JP2016084320A - Microgel formulation and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a formulation which is excellent in dispersion stability, has good ingestibility, and holds the drug in the formulation sufficiently in the organ having a short passing time, such as an oral cavity or esophagus.SOLUTION: The invention provides a microgel formulation containing (A) a drug which is a tertiary metal salt, (B) organic acid, and(C) a water soluble polymer compound gelating with tertiary metal salt, the microgel formulation having microgel particles.SELECTED DRAWING: None

Description

  The present invention relates to a microgel preparation containing a drug which is a trivalent metal salt.

  For organs with a short preparation transit time such as the oral cavity and esophagus, a technique for sufficiently retaining the active ingredient in the preparation is desired. As a technique for improving retention in the oral cavity or esophagus, it is known to incorporate an anionic polymer such as carbopol. However, the anionic polymer interacts with metal ions such as aluminum in the preparation, so that it gradually gels and precipitates in the preparation and does not disperse even when shaken. As a result, there are problems such as (1) the appearance (appearance) of the preparation is impaired, (2) the dischargeability from the container is poor, and (3) the component content uniformity of the preparation cannot be obtained.

JP-A-8-268895

  Drugs that are trivalent metal salts, for example, preparations containing medicinal ingredients containing aluminum (sucralfate, aluminum-based antacid, allantoin chlorohydroxyaluminum), have excellent dispersion stability, and there is no problem with ingestion In organs with a short transit time such as the oral cavity and esophagus, it is difficult to sufficiently retain the drug in the preparation. An object of the present invention is to solve the above-mentioned problems and to provide a preparation that sufficiently retains the drug in the preparation in an organ having excellent dispersion stability, good ingestion, and a short transit time such as the oral cavity and esophagus. And

  As a result of intensive studies to achieve the above object, the present inventors have found that (A) a drug that is a trivalent metal salt, (B) an organic acid, and (C) a water-soluble gel that gels with a trivalent metal salt. A microgel obtained by forming a gel with a polymer compound and crushing the gel is excellent in dispersion stability, good ingestion, and in an organ having a short transit time such as the oral cavity or esophagus ( A) It has been found that the drug is sufficiently retained, and the present invention has been made.

Accordingly, the present invention provides the following microgel formulation and method for producing the same.
[1] A microgel particle comprising (A) a drug that is a trivalent metal salt, (B) an organic acid, (C) a water-soluble polymer compound that gels with a trivalent metal salt, and (D) water. A microgel formulation having:
[2] The microgel preparation according to [1], wherein the component (A) is a drug selected from sucralfate and an aluminum antacid.
[3] The microgel preparation according to [1] or [2], wherein the component (B) is an organic acid selected from citric acid, malic acid, lactic acid and acetic acid.
[4] Any one of [1] to [3], wherein the component (C) is one or more polymer compounds selected from xanthan gum, sodium carboxymethylcellulose, sodium alginate, pectin and carboxyvinyl polymer. The microgel formulation described.
[5] The microgel preparation according to any one of [1] to [4], wherein the average particle size of the microgel particles is 50 to 1,400 μm.
[6] The microgel preparation according to any one of [1] to [5], which is for esophageal retention.
[7] The microgel according to any one of [1] to [5], which has microgel particles obtained by generating a gel with the components (A), (B), and (C) and crushing the gel. Formulation.
[8] A microgel formulation comprising (A) a drug that is a trivalent metal salt, (B) an organic acid, and (C) a water-soluble polymer compound that gels with a trivalent metal salt and having microgel particles A method for producing a microgel preparation, characterized in that a mixture containing (A) component, (B) component and (D) water is added to an aqueous solution of component (C) while stirring the aqueous solution. Method.

  ADVANTAGE OF THE INVENTION According to this invention, it is excellent in dispersion stability, taking property is good, and provides the microgel formulation which fully retains the (A) drug in a formulation in organs with a short passage time, such as an oral cavity and an esophagus. it can.

Hereinafter, the present invention will be described in detail.
The microgel preparation of the present invention contains (A) a drug that is a trivalent metal salt, (B) an organic acid, (C) a water-soluble polymer compound that gels with a trivalent metal salt, and (D) water. And having microgel particles.

(A) Drug that is a trivalent metal salt The component (A) is not particularly limited as long as it is a drug that is a trivalent metal salt, and can be used alone or in combination of two or more. The trivalent metal salt is preferably aluminum, and functions as a crosslinking agent for the component (C) described later. Examples of the component (A) include sucralfate, synthetic hydrotalcite, magnesium silicate aluminate, aldioxa, aluminum hydroxide, and other aluminum antacids, which may be used alone or in combination of two or more. be able to. Among these, a drug selected from sucralfate and an aluminum-based antacid is preferable, and sucralfate is more preferable.

  (A) 1-50 mass% is preferable in a microgel formulation, and, as for the compounding quantity of a component, 1-40 mass% is more preferable. In the case of sucralfate, 1-20 mass% is preferable and 1-15 mass% is more preferable. The aluminum-based antacid is preferably 5 to 30% by mass, and more preferably 5 to 25% by mass. In addition, when using sucralfate and an aluminum type | system | group antacid, it is 1-50 mass%, 1-40 mass% is more preferable, 2-25% is still more preferable. By setting it as the said range, taking property improves more, and dispersion stability improves more by setting it as the said upper limit or less.

(B) Organic acid (B) The metal salt of the drug which is (A) a trivalent metal salt is liberated by the organic acid. The effect of the present invention cannot be obtained with an inorganic acid. Examples of the organic acid include citric acid, malic acid, lactic acid, and acetic acid, which can be used alone or in combination of two or more. Of these, citric acid, malic acid, and lactic acid are preferable.

  (B) 0.1-25 mass% is preferable in a microgel formulation, and, as for the compounding quantity of a component, 0.1-16 mass% is more preferable. (A) When a component is sucralfate, 0.1-10 mass% is preferable and 0.1-6 mass% is more preferable. When component (A) is an aluminum-based antacid, 0.5 to 15% by mass is preferable, and 0.5 to 10% by mass is more preferable. In addition, when using sucralfate and an aluminum type | system | group antacid, 0.1-25 mass% is preferable and 0.1-16 mass% is more preferable. By setting it to the above lower limit or more, the dispersion stability, the retention property, and the ingestibility are further improved.

  The blending mass ratio represented by (B) / (A) is preferably 0.1 to 0.5, and more preferably 0.1 to 0.4. When the blending mass ratio is 0.1 or more, dispersion stability and retention are further improved, and when it is 0.5 or less, there is no fear of deterioration of dosing due to excessive acid and unstable microgel dispersion.

(C) A water-soluble polymer compound that gels with a trivalent metal salt (B) A metal salt of a drug that is (A) a trivalent metal salt is liberated with an organic acid, and (C) ) The component can be gelled to form a gel. Therefore, when a polymer compound that does not gel with a trivalent metal salt is used, in organs with a short transit time such as the oral cavity and esophagus, it is difficult to take the active ingredient sufficiently to stay. It is necessary to increase the viscosity.

  The component (C) is not particularly limited as long as it is a water-soluble polymer compound that gels with a trivalent metal salt. For example, xanthan gum, sodium carboxymethylcellulose, sodium alginate, pectin, carboxyvinyl polymer, carrageenan, gellan gum and the like. Is mentioned. Among these, xanthan gum, sodium carboxymethylcellulose, sodium alginate, pectin and carboxyvinyl polymer are preferable, and xanthan gum is more preferable.

  (C) 0.1-2 mass% is preferable in a microgel formulation, and, as for the compounding quantity of a component, 0.15-1.2 mass% is more preferable. (C) By making the compounding quantity of a component into 0.1 mass% or more, it fully gelatinizes and a retention property and dispersion stability improve more. On the other hand, at 2% by mass or less, there is no risk of deterioration in dosage due to an increase in viscosity. Moreover, when (A) component uses sucralfate and an aluminum type | system | group antacid together, the ratio of (A) component which occupies in a microgel formulation becomes relatively large. When the component (A) is 20 to 50% by mass, the concentration of the solid content is high and the viscosity is likely to be high, so the component (C) is 0.1 to 0.5% by mass or less from the aspect of ingestion. It is preferable.

(D) Water The blending amount of water is preferably 22.5 to 98.7% by mass in the microgel preparation, and more preferably 70.0 to 95.0% by mass from the viewpoint of dispersion stability and ingestion.

[Microgel formulation]
The preparation of the present invention is a microgel preparation having microgel particles. The microgel refers to polymer fine particles of about 50 to 1,400 μm that are internally cross-linked, and has a fluidity like a liquid, but is an aggregate of fine granular gels. The microgel maintains the structural characteristics of the polymer gel, such as a three-dimensional cross-linked structure and a surface that hardly changes, and is characterized by being colloidally dispersed in a solvent. In the present invention, the presence of the microgel can be confirmed by detecting the peak derived from the microgel by measuring the particle diameter.
[Measurement of average particle size and determination of microgelation]
The particle size distribution in the sample is measured using a laser particle size measuring device (LS13320: Beckman Coulter) Universal Liquid module. For the sample added without dissolving the sucralfate, the peak around 8 μm of the sucralfate particles was excluded, and the median diameter was described as the average particle diameter. The average particle diameter refers to a 50% diameter (median diameter, volume basis) in the laser diffraction / scattering particle size distribution, and the microgel particles of the present invention have an average particle diameter determined from the above in the range of 50 to 1,400 μm. It is.

  The average particle size of the microgel particles is preferably 50 to 1,400 μm, and more preferably 180 to 800 μm. When it is 50 μm or more, the dispersion stability is further improved, and when it is 1,400 μm or less, the retention is further improved, and there is no possibility of adversely affecting the texture. In addition, the measuring method of an average particle diameter is measured using the laser particle diameter measuring apparatus, and an average particle diameter means 50% diameter (median diameter, volume reference | standard) in a laser diffraction scattering type particle size distribution. Details are as above.

  The pH (25 ° C.) of the microgel preparation is preferably in the range of pH 3 to 6.5 from the viewpoint of ingestion and retention. Examples of the pH adjusting agent include sodium hydroxide. Further, the viscosity (25 ° C.) is preferably 50 to 10,000 mPa · s from the viewpoint of ingestion, manufacturability and filling properties. In addition, a viscosity shows the result (Repeated average value of n = 3) measured at 60 rpm for 1 minute with a B-type viscometer.

  The microgel preparation of the present invention is an organ having a short preparation transit time, such as the oral cavity and the esophagus, and exhibits excellent retention. Therefore, the microgel preparation is suitable as an internal preparation, a microgel preparation for oral retention, and a microgel preparation for retention of the esophagus. It is more suitable as a microgel preparation for use. As an ingestion method, it may be taken orally.

  The dosage form is preferably a liquid, a hard capsule, a soft capsule, a cream, an ointment, a lotion, or a gel, and particularly preferably a liquid or a soft chewable capsule. Further, the microgel preparation can be dried to obtain tablets (including chewable tablets and orally disintegrating tablets), powders, and granules.

In the microgel preparation of the present invention, optional components can be appropriately blended within a range not impairing the effects of the present invention. Optional ingredients include excipients, binders, sugar alcohols, sweeteners, lubricants, preservatives, fragrances, pigments and the like.
Examples of the excipient include lactose, corn starch, crystalline cellulose, and potato starch.
Examples of the binder include hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, pregelatinized starch, agar, honey and the like.
Examples of the sugar alcohol include mannitol, erythritol, xylitol, sorbitol, palatinit, lactitol and the like.
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.

[Production method]
The microgel particles of the present invention can be obtained by forming a gel with the components (A), (B), and (C) and crushing the gel. Agitation is an example of the crushing method. (B) The metal salt of the drug which is (A) a trivalent metal salt is liberated with an organic acid, and the component (C) is gelled with this trivalent metal salt to form a gel. Examples of the production method include a method in which a mixture containing the component (A), the component (B) and the water (D) is added to the aqueous solution of the component (C) while stirring the aqueous solution. A stirrer and a stirrer are appropriately selected according to the average particle diameter of the target microgel particles, and a stirrer capable of controlling the shearing force by a stirring rotation speed or the like is preferable. Specific examples of the agitator include a homomixer and a three-one motor. The stirring speed is preferably 100 to 10,000 rpm, more preferably 500 to 8,000 rpm.

  (B) An aqueous solution of a water-soluble polymer compound in which an organic acid is dissolved in water together with a drug that is (A) a trivalent metal salt and sufficiently stirred, and then gelled with (C) a trivalent metal salt. By adding to, a microgel preparation can be easily obtained even with a low shear force. On the other hand, even if (B) component is further added after mixing (A) component and (C) component, the target microgel formulation is obtained.

  The amount of (D) water in the mixture containing (A) component, (B) component and (D) water is the ratio of (A) component to (D) component (A) / (D) = 0. It is preferable that it is 8-6 (mass ratio). The amount of (D) water in the (C) component aqueous solution is preferably (C) / (D) = 0.001 to 0.02 (mass ratio).

  EXAMPLES Hereinafter, although a preparation example, 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.

[Preparation Example 1: Preparation of sucralfate hydrate]
Sucralfate hydrate was pulverized at 15,000 rpm with a pin mill (fine pulverizer Coroplex 160Z type: manufactured by Paulek) to obtain a median diameter of 8 μm.

[Examples 1 to 16]
According to the composition of the following table, the composition was prepared as follows. For stirring, a magnetic stirrer (AMG-H: Asahi Rika) was used. The same amount of purified water and a predetermined amount of the component (B) were added to the component (A) to dissolve the component (A) to obtain a solution containing the components (A) and (B). Separately, a component (C) aqueous solution in which component (C) was dissolved in the remaining purified water was obtained. The solution was added to the aqueous solution while stirring the aqueous solution to obtain a microgel preparation.

[Comparative Examples 1 and 2]
A composition was obtained in the same manner as in the Examples except that the component (B) or the component (C) was not blended.

[Comparative Example 3]
The same amount of purified water and a predetermined amount of the component (B) were added to the component (A) to dissolve the component (A) to obtain a solution containing the components (A) and (B). Separately, agar is dispersed in the remaining purified water, heated to 90 ° C. and dissolved, and then rapidly cooled and the resulting gel is stirred to obtain a microgel. While stirring this, the above solution is added to the microgel. A composition containing the components (A) and (B) outside the microgel made of agar was obtained.

[Comparative Example 4]
The same amount of purified water and a predetermined amount of the component (B) were added to the component (A) to dissolve the component (A) to obtain a solution containing the components (A) and (B). The agar was dissolved in the remaining purified water heated to 90 ° C, allowed to cool, and the above solution was added with stirring before gelation by the agar. However, a microgel was not obtained and the liquid became poorly dispersed. It was.

[Comparative Examples 5 and 6]
(B) The composition was obtained by the method similar to an Example except changing a component into phosphoric acid or hydrochloric acid.

[Comparative Example 7]
The same amount of purified water and a predetermined amount of the component (B) were added to the component (A) to dissolve the component (A) to obtain a solution containing the components (A) and (B). Separately, hydroxypropyl starch was dispersed in the remaining purified water and heated at 80 ° C. for 30 minutes to obtain a gelatinized solidified product. While the solidified product was stirred, the solution was added to the solidified product to obtain a composition.

  The following evaluation was performed about the sample (microgel formulation or composition) obtained by the Example and the comparative example. The results are also shown in the table.

[Measurement of average particle size, determination of microgelation]
The particle size distribution in the sample was measured using a laser particle size measuring device (LS13320: Beckman Coulter) Universal Liquid module. For samples added without dissolving sucralfate, the peak around 8 μm of sucralfate particles is excluded and the median diameter is described as the average particle diameter. The average particle diameter refers to a 50% diameter (median diameter, volume basis) in a laser diffraction / scattering particle size distribution. In the table below, “no micro-gelation” means that the sample does not form a gel and the polymer and other molecules are dispersed in the liquid or are completely liquid. This means that the peak of particle diameter derived from microgel was not observed.

[Appearance (dispersion stability)]
Appearance (dispersion stability) when 100 mL of a sample was placed in a 200 mL beaker and allowed to stand for 1 day was determined according to the following evaluation criteria.
<Evaluation criteria>
A: The whole is uniformly dispersed.
○: Water separation of less than 5 mm is confirmed, but is uniformly dispersed by stirring.
Δ: Water separation of 5 mm or more is confirmed, but is uniformly dispersed by stirring.
X: Even if it is stirred, it is not uniformly dispersed. Or it cannot be uniformly dispersed from the time of manufacture.

[Ingestion (ease of swallowing)]
Five adult men and women swallowed 5 mL of each preparation, and “ease of swallowing” was evaluated according to the following evaluation criteria. A result is shown with the following criteria based on the average value of five persons.
<Evaluation criteria>
5: It is quite easy to swallow.
4: Slightly easy to swallow.
3: Neither can be said.
2: Slightly difficult to swallow.
1: Very difficult to swallow.
<Criteria>
◎: 3.5 or more ○: 3.0 or more and less than 3.5 Δ: 2.0 or more and less than 3.0 ×: less than 2.0

[Retention rate, retention of component (A)]
A vertically installed polyethylene tube (inner diameter 10 mm, length 125 mm) was used as an esophageal model. In addition, the esophageal residence evaluation method using a polyethylene tube is used as an evaluation method in the following literature, and is an evaluation method that has a high correlation with the experimental results in model animals.
Potential Efficacy of a Delta 5- Aminolevulinic Acid Bioadhesive Gel Formulation for the Photodynamic Treatment of Lesions of the Gastrointestinal Tract in Mice, V. Vonarx et al., J. Pharm. Pharmacol. (1997)

Inject approximately 5.0 g of sample from the top of the polyethylene tube. Then, after injecting a saliva model (0.5% mucin solution) at 2.5 mL / min for 2 minutes, a sample is collected from the bottom of the tube. In the case of sucralfate, sucrose octasulfate is analyzed by high-performance liquid chromatography. When other components were used as (A), aluminum was quantified by a titration method, and the residual rate in the tube was calculated as the retention rate. Each quantification was performed according to the method described in the Japanese Pharmacopoeia. The average of 6 repetitions is taken, and the result is shown by the following criteria based on this average value.
<Criteria for determining retention of component (A)>
◎: 8% or more ○: 6% or more and less than 8% △: 4% or more and less than 6% ×: less than 4%

The raw materials used in the examples and comparative examples shown in Tables 1 to 3 are shown below. Unless otherwise specified, the amount of each component in the table is the pure amount of the component described.
Sucralfate: manufactured by Fuji Chemical Industry Co., Ltd., “Japanese Pharmacopoeia Sucralfate”
Magnesium aluminate metasilicate: “Neusilin NFL2N” manufactured by Fuji Chemical Industry Co., Ltd.
Synthetic hydrotalcite: “Alkamak VF” manufactured by Kyowa Chemical Industry Co., Ltd.
Lactic acid: DSP Gokyo Food Chemical Co., Ltd., “Japanese Pharmacopoeia DL-lactic acid”
Malic acid: “DL-malic acid special grade” manufactured by Wako Pure Chemical Industries, Ltd.
Hydrochloric acid: Wako Pure Chemical Industries, “Reagent special grade”
Phosphoric acid: Wako Pure Chemical Industries, “Reagent special grade”
Xanthan gum: DSP Gokyo Co., Ltd., “Keldent”
Carboxymethylcellulose sodium: “AG Gum M Kyokuho” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.
Carrageenan: manufactured by Sanki Co., Ltd., “GENUVISCO X-928-03”
Agar: manufactured by Ina Food Industry Co., Ltd., “Pharmacopea Agar PS-7”
Hydroxypropyl starch: Freund Sangyo Co., Ltd. “HPS-101 (W)”

  From the results of Tables 1 and 2, microgel particles containing (A) a drug that is a trivalent metal salt, (B) an organic acid, and (C) a water-soluble polymer compound that gels with a trivalent metal salt It was confirmed that the microgel preparation having an excellent dispersion stability, good ingestibility and retention of the component (A). In particular, when the component (A) is sucralfate, the blending amount is in the range of 1 to 15% by mass, the component (B) is in the range of 0.1 to 6% by mass, and the component (C) is 0.15 to 1.2%. It was confirmed that better results could be obtained in any evaluation by adjusting the ratio of (B) / (A) to the range of 0.1 to 0.4 in the mass% range (Examples). 1, 3, 4, 6, 7, 10, and 11). Furthermore, it was confirmed that good dispersion stability can be obtained by selecting xanthan gum as the component (C) (Examples 1, 14 and 15). Moreover, it was confirmed that a better result is obtained in any evaluation by setting the particle size of the microgel to 180 to 800 μm (Examples 1 and 17 to 19).

  On the other hand, from the results of Table 3, it was confirmed that when any of the essential requirements of the present invention is lacking, good dispersion stability, ingestibility and retention are not obtained. The comparative example 1 which does not mix | blend (B) component did not generate | occur | produce microgelling, but since the viscosity was high, the ingestibility was inferior and the retention was not high. In Comparative Example 2 where the component (C) is not blended, the acid-treated component (A) does not disperse and becomes a high-viscosity liquid. The dosing and dispersibility are poor, and the viscosity is too high to evaluate the retention rate. Met. Comparative Example 3 in which agar that gels without using a trivalent metal salt is used instead of the component (C) is a liquid composition having a high viscosity containing a microgel portion and the component (A), although an agar microgel is produced. Separated and the dispersibility and retention were poor. Furthermore, Comparative Example 4 in which the method of adding the components (A) and (B) was changed to the method of adding the components (A) and (B) in the middle of the agar gelation from the production method of Comparative Example 3, shows that the agar gelation is poor and a uniform liquid composition is used. Since the composition could not be obtained and the gel-like lump was floating, the composition could not be injected into the polyethylene tube, and the retention rate could not be evaluated. In Comparative Examples 5 and 6 in which phosphoric acid or hydrochloric acid, which is an inorganic acid, is blended in place of the component (B), not only does the microgel not form, but the component (A) is not sufficiently dispersed and a large gel precipitate lump is formed. A formulation capable of evaluating dosing properties and retention rate was not obtained. This is considered because the aluminum derived from the component (A) was insufficiently liberated. Comparative Example 7 in which hydroxypropyl starch that does not gel with a trivalent metal salt was blended in place of component (C) resulted in poor retention because the microgel could not be obtained, and poor dosing due to high viscosity. .

Claims (8)

  (A) a drug that is a trivalent metal salt, (B) an organic acid, (C) a water-soluble polymer compound that gels with a trivalent metal salt, and (D) a microgel having water and containing microgel particles Formulation.   The microgel preparation according to claim 1, wherein the component (A) is a drug selected from sucralfate and an aluminum antacid.   The microgel preparation according to claim 1 or 2, wherein the component (B) is an organic acid selected from citric acid, malic acid, lactic acid and acetic acid.   The microgel preparation according to any one of claims 1 to 3, wherein the component (C) is one or more polymer compounds selected from xanthan gum, sodium carboxymethylcellulose, sodium alginate, pectin and carboxyvinyl polymer.   The microgel formulation according to any one of claims 1 to 4, wherein the average particle size of the microgel particles is 50 to 1,400 µm.   The microgel preparation according to any one of claims 1 to 5, which is used for esophageal retention.   The microgel preparation according to any one of claims 1 to 5, which has microgel particles obtained by producing a gel with the components (A), (B) and (C) and crushing the gel.   (A) A method for producing a microgel preparation having microgel particles, comprising a drug that is a trivalent metal salt, (B) an organic acid, and (C) a water-soluble polymer compound that gels with a trivalent metal salt. A method for producing a microgel preparation, comprising adding a mixture containing the component (A), the component (B) and the water (D) to the aqueous solution of the component (C) while stirring the aqueous solution.