and reduction of side effects are achieved. However, because of its strong laxative effect, sennosides A and B are
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 is desired.

Regarding an aqueous solution preparation using senna extract or senna extract granules having a low sennoside content, Japanese Patent Publication No. 7-5470 discloses that a solution containing sennosides is stably filtered through a porous filter medium in a state where no precipitate is formed. A manufacturing method for obtaining an internal drug solution is disclosed.

On the other hand, regarding aqueous solutions using high-purity sennosides A and B, Rainonen et al. (Pharm
acology & Toxicology, 63, 37
P., 1988), reports its stability and reports that pH 6.5 is most stable with citrate-phosphate buffer.

Next, Japanese Patent Laid-Open No. 49-118820 discloses that
Powders stabilized as crystals of the calcium salts of sennosides A and B are disclosed and used in the manufacture of tablets. However, nothing is known about the solution formulation 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 simple aqueous solution has a defect that an insoluble matter is deposited during storage during storage, and a long-term stable water-soluble preparation has not been obtained.

An aqueous solution of the calcium salt of sennosides A and B was filtered through a cellulose filter, which is the method disclosed in Japanese Patent Publication No. 7-5470, but the stability was the same before and after filtration. It is considered that this is because the calcium salts of sennosides A and B before filtration were highly purified and did not contain components such as β-glucosidase that inactivates sennosides, and stabilization of the calcium salt solution formulation. On the other hand, the filtration method described in JP-B-7-5470 is not sufficient.

In the calcium salts of sennosides A and B, calcium phosphate is precipitated in the buffer solution containing phosphoric acid as shown in the above-mentioned report of Rainonen et al. Since the precipitated calcium phosphate is a fine crystal and is hard to settle, decantation is difficult, and there is a problem that the filtering material is clogged by filtration and it takes a long time to remove it. As described above, in order to obtain a stable solution formulation of a high content calcium salt of sennoside, it is necessary to solve stabilization of sennoside and prevention of precipitation of insoluble matter.

[0010]

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

2. The content of calcium salts of sennosides A and B is 0.2 to 55 mg as sennosides A and B.
2. The aqueous solution preparation according to item 1, which is / ml. 3. The aqueous solution preparation according to the above 1, wherein the carboxylic acid is a water-soluble di-to-basic acid. 4. The aqueous solution preparation according to the above 1, wherein the pH of the aqueous solution is 5-8. 5. The aqueous solution preparation according to 1 above, which optionally contains a preservative and an auxiliary agent, that is, a sweetener as a corrigent, a flavor as a flavoring agent, and a consistency modifier. Aqueous solution containing calcium salts of sennosides A and B, carboxylic acids or pharmacologically acceptable salts thereof, water, and optionally preservatives and auxiliaries, the contents of which are as follows with respect to the entire solution. Preparation, calcium salt of sennoside A and B as sennoside A and B 0.2 to 55 mg / ml Carboxylic acid or pharmaceutically acceptable salt thereof 1 to 80 mg / ml Preservative 0 to 8 mg / ml Auxiliary agent 0 to 700 mg / Ml pH of aqueous solution pH 5-8 Water balance

7. 12 to 40 mg / ml citric acid or its alkali metal salt as a sennoside A and B calcium salt of sennoside A and B to the whole preparation 5 to 30 mg / ml preservative 0.2 to 5 mg / ml auxiliary agent 3 to 300 mg / Ml pH of aqueous solution pH 6-7.5 water The formulation according to the above item 6, which is the balance. An aqueous sennoside calcium preparation containing at least one of calcium salts of sennosides A and B and free from insoluble matter or precipitate even when stored at 40 ° C. for 2 weeks,

9. 10. An aqueous sennoside calcium preparation containing at least one of sennoside A and B calcium salts and free from insoluble matter or precipitate even after storage at 25 ° C for 13 weeks. 10. The formulation according to the above 8 or 9, wherein the pH of the aqueous solution is 5 to 8. 10. The preparation according to claim 8 or 9, further comprising a carboxylic acid or a pharmaceutically acceptable salt thereof. Calcium salts of sennosides A and B were used as sennosides A and B in an amount of 0.2 to 55 mg /
13. The preparation according to the above 8 or 9, which contains ml. The formulation according to the above 12, further comprising 1 to 80 mg / ml of a carboxylic acid or a pharmacologically acceptable salt thereof, based on the entire formulation.

14. The carboxylic acid or its pharmacologically acceptable salt is added in an amount of 0.02 to 1 part by weight of the calcium salt of sennoside A and B as sennoside A and B.
120 parts by weight, preferably 0.1 to 60 parts by weight
14. The preparation according to the item 15. The present invention relates to the preparation according to the above 1, which is substantially free of orthophosphoric acid or a pharmaceutically acceptable salt thereof. The term "substantially free of orthophosphoric acid or a salt thereof" means that an amount of orthophosphoric acid that causes an insoluble precipitate during storage is not included.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below. The sennosides A and B are the erythro and threo forms of the stereoisomers of the reidianthrone glucoside present in senna, rhubarb, and the like. As a high content product of sennosides A and B, a calcium salt product is commercially available and can be used as a drug substance. The content of the calcium salt of sennosides A and B of the present invention in the aqueous solution preparation is generally 0.2 mg / ml or more, preferably 5 mg / ml or more, more preferably 10 mg / ml as sennosides A and B.
More than mg / ml, the upper limit is generally 55 mg
/ Ml, preferably 50 mg / ml, more preferably 4
It is 0 mg / ml. Therefore, the content of the aqueous solution preparation of the calcium salt of sennoside 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 solubilizing agent include water-soluble carboxylic acids. These carboxylic acids may be used as a salt with an alkali, and examples of the alkali salt 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. Alkali metal salts such as sodium and potassium are preferred. The carboxylic acids or their pharmacologically acceptable salts include
Examples thereof include water-soluble polybasic acids or salts thereof, such as dibasic acids such as succinic acid, glutaric acid, maleic acid, malic acid, tartaric acid, tribasic acids such as citric acid, and tetrabasic acids such as edetic acid. Examples thereof include alkali metal salts thereof, and citric acid and its alkali metal salts are particularly preferable. The content of the solubilizer is generally 1 mg / ml or more, preferably 3
It is at least mg / ml, more preferably at least 5 mg / ml, and the upper limit is generally 80 mg / ml, preferably 50 mg / ml, more preferably 30 mg / ml. Therefore, the content of the solubilizer is generally 1 to 8
It is 0 mg / ml, preferably 3 to 50 mg / ml, more preferably 5 to 30 mg / ml.

Examples of the pH adjusting agent for the aqueous solution include acids and bases usually used in medicine, with hydrochloric acid and sodium hydroxide being preferred. Further, it may be adjusted with carboxylic acids as a solubilizing agent and alkali metal salts thereof. The pH of the aqueous solution is 5 or more, preferably 6 or more, and the upper limit thereof is 8 or less,
It is preferably 7.5 or less. Therefore, the pH of the aqueous solution
Is 5 to 8, preferably 6 to 7.5.

Examples of preservatives include paraoxybenzoic acid esters (such as methylparaben), benzoic acid, sorbic acid, dehydroacetic acid and salts thereof. The addition amount of the preservative may be no addition, 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, auxiliary agents commonly used in pharmaceutical preparations in addition to solubilizing agents, pH adjusters and preservatives. Examples of the auxiliaries include flavoring agents, flavoring agents, and consistency adjusting agents. The flavoring agent is
Examples include sweeteners such as sucrose, mannitol, sorbitol, xylitol, sodium saccharin, and aspartame. Examples of the flavoring agent include fragrances such as cinnamon oil, peppermint oil, and menthol. As a consistency adjusting agent, ethanol,
Propylene glycol, solvents such as glycerin, grapes, sugars such as lactose, macrogol, hydroxypropyl cellulose, polymers such as polyvinylpyrrolidone, polyoxyethylene hydrogenated castor oil, polysorbate, polyoxyethylene polyoxypropylene glycol, etc. Examples thereof include surfactants. The amount of auxiliary agent added varies depending on the type of auxiliary agent, so it cannot be generally stated, but 700 mg /
ml or less, preferably 300 mg / ml or less, for example 0
~ 700 mg / ml, preferably 3-300 mg / ml
Is.

In the sennoside calcium aqueous solution preparation of the present invention, the compounding amounts of the calcium salts of sennosides A and B, the solubilizing agent, water, the optional preservative, and the auxiliary agent are preferably as follows with respect to the entire aqueous solution preparation. Is. Sennoside A is generally 0.2 mg / ml or more, preferably 5 mg / ml or more and on the basis of B, more preferably 10 mg / ml or more, and the upper limit thereof is a monocium salt, generally 55 mg / ml. , Preferably 50 mg / ml, more preferably sennoside A, more preferably 40 mg / ml. Therefore, it is generally 0.2 to and 55 mg / ml as B, preferably 5 to 50 mg / ml, more preferably 12 to 40 mg / ml. Dissolution aid Generally, it is 1 mg / ml or more, preferably 3 mg / ml or more, more preferably 5 mg / ml or more, and the upper limit thereof is generally 80 mg / ml, preferably 50 mg / ml, more preferably 30 mg. / Ml. Therefore, the content of the solubilizing agent 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, preferably 0.2 to 5 mg / ml. It may be added without an auxiliary agent, but may be 700 mg / ml or less, preferably 300 mg / ml or less, for example 0 to 700 mg / ml, preferably 3 to 300 mg / ml. Remaining water

The aqueous solution preparation of the present invention contains 0.02 to 120 parts by weight of carboxylic acid or a pharmacologically acceptable salt thereof, based on 1 part by weight of the calcium salt of sennosides A and B as sennosides A and B. , Preferably 0.1-60
It is preferably part by weight. The sennoside calcium aqueous solution preparation of the present invention is prepared by a conventional method. That is, the 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 insoluble matter and foreign matter,
Filter, decant and / or centrifuge to give 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 depending on the age, weight, symptoms, treatment purpose, etc. of the patient, but usually an adult aqueous solution preparation containing 12 to 24 mg of sennoside AB calcium salt is taken once a day. It can be increased or decreased depending on the symptoms. In the present invention, the aqueous solution formulation 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 action and effect of the present invention will be specifically shown by test examples. Test example. Aqueous solution stability test 1. Sample of the present invention: aqueous solution of calcium salt of sennoside A and B of Examples 1 to 4 Control: aqueous solution of calcium salt of sennoside A and B of Control Example 1

2. 2 ml of the test sample aqueous solution was placed in a 10 ml vial, the container was tightly closed, and the mixture was stored at 40 ° C. for 2 weeks, and the appearance, content and pH were measured. The content is determined by high performance liquid chromatography (detection wavelength 2
70 nm) to determine the residual rate at the start of storage.

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 in which insoluble matter and precipitate did not deposit.
On the other hand, in the control example, insoluble matter was deposited and the stability was poor. The insoluble matter of Control Example 1 (containing no solubilizing agent) was estimated to be a degradation product derived from the commercially available sennoside A and B drug substances. In the product of the present invention, it was presumed that the precipitation and the like did not occur because sennoside calcium and citric acid had a special dissolved state structure.

[0025]

[Table 1]                   Prescription       Inventive product: Aqueous solution preparation of Example 1 No change       Inventive product: Aqueous preparation of Example 2 No change       Inventive product: Aqueous preparation of Example 3 No change       Inventive product: Aqueous preparation of Example 4 No change         Control: aqueous solution preparation of Control Example 1 brown insoluble matter precipitation

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

[0027]

【Example】

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

Example 2 Calcium salts of sennosides A and B (sennoside-7
0, Japanese powder chemicals, content 5 as sennoside A and B
3.0% (5.1%) was dissolved in 140 ml of 50 mM citrate buffer with pH 6.0. An aqueous sodium hydroxide solution was added to adjust the pH to 7.0. Insoluble matter was removed with a 0.22 μm membrane filter, and sennoside A was used.
And B concentration 12 mg / ml, citric acid about 10 mg / m
A clear, dark brown aqueous solution having a pH of 7.0 was obtained.

Example 3 Calcium salts of sennosides A and B (sennoside-9
0, Japan powder chemical, content 8 as sennoside A and B
(6.9%) 0.35 g, anhydrous citric acid 0.25 g, and methylparaben 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 make 25 ml. Insoluble matter was removed with a 0.45 μm pore size membrane filter, and sennoside A and B concentrations were 1
A dark brown clear aqueous solution of 2 mg / ml, citric acid 10 mg / ml, methylparaben 0.3 mg / ml, pH 7.0 was obtained.

Example 4 Calcium salts of sennosides A and B (sennoside-7
0, Japanese powder chemicals, content 5 as sennoside A and B
(5.1%) 1.64 g, citric acid 0.5 g, sucrose 12.
5 g and methylparaben 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 make 25 ml. Insoluble matter has a pore size of 0.4
Sennoside A was removed with a 5 μm membrane filter.
And B concentration about 36 mg / ml, citric acid about 20 mg / m
1, sucrose 500mg / ml, methylparaben 0.3mg
/ Ml, pH 7.0 a dark brown clear aqueous solution was obtained.

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

Control Example 1 Calcium salts of sennosides A and B (sennoside-7
0, Japanese powder chemicals, content 5 as sennoside A and B
8.8%) was dissolved in purified water. The insoluble matter has a pore size of 0.
It was removed by a 45 μm membrane filter to obtain a dark brown clear aqueous solution having a sennoside A and B concentration of 12 mg / ml and a pH of 7.0.

[0033]

The sennoside aqueous solution preparation of the present invention contains the highly effective calcium salts of sennosides A and B, and is stable without precipitation or precipitation of insoluble matter. In addition, it is easy to set a suitable dose for each patient, and the preparation is easy to take even for children and the elderly.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI // C07H 15/244 C07H 15/244 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/70-31 / 80 A61K 9/00-9/72 A61K 35/78 A61K 47/00-47/48 A61P 1/10 C07H 15/244 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. It comprises (1) at least one of calcium salts of sennosides A and B, and (2) a carboxylic acid of a water-soluble polybasic acid or a pharmaceutically acceptable salt thereof. Sennoside calcium aqueous solution preparation. 2. The content of calcium salts of sennosides A and B is 0.2 to 55 mg / m as sennosides A and B.
2. The aqueous solution preparation according to claim 1, which is 1. 3. The aqueous solution preparation according to claim 1, wherein the carboxylic acid is a water-soluble di- to tetrabasic carboxylic acid. 4. The aqueous solution preparation according to claim 1, wherein the pH of the aqueous solution is 5-8. 5. The aqueous solution preparation according to claim 1, which further contains a preservative and an auxiliary agent, that is, a sweetening agent as a corrigent, a flavoring agent as a flavoring agent, and a consistency adjusting agent, if necessary. 6. A calcium salt of sennosides A and B, a water-soluble polybasic carboxylic acid or a pharmacologically acceptable salt thereof, water, and if necessary, a preservative and an auxiliary agent, the contents of which are An aqueous solution formulation as follows for the entire solution. Calcium salts of sennosides A and B as sennosides A and B 0.2 to 55 mg / ml Water-soluble carboxylic acid of polybasic acid or pharmaceutically acceptable salt thereof 1 to 80 mg / ml Preservative 0 to 8 mg / ml Auxiliary agent 0-700 mg / ml pH of aqueous solution pH 5-8 Water balance 7. The whole formulation, Calcium salts of sennosides A and B 12 to 40 mg / ml as sennoside A and B Citric acid or its alkali metal salt 5-30 mg / ml Preservative 0.2-5 mg / ml Auxiliary agent 3 to 300 mg / ml PH of aqueous solution pH 6-7.5 Remaining water The formulation according to claim 6, which is 8. A carboxylic acid of a water-soluble polybasic acid or a pharmacologically acceptable salt thereof is used in an amount of 0.02 to 120 parts by weight based on 1 part by weight of the calcium salt of sennoside A and B as sennoside A and B. The formulation according to claim 1, which comprises parts by weight.