JP2018052869A - Powder composition and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide powder compositions containing sucralfate which rapidly gelate from powder state by contacting to water and exert excellent mucosal adhesiveness even against the mucosa of an organ having a short transit time, such as oral cavity or esophagus.SOLUTION: A powder composition contains (A) sucralfate, (B) organic acid, and (C) water, the content of the component (C) being 10 to 30 mass%. The sum of the amount of the heat of fusion calculated from the area of the endothermic peak appearing in the temperature range of -20 to 0°C is 0 to 0.05 J/g, in the DSC curve measured by a differential scanning calorimeter.SELECTED DRAWING: None

Description

  The present invention relates to a powder composition containing sucralfate.

  Sucralfate specifically adheres to the ulcer in the stomach and physically protects the ulcer by forming a protective film (paste). In recent years, attempts have been made to apply the characteristics of sucralfate to affected areas other than the stomach such as esophagitis, esophageal ulcer, small intestine and large intestine ulcer, and stomatitis. For example, in JP-A-8-268895 (Patent Document 1), an esophagitis or ulcer is caused by using an organic carboxylic acid having two or more carboxyl groups or one or more hydroxyl groups in the molecule and sucralfate. In addition, techniques for improving adhesion to small intestine / colon ulcers, stomatitis and the like have been disclosed.

  JP-T-10-505822 (Patent Document 2) reports that a solid compound obtained by spray-drying an aqueous suspension containing sucralfate and polyalcohol exhibits thixotropic properties when dispersed in water again. Has been. However, since the water content of the solid compound obtained here is too low (less than 5%), sufficient storage stability of sucrose octasulfate cannot be obtained, and there is still room for improvement. In addition, since an acid that is hardly soluble in water, such as acetylsalicylic acid, is used, sucralfate is not dissolved in the acid during the production process. Therefore, the obtained solid compound does not gel quickly when it comes into contact with water.

  In this way, liquid or gel-like drugs that rapidly demonstrate good mucoadhesive properties have been obtained, but they quickly gel from the powder state when in contact with water, and pass through like the oral cavity or esophagus. A solid agent that exhibits good mucoadhesive properties even against the mucous membranes of short organs has not yet been obtained.

JP-A-8-268895 JP 10-505822 A

  The present invention has been made in view of the above circumstances, and is a powder composition containing sucralfate, which is brought into contact with water to quickly gel from the powder state and has a short transit time such as the oral cavity and esophagus. An object of the present invention is to provide a powder composition that exhibits good mucoadhesiveness to the mucous membrane of an organ and a method for producing the same.

  The inventor of the present invention once mixed sucralfate with an organic acid and water, and then dried the powder composition from the water content and the endothermic peak area of the DSC curve measured by a differential scanning calorimeter. When the total amount of heat of fusion required is adjusted to an appropriate range, it has been found that when it comes into contact with water again, it rapidly gels and exhibits excellent mucoadhesiveness, leading to the present invention It is.

Accordingly, the present invention provides the following powder composition and method for producing the same.
[1] Powder containing (A) sucralfate, (B) organic acid, and (C) water, the content of component (C) is 10 to 30% by mass, and measured by a differential scanning calorimeter A powder composition characterized in that, in the DSC curve, the total amount of heat of fusion determined from the area of the endothermic peak appearing in the temperature range of -20 to 0 ° C is 0 to 0.05 J / g.
[2] The powder composition according to [1], wherein the sum of the heat melting amounts is derived from free water and bound water.
[3] The powder composition according to [1] or [2], wherein the content mass ratio represented by (A) / (C) is 1 to 8.
[4] The powder composition according to any one of [1] to [3], wherein the mass ratio represented by (B) / (C) is 0.2 to 10.
[5] A method for producing a powder composition, comprising a step of preparing a liquid composition containing (A) sucralfate, (B) an organic acid, and (C) water, and a step of drying the liquid composition.
[6] The production method according to [5], wherein the drying is performed by microwave drying or freeze drying.

  According to the present invention, it is possible to provide a powder composition that quickly gels upon contact with water and exhibits good mucoadhesive properties even on the mucous membranes of organs with a short transit time such as the oral cavity and esophagus. it can.

6 is a DSC curve of a powder composition according to Comparative Example 4. 2 is a DSC curve of the powder composition according to Example 1.

Hereinafter, the present invention will be described in detail.
The powder composition of the present invention is obtained by drying a liquid composition containing (A) sucralfate, (B) an organic acid, and (C) water, and (C) the water content and the endothermic peak of the DSC curve. It is obtained by setting the total amount of heat of fusion determined from the area within an appropriate range. In the following description, the “liquid composition” means a liquid composition at a stage where the components (A) to (C) are blended, and the “powder composition” means “liquid composition”. It means a powdery composition obtained by drying.

(A) Sucralfate (A) Sucralfate (sucrose octasulfate aluminum salt) binds to proteins in the mucosal inflammation area and has a function of covering and protecting the inflamed area, and is also called “stomach bandage” It is a drug. In the present invention, in addition to the effect on the inflamed part of the stomach, the use of an orally disintegrating tablet can exert an excellent effect on the inflamed part of the esophagus that is the cause of heartburn.

  (A) 5-80 mass% is preferable, as for content in the liquid composition of sucralfate, 10-65 mass% is more preferable, and 20-50 mass% is still more preferable. By making content of (A) component into the said range, dispersion stability and manufacturing aptitude (viscosity stability in a manufacturing process) become more favorable.

  The content of the component (A) in the powder composition is preferably 30 to 80% by mass. By setting the content of the component (A) within the above range, a gel having a high mucoadhesive property can be obtained and a mucosal protective effect can be exhibited.

(B) Organic acid (B) The organic acid is not particularly limited as long as it is a water-soluble (that is, water-soluble) organic acid, and it can be used alone or in combination of two or more. . Among them, in terms of flavor and dispersion stability, alginic acid, citric acid, malic acid, ascorbic acid, glucuronic acid, aspartic acid, glutamic acid, adipic acid, gluconic acid, tartaric acid, succinic acid, lactic acid, acetic acid, butyric acid, maleic acid and One or more selected from fumaric acid is preferable, and citric acid, malic acid and lactic acid are particularly preferable.

  The content of the component (B) in the liquid composition is preferably 5 to 45% by mass, and more preferably 10 to 25% by mass. By making content of (B) component more than a minimum, the time-dependent dispersion stability of a liquid composition will become favorable and formulation will become easy. Moreover, mucoadhesion property becomes favorable because content of (B) component shall be below an upper limit.

  5-60 mass% is preferable and, as for content in the powder composition of (B) component, 9-55 mass% is more preferable. When the content of the component (B) is at least the lower limit, mucoadhesion is improved, and at the upper limit, the mucoadhesion is improved and the granule strength is increased.

(C) Water The content of the (C) water in the liquid composition is preferably 30 to 80% by mass, and more preferably 30 to 70% by mass. When the content of the component (C) is within the above range, the production suitability is improved.

  (C) Content (water content) in the powder composition of water is 10 to 30% by mass. When content of (C) component exceeds 30 mass%, granule intensity | strength will become weak and powderization will become difficult. When content of (C) component will be less than 10 mass%, stability of sucrose octasulfate will deteriorate.

[Moisture content of powder composition]
In the present invention, the content (water content) of (C) water in the powder composition is a value (%) calculated from the following formula. The moisture content can be measured with a commercially available moisture meter (for example, “MOC63u” manufactured by Shimadzu Corporation).
Moisture content (%) = (water content reduced at 105 ° C. for 2 hours) / (mass of powder composition) × 100

[(A) / (C) ratio]
In the liquid composition, the content mass ratio represented by (A) / (C) is preferably 0.8 to 6. By setting this ratio to the lower limit or higher, mucoadhesiveness is improved, the dispersion stability of the liquid composition itself is improved, and formulation is facilitated. Moreover, favorable dispersion stability is obtained by making the said ratio below into an upper limit.

  Moreover, in a powder composition, 1-8 are preferable and, as for the containing mass ratio represented by (A) / (C), 2.5-6 are more preferable. By setting the content of the component (C) to the lower limit or more, the granule strength of the powder composition is increased, and even when tableting or the like is performed, a granule suitable for formulation can be obtained. By making content of (C) component below an upper limit, in addition to improving the stability of sucrose octasulfate, mucoadhesiveness is improved.

[(B) / (C) ratio]
In the liquid composition, the mass ratio represented by (B) / (C) is preferably 0.05 to 4, and more preferably 0.1 to 2. By making this ratio within the above range, the handling property during the production of the liquid composition is improved.

  Moreover, in the powder composition, the content mass ratio represented by (B) / (C) is preferably 0.2 to 10, and more preferably 0.4 to 5. By setting this ratio within the above range, a gel having a high mucoadhesive property can be obtained.

[Liquid composition]
The “liquid” in the present invention means a fluid having a viscosity (25 ° C.) of about 100 to 50,000 mPa · s. The viscosity is preferably 100 to 10,000 mPa · s from the viewpoint of production suitability. The viscosity is measured at a rotational speed of 12 rpm / 20 ° C. using a B-type viscometer (for example, “RB-80” manufactured by Toki Sangyo Co., Ltd.), No. 3 or No. 4 rotor (changed according to the viscosity). To do. In the present invention, “manufacturability” means ease of handling at the time of preparation of a sucralfate liquid composition or when shifting to the next manufacturing process in order to add further formulation treatment (drying step, etc.) to the liquid composition. means. In particular, when the viscosity of the composition is too high, stirring, line transportation, and the like may be difficult, which is undesirable in terms of production suitability. Therefore, in the present invention, the viscosity of the liquid composition is preferably within the above range.

[Powder composition]
The powder composition is prepared by drying the liquid composition obtained above and adjusting the water content and the total amount of heat of fusion determined from the endothermic peak area of the DSC curve within the above range. It is obtained by this.
As a drying method, microwave drying, freeze drying, or the like can be employed. In particular, microwave drying that completes drying in a short time can be suitably employed. In addition, although it can be adjusted to a predetermined moisture content by thermal drying or natural drying, it is obtained from the area of the endothermic peak appearing in the temperature range of −20 to 0 ° C. in the DSC curve measured by a differential scanning calorimeter described later. The total amount of heat of fusion produced does not fall within the range specified in the present invention. Therefore, the powder obtained by these drying methods does not gel quickly.

  The single dose of sucralfate itself is preferably 700 to 3,600 mg, more preferably 800 to 1,300 mg. This can be taken by adding an antacid separately or encapsulating it in a soft chewable capsule.

  An arbitrary component can be appropriately blended with the liquid composition as long as the effects of the present invention are not impaired. Optional ingredients include antacids, other active ingredients, excipients, binders, sugar alcohols, disintegrants, sweeteners, lubricants, preservatives, fragrances, dyes and the like.

  As a dosage form to which the powder composition of the present invention is applied, the powder composition may be used as a granule or a powder as it is, and further, an excipient, a binder, a disintegrant, a lubricant, a surfactant, an emulsifier. In addition, an optional component such as a base can be appropriately blended within a range that does not impair the effects of the present invention, whereby tablets (including chewable tablets and orally disintegrating tablets), hard capsules, granules, and powders can be obtained. In the present invention, tablets, granules and powders are particularly preferable. For delivery to the stomach or intestinal mucosa, enteric hard capsules are preferred.

  Antacids include sodium bicarbonate, dry aluminum hydroxide gel, magnesium aluminate silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium magnesium hydroxide, aluminum hydroxide gel, magnesium hydroxide, magnesium oxide, water Aluminum oxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium metasilicate aluminate, dimagnesium bismuth aluminate silicate , Magnesium hydroxide / potassium aluminum sulfate coprecipitation product, calcium hydrogen phosphate, calcium carbonate, volley, aminoacetic acid, funnel extract and the like. Most preferred are magnesium aluminate metasilicate, synthetic hydrotalcite, and magnesium aluminate silicate. These can be used individually by 1 type or in combination of 2 or more types.

  Although content of an antacid is not specifically limited, From a viewpoint of an antacid effect, 100-1500 mg is preferable as a single dose, and 200-1,000 mg is more preferable. Further, (A) 100 to 1,500 mg of antacid is preferable, and 200 to 1,000 mg is more preferable with respect to 500 mg of sucralfate.

  Other active ingredients include ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole, omeprazole, etc., gastric acid secretion inhibitors, pirenzepine, atropine, scopolamine, and other antagonists And protective factor promoters such as aldioxa, azulene, L-glutamine, and rebamipide.

  Examples of the excipient include lactose, corn starch, crystalline cellulose, and potato starch. Examples of the binder include hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, honey and the like. Examples of the sugar alcohol include mannitol, erythritol, xylitol, sorbitol, palatinit, lactitol and the like. Examples of the disintegrant include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropylcellulose. Examples of the sweetener include sucrose, fructose, aspartame, acesulfame potassium, stevia, purified sucrose, saccharin, glycyrrhizin and the like. Examples of the preservative include parabens, paraoxybenzoic acid ester, sodium benzoate and the like. Examples of the fragrances include menthol, limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Examples of the pigment include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, and copper chlorophyllin sodium.

[Heat of fusion]
In the present invention, in the DSC curve measured by a differential scanning calorimeter, the total amount of heat of fusion determined from the area of the endothermic peak appearing in the temperature range of −20 to 0 ° C. is 0 to 0.05 J / g. 0.03 J / g is preferable, and 0 to 0.01 J / g is more preferable. When the total amount of heat of fusion exceeds 0.05 J / g, the water conductivity becomes poor when the powder composition comes into contact with water, so that it becomes difficult to gel quickly. Therefore, the desired mucoadhesiveness cannot be obtained.

  The heat of fusion measured by the above differential scanning calorimeter is a differential scanning calorimeter (DSC) (for example, manufactured by Netch Co., Ltd.) according to JIS K 7121 (plastic transition temperature measuring method) and JIS K 0129 (general rules for thermal analysis). "DSC 3500 Sirius") is calculated from the DSC curve. Specifically, the amount of heat of fusion is increased by heating from −30 ° C. to 30 ° C. in the freezing temperature raising process in which the powder composition is cooled from room temperature to −30 ° C., frozen, and then heated to 30 ° C. It is calculated from the area of the endothermic peak detected in the temperature process. The area of the endothermic peak can be calculated by an automatic peak detection function of DSC automatic area calculation software (eg, “Thermal Analysis System Ver5.1 SP3” manufactured by Netch Japan). In the present invention, in the DSC curve measured by a differential scanning calorimeter, the total amount of heat of fusion determined from the area of the endothermic peak appearing in the temperature range of −20 to 0 ° C. is the water constituting the powder composition of the present invention. Since none of the components has a melting peak in this temperature range, it agrees with the total heat of fusion derived from free water and bound water. In the present invention, free water refers to water other than bound water that is not associated with other molecules, and bound water is captured by physical interaction in the voids of tissues, or is a constituent molecule due to hydrogen bonding or the like. (Solute, ion, dipole) and hydrated water.

  Here, in order to explain the endothermic peak more specifically, FIG. 1 and FIG. 2 show DSC curves measured for the powder composition. Measurement conditions and the like will be described in Examples described later.

  The DSC curve shown in FIG. 1 is that of Comparative Example 4. In this figure, it can be confirmed that an endothermic peak derived from bound water is observed in the vicinity of −10 to −5 ° C. during the temperature rising process, and an endothermic peak derived from free water appears in the vicinity of −4 ° C. When free water and bound water are present in the powder composition, these appear as endothermic peaks, so the total amount of heat of fusion can be determined from the area.

  On the other hand, the DSC curve shown in FIG. In this figure, it can be confirmed that no endothermic peak appears in the temperature rising process, and free water and bound water are not present (or below the detection limit). In this case, the total amount of heat of fusion derived from free water and bound water is 0 J / g. Note that the total heat of fusion is 0 J / g when there is no bound water or free water in the powder composition, but this is not automatically detected by DSC automatic area calculation software (= deemed as a peak). N) means that the area cannot be measured. At this time, the physicochemical existence state of water molecules present in the composition is “the free structure is not present as bound water, but is taken into the higher-order structure formed by sucrose octasulfate and acid and moves. Is considered to be in a “bound state”.

  In the present invention, it is particularly effective to treat (A) sucralfate once with a water-soluble (B) organic acid, and through this treatment in the step of preparing a liquid composition, free water as defined in the present invention. And the total heat of fusion of the bound water can be in the above range. In addition, in the DSC curve measured by the differential scanning calorimeter, even when the above components are mixed so that the water content is simply 10 to 30% by mass without passing through the drying step, it is −20 to 0 ° C. The total amount of heat of fusion determined from the area of the endothermic peak appearing in the temperature region (the total amount of heat of fusion of free water and bound water) cannot be within the above range, and it quickly gels and has good mucoadhesiveness. The powder composition of the present invention cannot be obtained.

[Production method]
The powder composition of the present invention includes a step of obtaining a liquid composition by mixing (A) sucralfate, (B) an organic acid, and (C) water at a predetermined ratio, and drying the obtained liquid composition. It can manufacture by passing through a process.

  In the step of preparing the liquid composition, a known stirring / mixing method can be adopted without the need for special stirring / mixing. Examples of the stirring device include stirrer stirring, propeller stirring, homogenizer, homomixer, and emulsifier.

  In the drying step, the powder composition of the present invention can be obtained by drying the liquid composition obtained above by a predetermined drying method. The drying method is not particularly limited as long as the liquid composition can be sufficiently dried and a powder composition satisfying the requirements specified in the present invention can be obtained. Can be adopted. In the present invention, from the viewpoint of manufacturability, microwave drying that can complete drying in a shorter time can be suitably employed.

  In the case of performing microwave drying, a known microwave oven (for example, “MOH-1500HP” manufactured by Micro Electronics Co., Ltd.) can be used. The drying conditions are not particularly limited. For example, the drying temperature is 60 ° C. or less, preferably 40 ° C. or less, the drying pressure is 20 to 100 Torr, preferably 20 to 30 Torr, and the drying time is 20 to 180. Conditions such as minutes, preferably 20-60 minutes can be employed.

  When lyophilization is performed, a known lyophilizer (eg, “DRZ350WA” manufactured by ADVANTEC Co., Ltd.) can be used. Drying conditions are not particularly limited. For example, after pre-cooling the inside of the chamber to −40 ° C., a sample is put, the pressure is reduced to 20 Pa or less, and drying is performed for 72 hours.

  Other drying methods include thermal drying, natural drying, spray drying, and the like. When these drying methods are employed in the present invention, the total amount of heat of fusion is the present invention even if it is sufficiently dried. It is not within the specified range. When a liquid composition containing sucralfate is pulverized by these drying methods, the resulting powder does not gel quickly because it has poor redispersibility even when wet with water. The intended mucoadhesive effect cannot be obtained. This is presumably because the higher-order structure of the complex of sucralfate and organic acid changes during the drying process, resulting in poor water conductivity. On the other hand, in microwave drying and freeze drying that can be employed in the present invention, the higher-order structure of the complex of sucralfate and organic acid is maintained in the drying process, so that such inconvenience does not occur.

  In the present invention, the total amount of heat of fusion of free water and bound water is within the above range even if the above components are mixed so that the water content is simply 10 to 30% by mass without passing through the drying step. It is not possible to obtain a powder composition of the present invention that gels quickly and has good mucoadhesive properties.

[Hard capsule]
The powder composition of the present invention is encapsulated in an outer skin made of an edible base such as gelatin, pullulan or cellulose. For the capsule itself, an agent obtained by a general method (immersion method or the like) can be used. The internal filling is not a method generally used in powder filling (auger type, die compression type, funnel type, etc.), but a method used for filling a liquid agent such as a pump type. For the same purpose as in the case of soft capsules, inorganic salts and sugar alcohols may be dissolved in the liquid composition and added.

  In addition, when using the powder composition of this invention as a capsule, it is preferable that mass ratio of a powder composition and a film | membrane shall be powder composition / film | coat = 8.0-0.5. In the case of hard capsules, the contents (powder composition) are chewed or licked in the oral cavity and the contents (powder composition) are exposed in the mouth to stay in the oral mucosa, or the exposed contents are swallowed to esophageal mucosa It can directly act on the esophageal mucous membrane by passing it through. By setting the single dose to a small volume (at most 10 g, preferably about 0.5 to 4 g, more preferably about 1 to 3 g) as in the present invention, especially immediately after swallowing Most of them stay in the esophagus, so they don't flow into the stomach immediately. By these, a high therapeutic effect can be expected.

EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio.
In addition, about 12 mass% of water | moisture content is contained in the sucralfate (Fuji Chemical Industry Co., Ltd. product, "sucralfate hydrate") used in the following examples. Therefore, in the table below, the content of (A) sucralfate describes the solid content and the moisture content individually. In the examples and comparative examples shown in the following table, 500 g of sucralfate (solid content) and 70 g of water content are contained, which indicates that 570 g is blended as sucralfate hydrate. Moreover, the ratio of each component, (A) / (C) ratio, and (B) / (C) ratio were calculated by including the water content contained in sucralfate hydrate in (C) water.

[Examples 1-11, Comparative Examples 1-6]
According to the composition of the following table, a composition was prepared as follows.
(1) Preparation of liquid composition (B) The organic acid was dissolved in (C) water (purified water). (A) Sucralfate powder was directly added while stirring with a stirrer (rotation speed: 100 to 1,000 rpm), and after stirring all day and night, a liquid composition was obtained (sucralfate liquid composition: viscosity 100 to 48,000 mPa · s). Details of the obtained liquid composition are shown in Table 1. In addition, Comparative Example 1 is a powder composition prepared by simply mixing the components (A) to (C) and without performing a drying treatment.

(2) Preparation of powder composition 50 g of the liquid composition obtained in (1) above was placed in a 500 mL beaker and dried until the target moisture content was reached by the following methods (A) to (D). Body composition). The obtained flakes were ground in a mortar and then sieved with an automatic vibration sieve device having a diameter of 75 mm, and 177 to 425 μm powder was collected and used as a sample for evaluation. The measurement of the moisture content of the obtained powder composition will be described later.

(A) Microwave drying Dryer: Microelectronics, "MOH-1500HP" (microwave oven)
Output: 200W or 100W
Drying temperature: 40 ° C. or less Pressure: 20-30 Torr (Adjust while observing the foaming condition of the sample)
Drying time: 20 to 60 minutes Stirring during drying: No (B) Freeze-drying Dryer: “DRZ350WA” (freeze dryer) manufactured by ADVANTEC Co., Ltd.
Drying method: After pre-cooling the inside of the chamber to −40 ° C., a sample was put, the pressure was reduced to 20 Pa or less, and the sample was dried for 72 hours. The dried product was lightly crushed to obtain flakes.
(C) Thermal drying Dryer: “Vacuum Drying SVD10” manufactured by Sansho Co., Ltd.
Drying method: It was left to stand at 105 ° C. for 3 hours and dried to obtain flakes.
(D) Natural drying It left still by the open system for 1 week at room temperature, and obtained flakes.

(3) Measurement of moisture content of powder composition Using a moisture meter “MOC63u” manufactured by Shimadzu Corporation, the moisture content of the powder composition obtained above was measured, and the moisture content was calculated using the above formula. Asked.

  The following evaluation was performed about the powder composition obtained above. The results are shown in Tables 1 and 2.

[Heat of fusion]
Differential scanning calorimetry (DSC) was performed according to JIS K 7121 (Plastic Transition Temperature Measurement Method) and JIS K 0129 (General Rules for Thermal Analysis). Then, in the obtained DSC curve, the total amount of heat of fusion (total amount of heat of fusion of free water and bound water) obtained from the area of the endothermic peak appearing in the temperature range of −20 to 0 ° C. was calculated.
<Conditions>
Differential scanning calorimeter: “DSC 3500 Sirius” manufactured by Netch
Measurement conditions: After cooling from room temperature to −30 ° C. at 10 ° C./min, the mixture was allowed to stand for 5 minutes, and then heated to 30 ° C. at a rate of 1 ° C./min.

[In vitro adhesion amount]
As a mucosal model, an aminoalkylsilylated glass plate having a cationic surface was used.
30 mg of the powder composition was weighed on a glass plate, 100 mg of purified water was added and allowed to stand for 30 seconds, then washed with purified water and the weight of the remaining gel was measured. The gel produced when the powder composition of the present invention comes into contact with water is a hydrogel containing acid and water in addition to sucralfate, which is an active ingredient, and has a protective ability to cover the damaged mucous membrane as a whole. Therefore, the evaluation was based on the total weight of the gel remaining on the glass plate, not the remaining amount of the powder composition.
A case where 30 mg or more of the gel remained on the glass plate was regarded as acceptable.

[Granule strength]
The strength against compression of the granules was measured using a granule strength measuring machine. The average value of the three granules was defined as the granule strength. 30 g or more was regarded as acceptable.
<Conditions>
Granule strength measuring machine: Grano Particle Hardness Tester (Okada Seiko Co., Ltd.)
Measurement conditions: Each granule is measured at room temperature.

[Storage stability of sucrose octasulfate]
The sample was hermetically stored in a bottle, and the content of sucrose octasulfate after storage for 1 week in a thermostatic bath at 50 ° C. and before storage was evaluated. The test was conducted according to the quantitative method (HPLC method) of JP JP “Sucralfate Hydrate”.

[Time required]
The time required for production of the powder composition was measured under the following conditions. A shorter time is desirable from the viewpoint of production efficiency. In the table below, the unit of the required time is “minute” unless otherwise specified, but “hr” represents “hour”, and “d” represents “day”.
(start point)
When drying with a dryer: A sample was placed in the chamber, and the time when the desired temperature and pressure conditions were reached was defined as the drying start time.
In the case of natural drying: The sample was filled in a petri dish, and the standing time was defined as the drying start time in an open room temperature system.
(end point)
The time when the desired amount of water was reached was taken as the end point of drying. The moisture content was measured with a moisture meter manufactured by Shimadzu Corporation.

Moreover, the following could be confirmed from the result of the comparative example.
In Comparative Example 1, the powder having excellent mucoadhesiveness as a result of rapid gelation as in the present invention was not obtained simply by blending each component and adjusting the water content without going through the drying step. .
In Comparative Example 2, since the moisture content after drying was too high, the gel became a sticky gel and the mucoadhesiveness was good, but the target powder was not obtained.
Comparative Example 3 was inferior in storage stability because the moisture content after drying was too low.
In Comparative Example 4, since the total heat of fusion was high, the adhesion to the mucosa was poor.
In Comparative Example 5, the total amount of heat of fusion was high, so that the adhesion to the mucosa was poor.
Since the comparative example 6 did not mix | blend (B) organic acid, it became inferior to mucous membrane adhesiveness.

The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Sucralfate: "Sucralfate hydrate" manufactured by Fuji Chemical Industry Co., Ltd.
Lactic acid: DSP Gokyo Food & Chemical Co., Ltd., 90% DL-lactic acid Malic acid: Kanto Chemical Co., Ltd., “malic acid”
Citric acid: "Citric acid" manufactured by Kanto Chemical Co., Inc.
Purified water: Kyoei Pharmaceutical Co., Ltd., “Purified water (distilled)”

Claims (6)

  In a DSC curve measured by a differential scanning calorimeter, the powder containing (A) sucralfate, (B) an organic acid, and (C) water, and the content of the component (C) is 10 to 30% by mass. A powder composition, wherein the total amount of heat of fusion determined from the area of the endothermic peak appearing in the temperature range of -20 to 0 ° C is 0 to 0.05 J / g.   The powder composition according to claim 1, wherein the total amount of heat melting is derived from free water and bound water.   The powder composition according to claim 1 or 2, wherein the content mass ratio represented by (A) / (C) is 1 to 8.   The powder composition according to any one of claims 1 to 3, wherein the mass ratio represented by (B) / (C) is 0.2 to 10.   (A) The manufacturing method of the powder composition including the process of preparing the liquid composition containing a sucralfate, (B) organic acid, and (C) water, and the process of drying this liquid composition.   The production method according to claim 5, wherein the drying is performed by microwave drying or freeze drying.

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