JP3281002B2 - Sucralfate aqueous suspension stock solution and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an aqueous suspension concentrate for producing a sucrose polysulfate aluminum salt (sucralfate) preparation.

[0002]

[0002] Sucralfate is a drug substance used as a therapeutic agent for gastritis, stomach and duodenal ulcer.

The therapeutic effect of sucralfate is
It is necessary to selectively adsorb sucralfate to the site of ulcer / inflammation. The characteristic of the biological activity of sucralfate is that sucralfate particles are non-specifically adsorbed to tissue proteins, the acid in gastric juice increases the viscosity, sticks sucralfate to diseased parts, and is further secreted in the stomach The expression of the total effect of adsorbing and inactivating hepsin improves tissue repair ability and promotes a biological defense effect that leads to healing of ulcers and inflammation.

[0004] Sucralfate is disclosed in JP-B-44-1167.
No. 3, as described in JP-B-44-16037, aluminum ions are reacted with sucrose polysulfate to disperse the wet powder that precipitates, and then heat-dried (spray-dried). The obtained dried product was used as a bulk material. The reason for this is that the use of a dried product is advantageous in producing a solid preparation.

[0005] Sucralfate is insoluble in water, and considering its ability to adsorb proteins, it is important to minimize the particle size and increase the surface area when applied to living organisms.

[0006] An aqueous suspension of sucralfate is considered to be applied to an inflammation or ulcer site as an internal or external preparation. A conventional aqueous suspension of sucralfate has been prepared by micronizing the above heat-dried product, adding water again, and mixing.

[0007]

A conventional aqueous suspension of sucralfate is prepared by mechanically pulverizing a dry powder obtained by heating and drying a wet powder of sucralfate, adding the finely powdered powder to water again, and mixing. . In this production method, the production method comprising the steps of (1) drying, pulverizing, and suspending the wet powder in water is inferior in operability and high in cost, and (2) pulverization of the dried powder has a large variation in particle diameter. (3) there is a problem of production environment contamination due to fine powder generated when the dry powder is pulverized;
(4) The finely powdered sucralfate is sealed in a container,
It has drawbacks such as easy dissipation at the time of opening and during the operation of the preparation of the preparation, which may lead to contamination, and cannot be said to be an industrially superior production method.

The present inventors have tried to solve these drawbacks.
As a result of intensive studies, wet grinding of wet powder has a shorter process and lower cost than conventional methods, has less variation in particle size, and furthermore, contamination of the production environment due to fine powder during grinding. The present inventors have found an industrially excellent manufacturing method which is free from environmental pollution due to the dispersal of fine powder during packaging, transportation, and use, and completed the present invention.

[0009]

The aqueous suspension stock solution for producing sucralfate preparation according to the present invention is obtained by dispersing sucralfate wet powder in water or water containing additives, and then dispersing the resulting powder. . The sucralfate wet powder used here is, for example, Japanese Patent Publication No. 44-11 / 1972.
No. 673 and JP-B-44-16037. That is, it can be obtained by reacting aluminum ion (aluminum hydroxychloride, polyaluminum chloride, etc.) with the salt of sucrose polysulfate, performing a water washing operation on the precipitated sucralfate, and separating it. Unreacted raw materials and the like remain in the aluminum chloride reaction solution during the production of sucralfate, and a large amount of chloride ions resulting from the reaction is contained. Therefore, it is necessary to perform a water washing operation to remove these. It is. For example, the reaction solution can be removed by repeated operations of standing sedimentation, supernatant exchange, stirring, and standing sedimentation. Furthermore, a sucralfate wet powder can be obtained by, for example, centrifugation, decantation, or the like.

The thus obtained sucralfate wet powder is dispersed in water or an aqueous medium without drying, and then pulverized to produce an aqueous suspension stock solution for producing sucralfate preparations. Additives to be added to water include suitable preservatives for suppressing the growth of microorganisms and molds, such as benzoic acid, p-oxybenzoic acid esters, and chlorobutanol. Due to the presence of such a preservative, it can be transferred to a preparation manufacturing site or stored in a container as a stock solution for a long period of time without impairing the inherent properties of sucralfate. Further, instead of or in addition to the addition of a preservative, an operation of heat sterilization may be added to the sucralfate suspension. The heating operation can usually be performed, for example, at a temperature of 50 to 100 ° C. for about 10 to 60 minutes after the stock solution is manufactured, before long-term storage, or before moving to a preparation manufacturing place.

The amount of water used for dispersing the wet powder may be added so as to have a concentration which can be set as a desired concentration of the sucralfate stock solution. It is preferably added within a range of 1-2 g / ml as the concentration of sucralfate,
More preferably, it is 1.1 to 1.5 g / ml, most preferably about 1.2 g / ml. In the step of forming fine particles, the average particle diameter of the fine particles is preferably set to 50 μm or less. In particular, if the concentration of the sucralfate having the average particle diameter is set to 1.1 to 1.5 g / ml, a uniform and stable suspension of sucralfate which is difficult to be separated into two layers of an aqueous layer and a slurry layer can be obtained. Can be.

There is no particular limitation on the pulverizing device used for making sucralfate fine particles as long as it can obtain a particle size of 50 μm or less. The time required for micronization depends on the capacity of the model used, but it is carried out at room temperature or under water cooling (10 to 25 ° C.) for 3 to 30 minutes, preferably 5 to 20 minutes. The micronization operation is repeated until it is obtained.

The aqueous suspension stock solution obtained according to the present invention can be used as it is or diluted, depending on its concentration, for the manufacture of a sucralfate suspension preparation and as the stock solution for the manufacture of aqueous ointments and cataplasms.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples. The present invention is not limited to these.

Reference Example 1: Production of Sucralfate Wet Powder Sucrose polysulfate sodium salt (sulfur content 11.1)
(74%) was dissolved in 200 ml of water, and a solution prepared by dissolving 6 g of aluminum dihydroxychloride in 100 ml of water was gradually added thereto with stirring. As a result, a white precipitate gradually formed. Next, 1N caustic soda was added, and the pH was adjusted.
The mixture was adjusted to 4.5 to 5.0 and stirred at room temperature for about 30 minutes, after which a white precipitate was collected by filtration. This was washed several times with water to remove unreacted sucrose polysulfate, thereby obtaining 17.2 g of a wet powder. Aluminum content 14.2%, sulfur content 8.61
%Met.

Reference Example 2: Using dried sucralfate powder
Preparation of aqueous suspension (conventional method ) Sucralfate wet powder 380 obtained in Reference Example 1
800 ml of water, and high-speed stirring (3000-4000).
rpm) to give a slurry of sucralfate. This slurry is sprayed under pressure from the top of the spray dryer,
Hot air at 155 to 220 ° C was blown from the upper part of the apparatus to distill off water. The dried sucralfate powder was taken out from the lower part of the apparatus, and this was made into fine particles using an impact-type ultrafine pulverizer using a rotary type atomizer. 1 g of the dried powder of sucralfate obtained by pulverization and micronization was suspended in 4 ml of water to obtain about 5 ml of an aqueous suspension of sucralfate.

[0017]

Example 1 To 383 g of sucralfate wet powder, 797 ml of water was added and dispersed, and then wet-pulverized with a tabletop colloid mill (Millmix: manufactured by Nippon Seiki Seisaku-sho) to obtain about 1 part of an aqueous suspension stock solution for producing sucralfate preparation. Liters were obtained. Samples were taken at 5 minute intervals after the pulverization, and the average particle diameter, the cumulative 50% particle diameter, and the ratio of particles having a particle diameter of 50 μm or less were examined using a laser diffraction particle size distribution analyzer (manufactured by Nikkiso Co., Ltd.). Table 1 shows the results.

Table 1 Grinding time Average particle size 50% particle size cumulative 50% or less particle size (min) (μm) (μm) Size ratio (%) 0 30.1 22.3 81.25 14.9 10.1 96.5 10 12.9 8.7 98.5 15 12.1 8.0 99.0か ら From Table 1, the distribution of particle diameters of 50 μm or less became 95% or more after about 5 minutes, and both the average particle diameter and the cumulative 50% particle diameter showed almost constant values after about 10 minutes.

Example 2 An aqueous suspension of sucralfate dried powder obtained in Reference Example 2 (conventional product, hereinafter referred to as ULD-M) and Example 1
The sedimentability of the aqueous suspension of sucralfate wet powder (product of the present invention, hereinafter referred to as ULW-M) obtained by the above was examined.

Approximately 100 ml of each of the two aqueous suspension stock solutions was poured into a 100 ml graduated cylinder and allowed to stand at room temperature or 50 ° C. Sucralfate settled, and a water layer was separated at the top and a slurry layer of sucralfate was separated at the bottom. The ratio of the slurry layer to the total volume varies depending on the type of the aqueous suspension and the standing temperature, but became substantially constant in about one week. The volume ratio of the slurry layer to the total volume after one week and two weeks, and the density (average density) of the settled slurry part after two weeks were measured. The results are shown in Table 2.

Table 2 Volume of Settled Slurry Layer Density of Settled Slurry One Week After Two Weeks ULW-M 64% 63% 1.18 g / ml (59%) (59%) (1.19 g / ml) ULD -M 62% 62% 1.16 g / ml (55%) (55%) (1.20 g / ml) ────── Note: The values in parentheses are the values at 50 ° C standing. The density of the slurry of the two aqueous suspensions is about 1.2g.
/ Ml, suggesting that there is a critical slurry concentration at which the aqueous layer does not separate. The critical slurry concentration depends on the particle size of sucralfate, and it can be said that the water layer does not separate even at a low concentration as the particle size decreases. From the results shown in Table 2, the aqueous suspension obtained according to the present invention has a particle size of 5
0 μm or less and sucralfate concentration of 1.2 g
/ Ml or more, it is possible to produce a uniform suspension of sucralfate that is difficult to separate into two layers, an aqueous layer and a slurry layer.

Example 3 The same two aqueous suspensions as in Example 2 were used to examine their stability.

Each aqueous suspension (room temperature and 50 ° C.) was sampled with time, and about 1 g of the wet powder obtained by filtration was dissolved in 10 ml of a sulfuric acid / sodium hydroxide solution. After adding 15 ml of a sodium oxide solution to make a homogeneous solution, 50 μl of the solution was analyzed for sucrose sulfate by high performance liquid chromatography (HPLC).
The results are shown in Table 3.

Table 3 % HPLC area ratio of octasulfate 5 days after 6 days after 13 days ULW-M 98.1 98.3 98.4 (1.9) (1.7) (1.6) 97.7 97.0 98.3 (2.3) (3.0) (1.7) ULD-M 97.0 95.8 97.0 (3.0) (4.2) (3.0) 97. 5 96.3 96.6 (2.5) (3.7) (3.4) ──────────────────────────── ──── * The upper row of each stock solution shows the value when stored at room temperature, and the lower row shows the value when stored at 50 ° C.

(): HPLC of heptasulfate
Area ratio (%) In any of the aqueous suspensions, the ratio of the octa-form to the hepta-form was not changed over time.

Since ULD-M is slightly decomposed into heptasulfate in the drying process of the sucralfate wet powder, ULW-M is superior in stability.

Example 4 Using the same two aqueous suspensions as in Examples 2 and 3, the acid neutralization behavior of each was investigated.

At room temperature, 150 ml of each aqueous suspension was dispersed in 80 ml of distilled water, stirred, and 0.1N hydrochloric acid was dripped very slowly, and the change in the suspension state and the change in pH were visually examined. The results are shown in Table 4.

Table 4 Changes in Suspended State (Ame state) Hydrochloric acid amount during sucralfate and hydrochloric acid amount per 1 ml of pH ULW-M 4.5 ml 0.029 ml pH 2.7 ULD-M 6.2 ml 0.044 ml pH 3 .2 よ り From Table 4, the suspension obtained by the present invention is:
It changed to a viscous substance (candy state) with a smaller amount of hydrochloric acid than the conventional one.

Example 5 To 513 g of the sucralfate wet powder produced in Reference Example 1, 632 ml of water was added and dispersed, and then the opening degree was measured using a tabletop colloid mill (Millmix: manufactured by Nippon Seiki Seisakusho).
An aqueous suspension stock solution for production of sucralfate preparation (ULW-M) is wet-pulverized at 30 ° and 500 rpm for 20 minutes.
About 1 liter was obtained. Samples were taken at 5 minute intervals after pulverization, and the particle size distribution and the sedimentation rate over time were examined using a laser diffraction type particle size distribution analyzer (manufactured by Nikkiso Co., Ltd.).

For comparison, an unmilled aqueous suspension (ULW) was prepared by simply stirring the same raw materials as in this example without performing wet milling.

For comparison with a conventional product, 823 ml of water was added to 328 g of spray-dried sucralfate powder, and the mixture was stirred and mixed to obtain about 1 liter of a suspension (ULD). Further, 817 ml of water was added to 337 g of the pulverized sucralfate product obtained by further atomizing the spray-dried sucralfate powder using an impact-type ultrafine pulverizer, followed by stirring and mixing.
About 1 liter of suspension (ULD-M) was prepared.

The time-dependent changes in the particle size distribution and the sedimentation rate were similarly measured for each of these samples.

Table 5 shows the measurement results of the particle size distribution, and Table 6 shows changes with time of the sedimentation rate.

Fifth particle size distribution sample 50 μ or less (%) Average value (μ) ULW 74.6 43.7 ULW-M 97.7 13.7 ULD 82.2 27.5 ULD-M 100.0 8.0 ───────────────────────── Table 6: Volume of sedimentation volume ratio of sedimentation (%) Elapsed days Samples 0 1 2 4 6 10 ULW 100 64 62 62 62 62 62 ULW-M 100 83 71 70 70 70 ULD 100 98 83 85 84.5 84.5 84.5 ULD-M 100 98 86 82 81 80.5 Table 6: Sedimentation volume ratio (continued) Sedimentation volume rate (%) Aging sample 19 31 48 ULW 61 61 61 ULW-M 68 68 68 ULD 84 83 82.5 ULD-M 79 79 78 ────────────── ──── ──── sucralfate aqueous suspension stock of this invention prepared in Example 6 Example 5 (ULW-M) and comparative samples (ULW, ULD
And ULD-M) were measured for changes in the particle size distribution of the sucralfate particles.

Each sample was stored at room temperature for 58 days or under accelerated conditions of 50 ° C. for 43 days, and then measured by a laser diffraction type particle size distribution analyzer (manufactured by Nikkiso Co., Ltd.) for the average particle size and the integration rate of particles having a particle size of 50 μm or less. (%) Was measured.

The results are shown in Table 7.

Table 7: Samples stored at room temperature for 58 hours at the time of particle size change preparation Average particle size (μm) Same as left 50 μm or less Integration% Same as left ULW 43.7 41.8 74.6 78.9 ULD 27.5 25.4 82.2 84.5 ULW-M 13.7 13.7 97.7 97.7 ULD-M 8.0 7.8 100.0 100.0 Example 7 The aqueous suspension of sucralfate of the present invention at room temperature After storage for 58 days at room temperature, the cohesion under hydrochloric acid acidity was examined.

The sucralfate aqueous suspension stock solution (ULW-M) of the present invention prepared in Example 5 and a conventional product (ULD-M)
M) was stored at room temperature for 58 days, and 6 ml of 0.1N hydrochloric acid was added to 1 g of the sample (equivalent to 200 mg of sucralfate).
Was added, and the mass of sucralfate was visually observed with stirring, and the time was measured. Aggregation was determined for 30 minutes.

The results are shown in Table 8. However, the result is an average of three measurements.

Table 8 Sample Aggregation state after 30 minutes of aggregation time (58 days storage at room temperature) (seconds) ULW-M 264 Aggregated ULD-M-No aggregation ───────────── ８Example 8 About 6 g of (BSA) is accurately weighed, dissolved in Clark-Clark's buffer (CLB), and adjusted to exactly 1000 ml. And used as a standard stock solution. The aqueous suspension stock solution of sucralfate (ULW-M) of the present invention and the aqueous suspension stock solution of sucralfate (ULD-M) produced from the conventional dry fine powder were collected in different amounts of 0.15 to 3.0 g. And 50 ml of BSA standard stock solution.

The mixture was incubated at 37 ° C. for 30 minutes. Immediately after the reaction was completed, the mixture was made exactly 200 ml with CLB and filtered to obtain a sample solution.

Separately, the BSA standard solution was diluted to 0.1,
Standard solutions were prepared at 0.2, 0.4, 0.6, 0.8, and 1.0 mg / ml.

[0044] 0.1 ml of the standard solution and the sample solution were collected, and 5 ml of a protein assay reagent was added. The absorbance at a wavelength of 595 nm was measured, and the amount of unreacted BSA in the sample was quantified from the calibration curve of the standard solution. The weight ratio of sucrose octasulfate (SOS) to BSA was plotted on the horizontal axis, and the specific adsorption protein content was plotted on the vertical axis. An adsorption curve in which (%) was set was created.

The results are shown in FIG.

As is evident from the graph of FIG. 1, no substantial difference in protein adsorption ability was observed between the product of the present invention (ULW-M) and the conventional product (ULW-D).

EXPERIMENTAL EXAMPLE 1 The in vivo pharmacology of the aqueous suspension of sucralfate (ULW-M) made from the moist powder of the present invention and the suspension (ULW-D) made from the conventional dry membrane was investigated. The activities were examined and compared.

Seven-week-old SD rats were divided into groups of 10 rats each, and a Shay ulcer model and an acute gastric mucosal lesion model of ethanol were prepared to examine the efficacy of the sucralfate preparation.

(Shay ulcer model) Rats were fasted for 48 hours, laparotomized under ether anesthesia, ligated with the pylorus, and orally administered with a suspension of sucralfate at a dose of 1 ml / kg. The rats were sacrificed for 18 hours after the ligation procedure, after which the rats were sacrificed and the stomach was removed to evaluate the anti-ulcer effect. The evaluation was performed with a score of 0-5 according to the method of Adami et al.

(Ethanol acute gastric mucosal lesion model) A sucralfate suspension preparation was orally administered at 1 ml / kg to rats which had been fasted for 24 hours before administration of sucralfate and further deprived of water for 18 hours before administration. One hour after the administration, ethanol was administered, and two hours later, the rats were sacrificed and the stomach was removed. Evaluation is the sum of the major axis of the gastric mucosal injury area (mm)
Indicated by

Results (1) FIG. 2 shows the effect of suppressing the occurrence of Shay ulcer. ULW-M and ULD-M Samples of the Present Invention
Both showed significant inhibitory effects when administered at a dose of 100 mg / kg or more as compared to the control vehicle (Vehicle). On the other hand, there was no difference between them.

(2) Acute ethanol gastric mucosal lesion. The results are shown in FIG.

As a result, no significant difference was observed between the two samples.

Experimental Example 2: Anti-pepsin activity 2.5 ml (100 μg / ml) of pepsin dissolved in Clarklux buffer (CLB) and 0.5 m of sucralfate suspension (final concentration: 0, 10, 50 mg / ml) k
g) and incubated at 37 ° C. for 20 minutes.

Next, the mixture was centrifuged (300
(0 rpm, 5 minutes), and the supernatant was collected.

Two samples of 0.5 ml each of the supernatant were taken, and one of the samples was examined for the amount of adsorbed protein and the inhibition rate of pepsin activity.

FIG. 4 shows the results. There was almost no difference between the sucralfate suspension of the present invention (ULW-M) and the conventional product (ULD-M).

[0058] mixing the preparation Example 1 Ingredient amount sucralfate aqueous suspension stock 100.0g equivalent amount of 85% glycerol 100.0g xanthan gum 2.5g phosphoric acid monosodium 2.5g Purified water qs total amount 500ml The above components Thus, an aqueous suspension formulation of sucralfate was prepared. It had a pH of 4.91 and a specific gravity of 1.16, had a viscosity of 291.7 cps, and had good dispersibility and tackiness.

Production Example 2 Composition Amount of Sucralfate Aqueous Suspension Undiluted Solution 50.0 g Equivalent HPS * 15.0 g Purified Water qs 500 ml * HPS: Hydroxypropyl Starch A liquid formulation was obtained. pH: 4.21, specific gravity 1.06, viscosity 53.4
cps and showed good dispersibility and tackiness.

[0060] mixing the Production Example 3 Ingredient amount sucralfate aqueous suspension stock 50.0g equivalent amount of 85% glycerin 100.0 g HPS 15.0 g phosphate monosodium 2.5g Purified water qs total amount 500ml above components Thus, an aqueous suspension formulation of sucralfate was obtained. pH: 4.90, specific gravity 1.09, viscosity 44.2
cps and showed good dispersibility and tackiness.

[0061] mixing the Production Example 4 Ingredient amount sucralfate aqueous suspension stock 50.0g equivalent amount of 85% glycerin 100.0 g HPS 12.5 g 1 Sodium 2.5g Purified water qs phosphate total amount 500ml above components Thus, an aqueous suspension formulation of sucralfate was obtained. pH: 4.93, specific gravity 1.10, viscosity 40.6
cps and showed good dispersibility and tackiness.

[0062]

From the above results, the aqueous suspension of sucralfate obtained directly from the wet powder according to the present invention showed comparable values in both physical properties and pharmacological activity as compared with those from the conventional dry powder. Therefore, it is possible to obtain an aqueous suspension of sucralfate which is equivalent in both physical properties and pharmacological activity, while solving the problems caused by the conventional production method. That is, in the present invention, an undiluted solution can be obtained in a short process and at low cost without using a process having poor operability such as heating, drying, pulverization, and water suspension in the production process. In addition, wet pulverization has no fine powder generated by pulverization of dry powder, there is no contamination of the production environment (producers' health, etc.), and furthermore, wet pulverization requires more adjustment of particle size and continuity of the production process than dry pulverization. It is easy and industrially superior. In addition, there is an excellent effect that the fine powder is not dissipated at the time of transportation or use, and the environmental pollution due to the formulation step can be suppressed.

[Brief description of the drawings]

FIG. 1 is a graph comparing the protein adsorbing ability of an aqueous suspension of sucralfate (ULW-M) manufactured by a wet method of the present invention with an undiluted solution (ULD-M) manufactured by a conventional dry method. .

FIG. 2: ULW-M and U for Shay ulcer in rats
It is a graph which shows the in vivo suppression effect with LD-M.

FIG. 3. In vivo for acute gastric mucosal injury to ethanol
It is a graph which shows a vo suppression effect.

FIG. 4 is a graph showing a comparison between ULW-M and ULD-M in protein adsorption ability and pepsin activity suppression.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Sakae Takaku 5-5-1 Ukima, Kita-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. (56) References JP-A-1-250323 (JP, A) JP-A Sho 64-45312 (JP, A) JP-B-44-16037 (JP, B1) JP-B-44-11673 (JP, B1) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/70 -31/80 A61K 9/00-9/66 CA (STN) WPI (DIALOG)

Claims (3)

(57) [Claims] 1. A method wherein the synthesized sucralfate wet powder is dispersed in water or an aqueous medium without drying, and the dispersed sucralfate wet powder is pulverized to an average particle size of 50 μm or less by wet pulverization. A method for producing an aqueous suspension of sucralfate. 2. The method according to claim 1, wherein the sucralfate wet powder is dispersed in water or an aqueous medium at a sucralfate concentration of 1 to 2 g / ml. 3. The method according to claim 1, wherein the sucralfate wet powder is dispersed in water or an aqueous medium at a sucralfate concentration of 1.1 to 1.5 g / ml.