JP2017218401A - Liquid-filled product and method for suppressing adsorption of oily component - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid-filled product in which adsorption of oily components to a resin container is suppressed as much as possible, the product having little bitterness and excellent dosing property.SOLUTION: According to the present invention, there is provided a liquid-filled product, which is filled in a resin container. The product comprises a liquid formulation including: (A) a sucralfate-containing composition; (B) one or more oily components selected from the group consisting of phenylpropanoid derivatives, isoquinoline alkaloids, and sesquiterpenoid derivatives; (C) 0.04 to 0.40 mass% of a nonionic surfactant; and (D) parabens. Here, a liquid-contacting part of the liquid formulation comprises any of polyethylene, polypropylene, polyethylene terephthalate, and polyacrylonitrile.SELECTED DRAWING: None

Description

  The present invention relates to a liquid-filled product in which a liquid preparation containing sucralfate is filled in a resin container.

  Recently, many gastrointestinal solutions that can be easily taken without using water have been sold. Most gastrointestinal solutions are sold in the form of products filled in glass bottles. However, because of portability and ease of disposal of containers, gastrointestinal solutions are used in resin containers such as film packaging containers that are lightweight and can be easily disposed of. There is a growing need for liquid-filled products filled with.

  In general, gastrointestinal drug solutions contain plant extracts (for example, an active ingredient “magnolol” contained in Koboku, which is a type of stomachic agent) and oil components such as menthol. When a container made of a resin such as polypropylene is filled, the oil component may be adsorbed to the container. In this case, the content of the oily component in the preparation may be reduced, or the preparation filled in the container may be altered to cause deterioration of the quality. For this reason, in the field of pharmaceuticals and the like, many attempts have been made so far to suppress the adsorption of the contained components to the container from the viewpoint of the material of the container and the formulation of the preparation.

  For example, Japanese Patent Application Laid-Open No. 2011-136734 (Patent Document 1) discloses a packaging bag for filling oil-containing liquid preparations such as cosmetics and quasi-drugs. It is described that the adsorption of polar oils such as oil-soluble vitamins and oil-soluble UV absorbers can be suppressed by forming the inside (ie, the wetted part) of the bag with a resin containing a cyclic polyolefin resin as a main component. Has been.

  Moreover, although what was mix | blended about a formulation is related to eye drops, in Unexamined-Japanese-Patent No. 2002-3364 (patent document 2), menthol contained in eye drops adsorb | sucks to a unit dose container. In order to improve, it has been proposed to incorporate one or more components selected from polyhydric alcohols, surfactants and cyclodextrins. JP-A-2002-161037 (Patent Document 3) discloses a prostaglandin. In order to prevent the derivative from adsorbing to the resin container, an ophthalmic solution combined with a nonionic surfactant has been proposed.

  On the other hand, it is effective to add a surfactant to suppress the adsorption of oily components in the preparation to the resin container. However, in the case of internal medicines and foods, etc. Could be damaged.

  As a technique for suppressing bitterness and the like caused by surfactants and improving dosage, Japanese Patent Application Laid-Open No. 2003-137797 (Patent Document 4) describes a mastic solubilized product used for pharmaceuticals and foodstuffs. As a technique for alleviating the taste and bitterness caused by polyglycerin or polysorbitan fatty acid ester-based and polyoxyethylene hydrogenated castor oil-based surfactants in the production of emulsions containing lecithin, A combination method has been proposed.

  In recent years, packaging materials using polyethylene terephthalate and the like have been developed for the purpose of suppressing the adsorption of oily components, and the problem of adsorption of oily components is being improved. However, depending on the mixing conditions, it may not be sufficiently suppressed. It was. Further, the adsorptivity can be lowered by blending the surfactant, but if an excessive amount is blended in order to obtain a desired adsorption suppressing effect, the bitterness derived from the surfactant is strongly felt. For this reason, it has been difficult for the conventional method to achieve both the adsorption suppression effect and the ingestibility. In particular, in the gastrointestinal solution, when trying to improve the adhesion of sucralfate to the mucous membrane, depending on the mixing conditions, the adsorption of the oily component to the resin container is promoted, and polyethylene terephthalate is used as the container material. Even if an appropriate amount of activator is blended, the adsorption may not be sufficiently suppressed.

JP 2011-136734 A JP 2002-3364 A JP 2002-161037 A JP 2003-137797 A

  The present invention has been made in view of the above circumstances, and even when a liquid formulation containing sucralfate is filled in a resin container, the oil component contained in the liquid formulation can be adsorbed to the resin container. Provided is a liquid-filled product that is suppressed as much as possible, has little bitterness and is excellent in dosage, and an adsorption suppression method that can suppress adsorption of the oil component to a resin container as much as possible For the purpose.

  As a result of intensive studies to achieve the above object, the present inventor has found that in liquid preparations containing sucralfate, one or more oily components selected from the group consisting of phenylpropanoid compounds, isoquinoline alkaloids, and sesquiterpenoid derivatives In addition, by combining a nonionic surfactant and parabens, the adsorption of the oil component to the resin container can be suppressed as much as possible without causing any bitterness caused by the nonionic surfactant. And have led to the present invention.

Accordingly, the present invention provides the following liquid-filled product and method for suppressing adsorption of oily components.
[1] (A) Sucralfate-containing composition,
(B) one or more oily components selected from the group consisting of phenylpropanoid derivatives, isoquinoline alkaloids, and sesquiterpenoid derivatives;
(C) Nonionic surfactant 0.04-0.40 mass%, and the liquid formulation containing (D) parabens, liquid contact part is either polyethylene, a polypropylene, a polyethylene terephthalate, and polyacrylonitrile. A liquid-filled product characterized by being filled in a resin container.
[2] The liquid-filled product according to [1], wherein the blending mass ratio represented by [(C) + (D)] / (B) is 100 to 700.
[3] The liquid-filled product according to [1] or [2], wherein the content of the component (D) is 0.001 to 0.04% by mass.
[4] The liquid-filled product according to any one of [1] to [3], wherein the blending mass ratio represented by (D) / (C) is 0.005 to 0.40.
[5] The liquid-filled product according to any one of [1] to [4], wherein the component (B) is one or more selected from the group consisting of magnolol, honokiol, magnoflorin, magnoclarin, and βeudesmol.
[6] The liquid filling product according to any one of [1] to [5], which is a liquid pharmaceutical product.
[7] A liquid preparation comprising (A) a sucralfate-containing composition and (B) one or more oily components selected from the group consisting of phenylpropanoid compounds, isoquinoline alkaloids, and sesquiterpenoid derivatives. In a liquid-filled product in which a liquid portion is filled in a resin container composed of any of polyethylene, polypropylene, polyethylene terephthalate and polyacrylonitrile, (C) a nonionic surfactant and (D) (B) The adsorption | suction suppression method with respect to the resin-made container of an oil-based component including adding parabens.

  ADVANTAGE OF THE INVENTION According to this invention, while being able to suppress adsorption | suction of the oil-based component with respect to resin-made containers as much as possible, there can be provided the liquid filling product which has little bitterness and is excellent in taking property.

Hereinafter, the present invention will be described in detail.
The liquid-filled product of the present invention includes (A) a sucralfate-containing composition, (B) a phenylpropanoid derivative (such as magnolol, honokiol, cinnamaldehyde, and eugenol), an isoquinoline-based alkaloid (such as magnoflorin and magnoclarin), and a sesquiterpenoid A predetermined resin container is filled with a liquid preparation containing one or more oily components selected from the group consisting of derivatives (β-eudesmol, etc.), (C) a nonionic surfactant, and (D) parabens. It is what.

(A) Sucralfate-containing composition The (A) sucralfate-containing composition of the present invention is a liquid or gel composition containing (a-1) sucralfate. In this case, (a-1) sucralfate may be used as a dispersion dispersed in water described later (a-3), and further, if necessary, a liquid composition or gel composition containing other components described later. It may be.

  In the present invention, the liquid composition is a liquid composition containing (a-1) sucralfate, (a-2) an organic acid, and (a-3) water in a predetermined ratio, and the gel composition is Further, (a-4) a pH adjuster is further added to the liquid composition to adjust to pH 5.0 to 8.0. In the following description, the “liquid composition” means a liquid composition at the stage where the components (a-1) to (a-3) are blended, and the “gel composition” means the liquid composition. (A-4) component is added to the product to adjust the pH, and if necessary, other components are blended to obtain an interaction product of the above components (a-1) to (a-4) It means a gel-like composition.

  In the present invention, by using the above-mentioned liquid composition or gel composition as the component (A), adhesion to the mucous membrane of an organ having a short transit time such as the oral cavity or the esophagus can be further improved. Hereafter, each said component is explained in full detail.

(A-1) Sucralfate (a-1) Sucralfate (sucrose octasulfate aluminum salt) binds to a protein of the mucosal inflammation part and has a function of repairing while covering and protecting the inflammation part. It is a drug called “adhesive plaster”. In the present invention, in addition to the effect on the inflamed part of the stomach, an excellent effect can also be exerted on the inflamed part of the esophagus that is the cause of heartburn.

  (A-1) Sucralfate can be used as an aqueous dispersion in (a-3) water. Moreover, when making (A) component into a liquid composition, the compounding quantity in (A) component of (a-1) component is although it does not specifically limit, 20-80 mass% is preferable. (A) When making a component into a gel composition, 18-70 mass% is preferable, 25-70 mass% is more preferable, and 30-50 mass% is still more preferable. (A-1) By making the compounding quantity of a component into the said range, dispersion stability and manufacture aptitude become favorable. In addition, although the compounding quantity in the liquid dosage amount of (a-1) component is not specifically limited, It is suitable to set it as the range of 250-1,000 mg from a viewpoint of effectiveness.

(A-2) Organic acid (a-2) It does not specifically limit as an organic acid, It can be used individually by 1 type or in combination of 2 or more types. 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.

  When the component (A) is a liquid composition, the blending amount of the component (a-2) in the component (A) is preferably 7.5 to 40% by mass, and more preferably 8 to 23% by mass. Moreover, when making (A) component into a gel composition, 7-30 mass% is preferable and 7-20 mass% is more preferable. When the proportion of the component (a-2) becomes too large, the adhesion to the mucosa becomes small, and the adhesion and convergence of the tooth surface may deteriorate. In the present invention, the blending mass ratio represented by (a-2) / (a-1) is preferably 0.1 to 1.2, and more preferably 0.2 to 0.4. In particular, the mucoadhesion effect can be further enhanced by setting this ratio to 0.2 to 0.4. Moreover, a problem may arise in the ingestibility in which said ratio exceeds 1.2.

(A-3) Water (a-3) The blending amount in the component (A) of water is preferably 5 to 60% by mass and more preferably 10 to 50% by mass when the component (A) is a liquid composition. preferable. Moreover, when making (A) component into a gel composition, 4-55 mass% is preferable, 9-45 mass% is more preferable, and 15-40 mass% is still more preferable. In the liquid composition, the blending mass ratio represented by (a-1) / (a-3) is preferably 0.8 to 6, and more preferably 0.8 to 4. By setting this ratio within the above range, good dispersion stability can be obtained.

(A-4) pH adjuster (a-4) The pH adjuster is not particularly limited, and one or two selected from alkali metal or alkaline earth metal oxides, hydroxides and carbonates may be used alone. Two or more species can be used in appropriate combination. In the present invention, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, calcium carbonate and magnesium carbonate In addition to carbonates such as antacids, antacids such as synthetic hydrotalcite, magnesium aluminate silicate, magnesium oxide, aluminum hydroxide, and magnesium aluminate hydroxide can be used. In the present invention, sodium hydrogen carbonate, calcium carbonate, sodium hydroxide, magnesium carbonate and magnesium hydroxide can be particularly preferably used from the viewpoint of productivity. Further, when a water-soluble component is blended as the component (a-4), the component is dissolved in water and consumed (metal ions, hydroxide ions, carbonate ions, etc. remain in the system).

  The compounding amount of the component (a-4) is an amount capable of adjusting the pH of the liquid composition containing the components (a-1) to (a-3) to a predetermined range, and is not particularly limited. Absent. In the present invention, the pH of the composition is preferably 5.0 to 8.0, more preferably 5.5 to 7.4, and still more preferably 5.5 to 7.0 by the component (a-4). By adjusting and gelling, a gel composition can be obtained that provides a liquid preparation having better adhesion and excellent dosing properties.

[Liquid composition]
The above “liquid” means a fluid having a viscosity (25 ° C.) of 100 to 50,000 mPa · s. The viscosity is preferably 100 to 10,000 mPa · s from the viewpoint of production suitability. In addition, by taking this range, the ingestibility (ease of swallowing) is also improved. The viscosity is measured using a B-type viscometer (for example, manufactured by Toki Sangyo Co., Ltd., RB-80), 3 or 4 rotor (changed according to the viscosity), and measured at a rotational speed of 12 rpm / 20 ° C. . In the present invention, the production suitability means that when the sucralfate liquid composition is filled into a packaging container, the viscosity is increased when the sucralfate liquid composition is transferred to the next production process in order to add further formulation treatment (such as microgelation). In this case, stirring, line transportation, etc. are difficult, and this is not desirable for suitability for production, so the viscosity of the liquid composition is below a certain value. Moreover, the pH (25 degreeC) of a liquid composition has the preferable range of 3.0-4.5 from the point of mucoadhesiveness.

[Gel composition]
The above-mentioned “gel composition” is composed of a dispersion medium and a dispersoid (particle). The dispersoid is mainly a complex of sucrose octasulfate, aluminum hydroxide and an organic acid, and the main component of the dispersion medium is water. The dispersion particles are uniformly dispersed throughout by the interaction between the dispersion medium and the dispersion particles, and the dispersion is stabilized for a long period of time. As a whole, it means a composition having a thixotropic property that is a fluid. Having thixotropy refers to that having a shear rate of 0.1 s ⁻¹ and a viscosity ratio (ρ0.1 s ⁻¹ / ρ10 s ⁻¹ ) of 1 to 20 when measured at 10 s ⁻¹ . The viscosity can be measured with an E-type viscometer type rheometer.

  10-60 mass% is preferable in a liquid formulation, as for the compounding quantity of the said (A) component, 20-50 mass% is more preferable, and 30-40 mass% is still more preferable. (A) By making the compounding quantity of a component more than the said minimum, sufficient medicinal effect can be acquired with a reasonable single dose. Moreover, it becomes easy to take a liquid formulation by setting it as the said upper limit or less.

(B) Oil component (B) The oil component is a component selected from the group consisting of phenylpropanoid derivatives, isoquinoline-based alkaloids, and sesquiterpenoid derivatives. Specifically, magnolol, honokiol, cinnamaldehyde, eugenol, and the like can be suitably used as the phenylpropanoid derivative. Moreover, as isoquinoline type | system | group alkaloid, magnoflorin, magnoclarin, etc. can be used conveniently. As the sesquiterpenoid derivative, β-eudesmol and the like can be suitably used. In the present invention, among these, magnolol, honokiol, magnoflorin, magnoclarin, and βeudesmol can be more preferably used. Moreover, these can be used individually by 1 type or in combination of 2 or more types.

  Moreover, (B) component has many components contained in the crude drug itself or the extract extracted from the crude drug, and in this invention, you may mix | blend said each component as an extract extracted from the crude drug itself or the crude drug. The herbal medicine component is not particularly limited as long as the component (B) is contained, and examples thereof include magnolia, persimmon, cinnamon bark, light load, proofed, spicy persimmon, yellow chain, ginger, honoki and eucalyptus oil. Can do. (B) Although the compounding quantity of a component is not specifically limited, From viewpoints, such as effectiveness as a pharmaceutical ingredient, 0.0003-0.02 mass% is preferable in a liquid formulation, and 0.0005-0.01 mass% is. More preferred.

(C) Nonionic surfactant (C) Examples of the nonionic surfactant include polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene alkylene ether, and polyoxyethylene alkyl. Phenyl ether or the like can be used. Among these, polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester are preferable. In the present invention, when an ionic surfactant such as cetyltrimethylammonium chloride (cationic surfactant) or sodium lauryl sulfate (anionic surfactant) is used, a high adsorption suppressing effect can be obtained. This is not preferable because of the increased irritation and unpleasant taste. (C) The compounding quantity of a component is 0.04-0.40 mass% in a liquid formulation, 0.07-0.40 mass% is preferable, and 0.15-0.35 mass% is more preferable. (C) When there are too few compounding quantities of a component, sufficient adsorption | suction suppression effect cannot be acquired. On the other hand, when there are too many compounding quantities of (C) component, the irritation | stimulation to a bitter taste and a tongue will become strong and dosing property will deteriorate.

  Moreover, 70-500 are preferable, as for the compounding mass ratio of (C) component with respect to (B) component represented by (C) / (B), 100-500 are more preferable, and 250-500 are still more preferable. By adjusting the blending mass ratio to 70 or more, the adsorption suppressing effect is increased, and by setting it to 500 or less, the taste, bitterness and irritation to the tongue derived from the active agent are decreased, and the dosage is improved.

(D) Parabens As the (D) parabens, for example, alkyl parabens (butyl paraben, propyl paraben, ethyl paraben) and sodium benzoate are desirable from the viewpoint of adsorption suppression. (D) As for the compounding quantity of a component, 0.001-0.04 mass% is preferable in a liquid formulation, and 0.001-0.03 mass% is more preferable. By making the blending amount of the component (D) 0.001% by mass or more, the adsorption suppressing effect is enhanced, and by setting it to 0.04% by mass or less, the precipitation of the component (D) hardly occurs and the stability of the preparation is improved. It will be good.

  Moreover, the blending mass ratio of the total mass of the (C) component and the (D) component with respect to the (B) component represented by [(C) + (D)] / (B) is preferably 100 to 700, 200 -600 is more preferable. Adsorption suppression effect becomes favorable by making the said compounding mass ratio 100 or more, and taking property becomes favorable by setting it as 700 or less.

  Furthermore, the blending mass ratio of the component (D) to the component (C) represented by (D) / (C) is preferably 0.005 to 0.4, and more preferably 0.005 to 0.2. When the blending mass ratio is 0.005 or more, the adsorption suppressing effect is good, and when it is 0.4 or less, precipitation of the component (D) with time is difficult to occur and the stability of the preparation is good.

  Thus, adsorption | suction with respect to the resin-made containers of (B) component can be effectively suppressed by combining (C) component and (D) component appropriately.

  In the liquid preparation containing the above components (A) to (D), each component described later can be appropriately blended as other components within a range that does not impair the effects of the present invention. In addition, the following each component may be used individually by 1 type, or may use 2 or more types together.

  General pharmaceutical active ingredients include, for example, gastric acid secretion inhibitors such as ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole and omeprazole; pirenzepine or pirenzepine hydrochloride, Muscarinic receptor antagonists such as atropine and scopolamine; defense factor promoters such as aldioxa, azulene, L-glutamine and rebamipide can be added.

  In addition, as inorganic antacids, antacid particles such as synthetic hydrotalcite, magnesium aluminate metasilicate, magnesium aluminate silicate and magnesium aluminum silicate, and inorganic clay minerals such as smectite, bentonite and montmorillonite Can be blended. Further, antipyretic analgesic components such as ibuprofen, acetaminophen, loxoprofen sodium and aspirin, and gastrointestinal related components such as funnel extract and berberine tannate may be blended.

  As additives, starches; celluloses such as hydroxypropylmethylcellulose and hydroxyethylcellulose; polyvinylpyrrolidone; polyols (sugar alcohols such as polyvinyl alcohol, mannitol, erythritol, xylitol, sorbitol, paratinite and lactitol, monosaccharides, oligosaccharides and poly In addition to saccharides, polyhydric alcohols such as polyethylene glycol and glycerin); lower alcohols such as ethanol and propylene glycol can be blended. Gum arabic, pregelatinized starch, carboxyvinyl polymer and the like may be blended. In addition, water-soluble polysaccharides such as xanthan gum, alginate, HM pectin, carrageenan, guar gum, gellan gum, tamarind gum and agar; water-soluble proteins such as gelatin and casein may be blended. These can be used singly or in appropriate combination of two or more. Among them, in particular, by combining two or more selected from xanthan gum, alginic acid ester and HM pectin, higher retentivity and swallowing improvement effect and dispersion stabilizing effect are expected.

  Examples of the sweetener include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, purified sucrose, saccharin, glycyrrhizin and the like. Examples of the flavor include known essential oils such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Examples of the flavoring agent include menthol. Examples of the pigment include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, and copper chlorophyllin sodium.

  The viscosity (25 ° C.) of the liquid preparation of the present invention is preferably 10 to 20,000 mPa · s, more preferably 500 to 5,000 mPa · s. By setting it to the above lower limit or more, the gastric mucosa retention is improved and the effect is improved. It becomes easy to take by making it below the upper limit. The above-mentioned viscosity is a value measured using a Brookfield viscometer (DV2T type, manufactured by Eihiro Seiki Co., Ltd.) by storing the sample in a thermostatic bath at 25 ° C. for 6 hours to obtain a measurement sample (measurement conditions: 12 rpm, 1 minute, the probe is appropriately selected according to the viscosity).

  As a resin container filled with the above liquid preparation, a film packaging container (pouch, sachet, stick packaging, etc.), a bottle container or the like can be used. Further, the layer structure of the container may be a single layer structure or a multilayer structure (laminated packaging material) in which metals such as the same kind or different kinds of resins and aluminum are laminated. In the present invention, a film packaging container (laminate container) using a laminate packaging material can be suitably used from the viewpoints of portability and ease of disposal.

  In addition, in the resin container described above, examples of the material of the liquid contact portion that comes into contact with the liquid preparation include polyethylene, polypropylene, polyethylene terephthalate, and polyacrylonitrile. In particular, in the case where the liquid contact portion is polyethylene, polypropylene, or polyethylene terephthalate, the adsorption of the component (B) is likely to occur in a normal blend, and thus the effect of the present invention can be more easily obtained.

  The thickness of the container is not particularly limited, but in the case of a film packaging container, it can be preferably 5 μm or more, more preferably 10 μm or more, from the viewpoint of durability and ease of use of the container itself. In addition, although the upper limit of the thickness is not specifically limited, Preferably it is 50 micrometers or less, More preferably, it can be 40 micrometers or less. In the case of a bottle container, the thickness is not particularly limited, but is preferably 500 μm or more, more preferably 800 μm or more. The upper limit of the thickness is not particularly limited, but is preferably 5,000 μm or less, more preferably 3,000 μm or less.

[Production method]
The (A) sucralfate-containing composition and liquid preparation described above can be prepared, for example, by the following method.

(1) (A) Method for producing sucralfate-containing composition (A) Component (a-1) Disperse sucralfate in (a-3) water and stir for a predetermined time by a known means such as a propeller mixer. The sucralfate aqueous dispersion obtained by the above can be used. When preparing a liquid composition containing (a-1) sucralfate, (a-2) carboxylic acids such as lactic acid, citric acid and malic acid, and (a-3) water, (a-2) It can be obtained by dissolving the component in the component (a-3), adding the component (a-1) thereto, and stirring the mixture for a predetermined time by a known means such as a propeller mixer. Furthermore, when preparing a gel composition by adding (a-4) a pH adjuster, the pH is adjusted by adding the component (a-4) to the liquid composition obtained above, and an appropriate amount of purified water ( In addition, the total amount can be adjusted and stirred for a predetermined time.

  Although normal conditions can be adopted for the mixing conditions in each of the above steps, it is preferable to maintain the temperature of the liquid composition at 5 to 50 ° C. when adjusting the pH of the liquid composition (at the time of neutralization), It is more preferable to maintain at 5-30 degreeC. By setting the temperature of the liquid composition to 50 ° C. or lower, adhesion to the tooth surface, convergence, and mucosal adhesion can be further improved. By setting the temperature of the liquid composition to 5 ° C. or higher, the water does not freeze, so that productivity is improved.

  In addition, in each process which prepares said liquid composition and gel composition, it is not necessary to perform special stirring and mixing, and can employ | adopt a well-known stirring and mixing method. Examples of the stirring device include stirrer stirring, propeller stirring, homogenizer, homomixer, and emulsifier.

(A-1) Sucralfate exists in the form of particles in which about 8 mol of aluminum hydroxide (Al ₂ (OH) ₅ ) is coordinated to 1 mol of sucrose octasulfate. In the present invention, (a-1) sucralfate, (a-2) an organic acid, and (a-3) water are first mixed at the above-described blending ratio, so that part or all of the sucralfate particles in acidic conditions are mixed. The aluminum hydroxide dissociates. Subsequently, the mixture of the components (a-1) to (a-3) (that is, the liquid composition) is neutralized with the pH adjuster (a-4), so that sucrose octasulfate and aluminum hydroxide It becomes a complex of organic acids. In addition, the said gel composition is obtained by the manufacturing method mentioned above, For example, even if it mixes said (a-1)-(a-4) component simultaneously, it is not obtained. In this case, the resulting composition is in a gel form but does not exhibit the desired mucoadhesiveness or the like.

  Moreover, the sucrose octasulfate ester / aluminum ratio in the dispersoid of the gel composition obtained above is in the range of 0.3 to 1.4 by mass ratio. In addition, this sucrose octasulfate ester / aluminum ratio is obtained by the measuring method of the Example mentioned later. When the sucrose octasulfate / aluminum ratio satisfies the above range, it has good adhesion to mucous membranes such as the esophagus, while astringent taste, astringency (salt taste, tingling feeling), heat feeling Uncomfortable taste such as can be greatly improved. In addition, since the structure of the sucralfate particles contained in the gel composition does not change even if the gel composition is diluted with water or the like as in the examples described later, the ratio of the above sucrose octasulfate and aluminum is It remains unchanged. Therefore, even if the said gel composition is diluted with water etc. and is taken, effects, such as adhesiveness, an unpleasant taste suppression, and a therapeutic effect, can fully be acquired.

  In particular, (a-1) 18-70% by mass of sucralfate, (a-2) 7-30% by mass of organic acid, (a-3) water, and (a-4) a pH adjuster are blended by the above production method. The sucrose octasulfate ester / aluminum ratio in the dispersoid is 0.3 to 1.4, and the pH is 5. A gel composition that is 0-8.0 can be obtained.

(2) Production method of liquid preparation and liquid-filled product (1) selected from the group consisting of (B) phenylpropanoid compound, isoquinoline alkanoid, sesquiterpenoid derivative in (A) sucralfate-containing composition obtained in (1) More than one oil component is added and stirred for a predetermined time by a known means such as a propeller mixer. Next, the liquid formulation according to the present invention can be obtained by adding separately prepared (C) nonionic surfactant and (D) ethanol dispersion of parabens and stirring until uniform. And the liquid filling product which concerns on this invention can be obtained by filling resin containers, such as a film packaging container, with the obtained liquid formulation.

  The liquid-filled product of the present invention thus obtained is one or more oily components selected from the group consisting of (A) a sucralfate-containing composition, (B) a phenylpropanoid compound, an isoquinoline alkaloid, and a sesquiterpenoid derivative. (C) Nonionic surfactant and (D) Parabens-containing liquid preparation (gastrointestinal solution), and the liquid contact portion filled with the liquid preparation is any of polyethylene, polypropylene and polyethylene terephthalate In particular, it is suitable as a liquid pharmaceutical product.

  Further, by adopting the above-described configuration, (A) a sucralfate-containing composition and (B) one or more oily components selected from the group consisting of phenylpropanoid compounds, isoquinoline alkaloids, and sesquiterpenoid derivatives In a liquid-filled product in which the liquid formulation contained is filled in a resin container whose wetted part is composed of any of polyethylene, polypropylene and polyethylene terephthalate, (C) a nonionic surfactant And (D) a method for suppressing adsorption of (B) an oily component to a resin container, which includes adding parabens.

  By adopting the adsorption suppression method of the present invention, the liquid-filled product obtained is a resin-made product even in the form of a product in which a liquid formulation (gastrointestinal solution) containing sucralfate and an oil component is filled in a resin container. The adsorption of the oil component to the container can be suppressed as much as possible, and the bitterness caused by the surfactant is suppressed and the dosage is excellent.

  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 addition, 12 mass% of water | moisture content is contained in the sucralfate (Fuji Chemical Industry Co., Ltd. product, "sucralfate hydrate") used in the following Examples.

[Examples 1 to 14, Comparative Examples 1 to 8, Reference Example 1]
(1) (A) Preparation of sucralfate-containing composition [Liquid 1]
(A-2) 140 g of lactic acid was dissolved in 500 g of (a-3) purified water, 500 g of (a-1) sucralfate was added, and the mixture was stirred with a propeller mixer for 10 hours. Next, (a-4) a pH adjusting agent is added to adjust the pH to 5 to 7, and an appropriate amount (balance) of purified water is added so that the total amount becomes 1,800 g. A composition (Liquid 1) was obtained. The sucrose octasulfate / aluminum ratio in the dispersoid was 0.7.
[Liquid 2]
(A-2) 140 g of lactic acid was dissolved in 500 g of (a-3) purified water, 500 g of (a-1) sucralfate was added, and the mixture was stirred with a propeller mixer for 10 hours. Next, an appropriate amount (balance) of purified water was added so that the total amount would be 1,800 g, and the mixture was stirred for 2 hours to obtain a liquid composition (Liquid 2).

  The sucrose octasulfate / aluminum ratio in the dispersoid of the liquid 1 (gel composition) was measured by the following method.

[Sucrose octasulfate / aluminum ratio in dispersoids]
The prepared gel composition was taken in a centrifuge tube and centrifuged at 2,000 rpm for 30 minutes (room temperature) to remove the supernatant. Purified water was added to the precipitate, washed, and the supernatant was removed by centrifugation. The same operation was repeated twice. The sucrose octasulfate content and the aluminum content of the resulting precipitate were determined, and the sucrose octasulfate / aluminum ratio (mass ratio) was determined.
The sucrose octasulfate content was determined according to the “JP / Sucralfate” quantitative method (HPLC method). For the aluminum content, the amount of aluminum oxide was determined according to the “JP / Dry Aluminum Hydroxide Gel” quantitative method (back titration method) and converted to the amount of aluminum.

(2) Preparation of liquid preparation and manufacture of liquid-filled product (A) The sucralfate-containing composition obtained in (1) is selected from the group consisting of (B) phenylpropanoid compounds, isoquinoline alkanoids and sesquiterpenoid derivatives One or more oily components were added and stirred with a propeller mixer for 1 hour. Next, separately prepared (C) nonionic surfactant and (D) paraben ethanol dispersion were added and stirred until uniform to obtain a liquid preparation. 10 mL of the obtained liquid preparation was taken and filled into a metal / resin laminate packaging container to obtain a liquid-filled product (liquid pharmaceutical product) according to the present invention. The material of the wetted part of the packaging material was made of polyethylene, polypropylene, or polyethylene terephthalate.

  Separately from the above liquid-filled product (liquid pharmaceutical product), (A) component and (B) component are blended, and (C) component and (D) component are not blended into a 50 mL glass bottle. The liquid-filled product of Reference Example 1 was obtained.

  The following evaluation was performed about the liquid filling product (liquid pharmaceutical product) produced above. The results are shown in Tables 1-3.

1) Adsorption of oil component After the prepared liquid-filled product is stored in a thermostatic bath at 60 ° C and 75% RH for one week, the content (residual amount) of the oil component in the liquid preparation taken out from the container is determined according to the following procedure. Asked.
<Method for measuring the content of oily components>
Take 15 g of the preparation, add 10 mL of purified water and 20 mL of 1 mol / L hydrochloric acid, shake well, then add 20 mL of diethyl ether, shake well, centrifuge and separate into supernatant and precipitate. The supernatant was collected. The operation from the addition of purified water to the separation of the supernatant and the precipitate was repeated once more on this supernatant, and the supernatant was collected. The solvent of the obtained supernatant was distilled off, and 10 mL of methanol was added to the residue to dissolve it, followed by filtration to obtain a sample solution. Separately from this, 1 mg of a standard product of the oil component to be measured was accurately weighed, diluted to 10 mL with diluted methanol (7 → 10), and filtered to obtain a standard solution. The sample solution and the standard solution were tested by liquid chromatography, and the content of oily components was calculated. In the present invention, an oil component content (residual amount) of 85% or more was determined to be acceptable.
The liquid chromatography apparatus and measurement conditions are as follows.
Apparatus: manufactured by Shimadzu Corporation, high-liquid liquid chromatography LC2010
Measurement conditions: 20 ° C., 1.5 mL / min, oil component retention time of about 15 minutes, using octadecylsilylated silica gel packed column, sample introduction amount 50 μL

2) Ingestion Nine panelists (healthy adult men and women) included a single dose of the preparation in their mouths, and the bitterness felt immediately after was evaluated based on the following criteria. In the table, the average score of all the panelists was listed.
<Criteria>
3 points: tasteless 2 points: slightly bitter but acceptable 1 point: bitter and cannot be taken 2 points or more were considered acceptable.

＊（Ｃ）成分の代わりに（Ｃ’）成分の配合量を用いて算出した値。

* Value calculated using the blending amount of the component (C ′) instead of the component (C).

The raw materials and containers 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: “90% DL-lactic acid” manufactured by DSP Gokyo Food & Chemical Co., Ltd.
Sodium bicarbonate: Asahi Glass Co., Ltd., “Sodium bicarbonate”
Purified water: Kyoei Pharmaceutical Co., Ltd., “Purified water (distilled)”
Magnolol: “Magnolol” manufactured by Wako Pure Chemical Industries, Ltd.
Honokiol: “Honokiol” manufactured by Wako Pure Chemical Industries, Ltd.
β Eudesmol: Wako Pure Chemical Industries, “β-eudesmol”
Polyoxyethylene hydrogenated castor oil 60: “HCO-60” manufactured by Nikko Chemicals Co., Ltd.
Sucrose fatty acid ester: “Sucrose fatty acid ester J-1816” manufactured by Mitsubishi Chemical Foods Corporation
Sodium lauryl sulfate: manufactured by Wako Pure Chemical Industries, Ltd., “Sodium lauryl sulfate”
Cetyltrimethylammonium chloride: manufactured by Wako Pure Chemical Industries, Ltd., “cetyltrimethylammonium bromide”
Butylparaben: “Butylparaben” manufactured by Midori Chemical Co., Ltd.
Propylparaben: “Propylparaoxybenzoate” manufactured by Ueno Pharmaceutical Co., Ltd.
Ethanol: Wako Pure Chemical Industries, “Special grade ethanol (95)”
Polyethylene laminate container: “PET / AL / PET / LLDPE” manufactured by Fujimori Kogyo Co., Ltd. (lamination of polyethylene terephthalate 12 μm / aluminum 9 μm / polyethylene 12 μm)
Polypropylene laminate container: “PET / AL / PET / CPP” manufactured by Fujimori Kogyo Co., Ltd. (lamination of polyethylene terephthalate 12 μm / aluminum 9 μm / polypropylene 12 μm)
Polyethylene terephthalate laminate container: “PET / AL / PET / G-PET” manufactured by Fujimori Kogyo Co., Ltd. (lamination of polyethylene terephthalate 12 μm / aluminum 9 μm / polyethylene terephthalate 12 μm)
Glass container: “SV-50A” manufactured by Nidec Rika Glass Co., Ltd.

From the results shown in the above Tables 1 to 3, by satisfying the configuration of the present invention, the adsorption of the oil component to the resin container is suppressed as much as possible, and the liquid filling with less bitterness and excellent dosing properties It was confirmed that the product was obtained.
Moreover, Reference Example 1 written together in Table 2 evaluated the liquid filling product which filled the glass formulation with the liquid formulation which does not contain (C) component and (D) component. From this result, it is understood that the component (B) is not adsorbed even if the components (C) and (D) are not blended in the glass bottle, and the problem of the present invention does not occur in the conventional product form filled in the glass bottle. Was confirmed.

Claims (7)

(A) a sucralfate-containing composition,
(B) one or more oily components selected from the group consisting of phenylpropanoid derivatives, isoquinoline alkaloids, and sesquiterpenoid derivatives;
(C) Nonionic surfactant 0.04-0.40 mass%, and the liquid formulation containing (D) parabens, liquid contact part is either polyethylene, a polypropylene, a polyethylene terephthalate, and polyacrylonitrile. A liquid-filled product characterized by being filled in a resin container.   The liquid-filled product according to claim 1, wherein the blending mass ratio represented by [(C) + (D)] / (B) is 100 to 700.   (D) Content of a component is 0.001-0.04 mass%, The liquid filling product of Claim 1 or 2 characterized by the above-mentioned.   The liquid filling product according to any one of claims 1 to 3, wherein a blending mass ratio represented by (D) / (C) is 0.005 to 0.4.   The liquid-filled product according to any one of claims 1 to 4, wherein the component (B) is at least one selected from the group consisting of magnolol, honokiol, magnoflorin, magnoclarin, and βeudesmol.   The liquid filling product according to claim 1, which is a liquid pharmaceutical product.   A liquid preparation containing (A) a sucralfate-containing composition and (B) one or more oily components selected from the group consisting of phenylpropanoid compounds, isoquinoline alkaloids, and sesquiterpenoid derivatives, In a liquid-filled product filled in a resin container composed of any of polyethylene, polypropylene, polyethylene terephthalate and polyacrylonitrile, (C) a nonionic surfactant and (D) parabens are added to the liquid preparation. (B) The adsorption | suction suppression method with respect to the resin-made container of an oil-based component including adding.