JPS5837284B2 - Seiyakusabutsunoseihou - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel method for making pharmaceutical compositions.

The novel pharmaceutical composition according to the invention is a bismuth-containing anti-ulcer agent in solid form.

Liquid compositions made from bismuth salts such as bismuth citrate or bismuth hyponitrite are known.

However, such liquid compositions have the disadvantage that they are inferior to solid compositions in terms of ease of storage and transport.

Moreover, the conversion of liquid compositions into useful solid products, for example by simple heating and drying operations, cannot be easily accomplished.

According to the present invention, an aqueous, colloidal solution consisting of effective amounts of bismuth citrate, ammonia and a polyhydric alcohol is converted by spray drying into the dry powder form of a novel pharmaceutical composition.

The starting liquid is pepsin, a coloring agent such as carmine, and an alkali metal (such as sodium or potassium).
hydroxide and a preservative such as p-hydroxybenzoic acid ester [trade name Nipacombin A (
(commercially available as Nipacombin A)].

The above liquid preparations sometimes contain volatile liquids such as ethanol and chloroform.

Such liquids should preferably not exceed 15% of the starting material present in the process of the invention, provided that they have no practical effect on the process or the products produced by the process.

Generally speaking, commercially available liquid products containing bismuth citrate, ammonia and polyhydric alcohols may be used in the practice of this invention.

It is not known with certainty whether bismuth citrate, ammonia and polyhydric alcohol exist in liquid form or whether these three form new molecules or ions.

Bismuth citrate can be used as the material, but it can also be formed for use with a biologically acceptable anion, for example from citric acid and a bismuth salt.

The liquid is most stable at a pH of approximately 9.

However, if the pH is too low or too high, a precipitate will form.

In special cases where the liquid is to be stored for a period of time before being subjected to spray drying, it is better not to use large amounts of ammour and alkali metal hydroxides to avoid reaching pH levels that will cause precipitation.

The amount of ammonia used should be at least sufficient to keep the bismuth in solution.

The polyhydric alcohol is preferably a disaccharide such as sucrose or maltose.

Other points to note in ammonia-containing liquid preparations are that the ammonia-containing liquid products are stable only within a limited pH range and that the escape of ammonia causes a significant decrease in pH.

The liquid starting material used in the process preferably contains 11-16% soluble solids, which may produce dry powder products according to the invention from liquids by using conventional spray drying equipment.

Preferably, the solution is preheated to a temperature of 60-65°C.

The length of preheating time should be such that it does not cause undesired reactions.

For example, when using sucrose, the preheating time should be 20 minutes or less to prevent conversion.

The solid products obtained according to the invention are highly hygroscopic.

Therefore, preheating e.g. the air temperature at the inlet to approx. 200-25
Moisture is removed from the spray drying apparatus by a preheating treatment for 30 to 60 minutes at 0 DEG C., followed by the drying process using air with a low moisture content.

The air temperature at the inlet during the drying process is 150-260℃
is preferably 170-190'C, and the outlet air temperature is 50-110'C.
It is preferable that

It should be understood that the liquid delivery rate to the spray dryer is such that sufficient evaporation capacity is maintained to form a dry powder.

It is an important aspect of the invention that the product obtained according to the invention is solid.

This powder product can be taken orally as is, or it can be dissolved in water to form an easy-to-take solution.

Included within the scope of the invention are pharmaceutical compositions in dosage forms suitable for oral administration, such as capsules or tablets, containing as the active ingredient a therapeutically active dry bismuth product.

This combination may contain a pharmaceutically acceptable carrier.

Conventional methods may be employed in formulating the tablets using one or more pharmaceutically acceptable diluents or excipients such as lactose or starch and the inclusion of lubricating substances such as calcium or magnesium stearate. obtain.

Capsules made of absorbent materials such as gelatin may contain the active substance alone or mixed with solid or liquid diluents.

The pharmaceutical composition according to the invention can be used to treat gastric ulcers, duodenal ulcers, post-surgical ulcers and hiatus hernias.
It is therapeutically effective in the treatment of peptic ulcers, including peptic ulcers associated with P. hernia).

The preferred daily dose for adults is 450 ml of Bi203.
It corresponds to ~1000 ■.

Dosages for children will vary depending on body weight and age and may be calculated according to routine medical practice.

The daily dosage for children under 10 years of age is Bi203.
This corresponds to 150 to 400 m9.

Therefore, the present composition in dosage form has Bi203 of 50 to
It is preferred to have a bismuth content of 250 mm.

The following examples illustrate the method of the invention.

Example 1 Bismuth citrate 180.360 kg Ammonia (25%) 118.279 l Pepsin (1
:]0000) 7.125kg anhydrous citric acid
2 3.7 0 0kg Carmine Nacala l- 0. 9 9 0 l(car
mine nacarat) 8.051l 3 3 0.0 0 0kg 39.900ky 3. OOOk9 8.700l Ethanol 94.0507 pure
1,500 by adding the remainder of the water. A liquid product of e was prepared.

Water was added to this solution to dilute it to a solids content of 12%, and the diluted solution was preheated to 60-65° C. for 15 minutes.

A spray dryer with an evaporation capacity of 10 kg/h was preheated to an inlet air temperature of 200° C. for 30 minutes.

The above diluted solution was then fed to the spray dryer at a rate of 9 l/h.

At this time, the supply port air temperature was maintained at 180° C., and the produced dry powder was collected.

The following example is glycerin sucrose potassium hydroxide nipacombin A (0.2%) chloroform illustrating a pharmaceutical composition according to the present invention.

Example 2 Spray-dried product prepared in Example 1 4 50 mI? Aerosil 2 0 0
Tablets were prepared using known pharmaceutical technology by incorporating 25■ (purified silicon dioxide) corn starch 50m9 and magnesium stearate 5m9.

Included within the scope of the invention is the production of aqueous solutions by using the dry powders described above as raw materials.

For example, by dissolving the powdered product 2001 obtained in Example 1 in 1 liter of water, a solution suitable for oral administration is obtained.

By adding other physiologically acceptable substances it is possible, for example, to produce solutions of a desired pH or taste-improved solutions.

Matters related to the present invention will be described below.

(1) The method of claim 1, wherein the liquid starting material contains from 1 liter to 16% soluble solids.

(2) A method according to claim or paragraph (1), wherein the liquid starting material is preheated to 60-65°C.

(3) The method according to claim 1 or item (1) or (2), in which the spray drying device is preheated and drying is performed in air with low moisture content.

(4) Preheat the spray dryer to 200-250℃ (
The method described in section 3).

(5) The method according to claims or items (1) to (4), wherein the inlet air temperature is 150 to 260°C.

(6) No. 5 where the inlet air temperature is 170 to 190°C
).

(7) A pharmaceutical composition comprising a powder product obtained by the method defined in the claims or any of paragraphs (1) to (6) in a dosage form for oral administration. How things are made.

(8) The method for producing the pharmaceutical composition according to item (7), which has a bismuth content corresponding to 50 to 250 m9 of B12o3.

(9) A therapeutically effective liquid product for oral administration consisting of dissolving in water a dry powder obtained by the method defined in the claims or in any of paragraphs (1) to (6). manufacturing method.

Claims (1)

[Claims] 1. Process for the preparation of a novel solid bismuth-containing pharmaceutical composition, characterized in that an aqueous, colloidal solution containing effective amounts of bismuth citrate, ammonia and a polyhydric alcohol is converted into a dry powder by a spray-drying process.