KR102684071B1 - Liquid pharmaceutical composition and medical supplies - Google Patents

Abstract

(Problem) By allowing the composition to remain on the mucous membrane and feeling stimulation by mucosal irritants on the mucous membrane, especially the esophagus, the retention of the composition on the mucous membrane can be felt, discomfort in the esophagus and stomach is relieved, and uniformity of the composition is maintained. Provides high-quality, easy-to-take liquid pharmaceutical compositions and medicines.
(Solution) A liquid pharmaceutical composition containing (A) a water-soluble polymer compound, (B) a porous water-insoluble inorganic particle component, (C) a mucous membrane irritating component, and (D) water.

Description

LIQUID PHARMACEUTICAL COMPOSITION AND MEDICAL SUPPLIES}

The present invention relates to liquid pharmaceutical compositions and pharmaceuticals that can be felt to remain on mucous membranes.

To combat inflammation of the esophagus or gastric mucosa, porous water-insoluble inorganic particle components such as antacids are generally mixed. These have the effect of neutralizing stomach acid, so by staying on the stomach and esophageal mucosa, they are directly neutralized on the spot and are expected to have the effect of protecting the mucous membrane itself. Additionally, in order to combat inflammation of the esophagus or gastric mucosa, a formulation technology has been disclosed to improve mucosal retention by thickening the formulation with a polymer compound or the like.

On the other hand, mucous membrane irritating ingredients such as menthol and eugenol are quickly absorbed from the esophagus or stomach mucosa after administration, so they can provide a feeling of effectiveness in the mucosa (relief of discomfort in the esophagus or stomach) and a good feeling of taking. In view of the above, porous water-insoluble inorganic particles and mucosal irritating ingredients such as menthol and eugenol are used together to retain mucous membranes, and the mucosal retention of the composition can be realized by feeling the irritation caused by the mucosal irritating substances in the mucous membrane, especially the esophagus. Skills that could do it were required.

Japanese Patent Publication No. 2002-193827

Although mucous membrane irritating components such as menthol and eugenol have the above-mentioned effects, these components are hydrophobic and have low molecules, so when co-mixed with a porous water-insoluble inorganic particle component and a liquid pharmaceutical composition containing water, the mucous membrane irritating component A new problem of being trapped within this porous material was discovered. This causes the problem that even if the composition itself containing the mucous membrane irritating substance stays in the mucous membrane, the irritation caused by the mucous membrane irritating substance cannot be felt, and the feeling of the composition staying there is not obtained. From this, the present invention allows the composition to remain in the mucous membrane, and by feeling the stimulation by the mucous membrane irritating substance in the mucous membrane, especially the esophagus, the retention of the composition in the mucous membrane can be felt, the discomfort in the esophagus and stomach is relieved, and the composition The purpose is to provide liquid pharmaceutical compositions and medicines that have high uniformity and are easy to take.

As a result of careful study to achieve the above object, the present inventor has found that by combining (A) a water-soluble polymer compound, (B) a porous water-insoluble inorganic particle component, (C) a mucosal irritant component, and (D) water, In addition to allowing the composition to remain in the esophagus when taking it, it was discovered that the retention of the composition in the mucous membrane can be felt by feeling the irritation caused by the mucous membrane irritating substance in the esophagus. In addition, the uniformity of the composition is high, the feeling of swallowing down the throat, and the ease of use when taking it. After discovering that a liquid pharmaceutical composition that is easy to take in terms of the feeling of remaining in the mouth and the feeling of remaining in the mouth after swallowing can be obtained, the present invention was achieved.

Accordingly, the present invention provides the following invention.

[1]. A liquid pharmaceutical composition containing (A) a water-soluble polymer compound, (B) a porous water-insoluble inorganic particle component, (C) a mucous membrane irritating component, and (D) water.

[2]. (C) The liquid pharmaceutical composition according to [1], wherein the component is one or two or more selected from menthol, menthone, carvacrol, eugenol, capsaicin, vitamin E, hesperidin, and osthole.

[3]. (C) The liquid pharmaceutical composition according to [2], wherein the component is selected from menthol, menthone, carvacrol, eugenol, and capsaicin.

[4]. The liquid pharmaceutical composition according to any one of [1] to [3], wherein the component (A) has a functional group selected from a straight-chain alkyl group, a cyclic hydrocarbon chain, a carboxyl group, a hydroxyl group, an amino group, and a hydroxyl group.

[5]. The mass ratio of component (A) and component (B) represented by (A)/(B) is 0.01 to 0.4, and component (A) and component (C) represented by (A)/(C). The liquid pharmaceutical composition according to any one of [1] to [4], wherein the mass ratio is 1.0 to 100.

[6]. The liquid pharmaceutical composition according to any one of [1] to [5], comprising an association of component (A) and component (C).

[7].(I) Process of obtaining solution (I) by mixing component (A), component (C), and some of component (D) (component (D) of step (I)),

(II) a step of mixing the component (B) and some of the component (D) (component (D) of step (II)) to obtain dispersion (II), and

(III) The liquid pharmaceutical composition according to any one of [1] to [6], obtained by mixing the solution (I) and the dispersion (II).

[8].(I) Process of obtaining solution (I) by mixing component (A), component (C), and some of component (D) (component (D) of step (I)),

(II) a step of mixing the component (B) and some of the component (D) (component (D) of step (II)) to obtain dispersion (II), and

(III) A method for producing the liquid pharmaceutical composition according to any one of [1] to [6], comprising the step of mixing the solution (I) and the dispersion (II).

[9]. A pharmaceutical product filled with the liquid pharmaceutical composition according to any one of [1] to [7] in a resin container made of polyethylene, polypropylene, or polyethylene terephthalate, or a container made of a glass bottle.

According to the present invention, the retention of the composition can be felt by feeling the stimulation by the mucosal irritating substance in the esophagus upon administration (hereinafter, the feeling of retention may be described), discomfort in the esophagus or stomach is relieved, and the composition It is possible to provide a liquid pharmaceutical composition that has high uniformity and is easy to take.

Hereinafter, the present invention will be described in detail.

[(A) Ingredient]

A water-soluble polymer compound refers to a polymer compound in which 1 g dissolves in 100 mL of water at 20°C. In the liquid pharmaceutical composition of the present invention (hereinafter sometimes referred to as a composition), component (A) is partially or completely dissolved, and a completely dissolved state is more preferable. By mixing the components (A), the composition is thickened and mucosal retention is improved, thereby improving the efficacy of the mixed drug. Additionally, by using it in combination with component (C), which will be described later, trapping of the mucous membrane irritating component in the porous material is suppressed, thereby providing a feeling of retention.

Water-soluble polymer compounds include xanthan gum, carrageenan, pectin, alginic acid and alginate, alginic acid derivatives such as alginic acid propylene glycol ester, gum-based polymer compounds such as guar gum, gellan gum, and tamarind gum, hydroxypropyl starch, and carboxymethyl cellulose. , hydroxyalkyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, water-soluble polysaccharides such as agar, water-soluble proteins such as gelatin and casein, etc., and can be used one type alone or in an appropriate combination of two or more types. there is. They are all water-soluble and have hydrocarbon chains or functional groups with intermolecular interactions within the molecule. Intermolecular interactions refer to hydrophobic interactions, electrostatic interactions, hydrogen bonds, dipole interactions, and ionic bonds. Suitable hydrocarbon chains include straight-chain alkyl groups such as ethyl groups and propyl groups, and cyclic hydrocarbon chains such as five-membered rings. Examples of the interactive functional group include a 1-4,1-6 glucosidic bond, carboxyl group, hydroxyl group, amino group, hydroxyl group, and hydroxypropyl group. Among them, those having functional groups selected from linear alkyl groups such as ethyl groups and propyl groups, cyclic hydrocarbon chains, carboxyl groups, hydroxyl groups, amino groups, and hydroxyl groups are preferable.

The compounding amount of component (A) in the composition is preferably 0.08 to 3.0% by mass (hereinafter referred to as %), more preferably 0.1 to 2.0%, and even more preferably 0.4 to 0.8%. By setting it at 0.08% or more, trapping of mucous membrane irritating components in the porosity is suppressed and better retention in the esophagus and gastric mucosa can be achieved, and by setting it at 3.0% or less, the composition has an appropriate viscosity and becomes easy to take.

[(B) Ingredient]

Porous water-insoluble inorganic particle components include alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, carbonates such as calcium carbonate and magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, magnesium aluminate silicate, magnesium oxide, and aluminum hydroxide. Antacids such as aluminum magnesium hydroxide can be used, and one type can be used alone or in an appropriate combination of two or more types. By staying in the mucous membrane, these ingredients achieve an on-site gastric acid neutralizing effect. Additionally, water insolubility means that 1 g does not dissolve in 100 mL of water at 20°C. The water supply amount is preferably 0.5 to 5 g/mL. By setting the water supply amount to 0.5 g/mL or more, a composition with high uniformity is obtained, and by setting it to 5 g/mL or less, the actual feeling of retention is further improved. In addition, the amount of water supplied is measured by the “weight of added water” when water is added to the powder until liquid fluidity is developed.

(B) The compounding amount of component in the composition is preferably 1 to 24%, more preferably 2 to 16%, and even more preferably 8 to 12%. By setting it at 1% or more, the desired antacid effect, etc. can be more obtained, and by setting it at 24% or less, the composition has an appropriate viscosity and becomes easier to take.

The mass ratio of component (A) and component (B) represented by (A)/(B) is preferably 0.01 to 0.4, more preferably 0.013 to 0.25, and even more preferably 0.025 to 0.1. By setting it at 0.01 or more, the effect of component (B) is developed more quickly, and by setting it at 0.4 or less, the feeling of staying is further improved.

[(C)Component]

The mucous membrane irritating component is not particularly limited as long as it stimulates the mucous membrane and provides a feeling of retention, and one type can be used alone or in an appropriate combination of two or more types. Specifically, essential oils such as fragrances, refreshing ingredients such as menthol, menthone, allyl isocyanate, caffeine, and cinnamaldehyde, warming ingredients such as carvacrol, eugenol, and thymol, capsaicin, zingerol, gingerol, sanchool, and allicin. Examples include ingredients that promote heat and irritation, such as vitamin E such as tocopherol acetate, and blood flow promoting ingredients such as hesperidin and ostol. Additionally, extracts such as mint, eucalyptus, cinnamon, mustard oil, oregano, thyme, laurel, pepper, ginger, sansho pepper, yam, onion, and pepper can be used as processing raw materials containing these. Additionally, processed raw materials containing these components may be used. Processed raw materials include dried cinnamon extract, bay extract (eugenol, etc.), dried thyme extract (carvacrol, thymol, etc.), red pepper extract (capsaicin), mint (menthol), etc. These ingredients activate TRP receptors in the esophageal and gastric mucosa, providing a feeling of retention.

Among them, cooling components, warming components, heat and stimulation components, and blood flow promoting components are preferable, menthol, menthone, carvacrol, eugenol, capsaicin, vitamin E, hesperidin, and osthol are more preferable, and menthol, menthone, Carvacrol, eugenol and capsaicin are more preferred.

(C) The compounding quantity of component in the composition is preferably 0.004 to 0.24%, more preferably 0.01 to 0.24%, and even more preferably 0.05 to 0.08%. By setting it at 0.004% or more, a more realistic feeling of staying can be obtained, and by setting it at 0.24% or less, appropriate stimulation can be obtained.

The mass ratio of component (A) and component (C) represented by (A)/(C) is preferably 1.0 to 100, more preferably 1.25 to 40, and even more preferably 1.5 to 10. By setting it to 1.0 to 100, you can get a more realistic feel of your stay.

Although the mechanism of the effect of achieving the staying sensation of the present invention is unclear, the functional groups having intermolecular interactions of the component (A), especially hydrophobic interactions and electrostatic interactions, act in a complex manner to form an intermolecular interaction with the mucous membrane irritating component of (C). Accordingly, it is predicted that component (A) and component (C) form an association and the mucous membrane irritating component (C) prevents trapping of the porous water-insoluble inorganic particle component (B) within the particles, thereby improving the feeling of staying. do. Additionally, aggregates can be confirmed by means such as NMR and IR.

[(D) Ingredient]

As water, purified water or the like can be used and is not particularly limited. 70 to 99% is preferable and, as for the compounding quantity of (D) component in a composition, 75 to 98% is more preferable.

Arbitrary components can be appropriately added to the composition of the present invention within a range that does not impair the effect of the present invention. Optional ingredients include other active ingredients, polyols, polymer compounds other than the component (A) above, sweeteners, flavorings, preservatives, flavoring agents, pigments, surfactants, emulsions, soluble inorganic ingredients, etc.

Other active ingredients include gastric acid secretion inhibitors such as ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, laptidine, lansoprazole, rabeprazole, and omeprazole, pirenzepine, atropine, and scoprofen. In addition to muscarinic receptor antagonists such as foramin, and defense factor stimulators such as sucralfate, aldioxa, azulene, L-glutamine, and rebamipide, turmeric, licorice, carrot, yellow perilla, spermatozoa, gentiana, ginseng, and ginseng. Herbal medicinal ingredients (herbal medicine powder, extract powder, sulfur extract) such as ginger, cinnamon, sesame oil, oxalum, bokryeong, jeoryeong, baekchul, hwangbaek, golden, mountain gardenia, ginseng, dermis, cucurbita, fennel, and wood incense, carnitine chloride, oxoamine You can also mix it with ginmal, ulsodeoxycholic acid, etc.

Polyols include sugar alcohols, monosaccharides, oligosaccharides and polysaccharides such as mannitol, erythritol, xylitol, sorbitol, paratinate and lactitol, as well as polyethylene glycol (PEG) and polyhydric alcohols such as glycerin and propylene glycol. Additionally, lower alcohols such as ethanol can also be mixed. When dissolving component (A) in component (D), it can be quickly dissolved by dispersing component (A) in ethanol in advance and then adding it to water (D).

As polymer compounds other than the component (A), linear polymer compounds such as polyethylene glycol can also be used.

Sweeteners include sucrose, fructose, aspartame, scurralose, thaumatin, acesulfame potassium, sorbitol, stevia, refined white sugar, saccharin, glycyrrhizin, etc.

Flavors include known essential oils, such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Colorants include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, and sodium copper chlorophyll.

Examples of preservatives include parabens such as alkylparaben, benzoic acid, paraoxybenzoic acid ester, and sodium benzoate.

[Manufacturing method]

The production method of the liquid pharmaceutical composition of the present invention is not particularly limited, but examples include a production method including the following steps.

(I) A process of obtaining solution (I) by mixing component (A), component (C), and some of component (D) (component (D) of step (I)),

(II) a step of mixing the component (B) and some of the component (D) (component (D) of step (II)) to obtain dispersion (II), and

(III) Process of mixing the solution (I) and the dispersion (II)

The amounts of component (D) in step (I) and component (D) in step (II) are not particularly limited, but solvents such as ethanol can be used in any step (particularly in step (I)). The mass ratio ((I) (D): (II) (D)) of the component (D) used in the (I) process and the (D) component used in the (II) process is 1:0.3 to 1:10. desirable. Additionally, in step (I), the mass ratio of component (D) is preferably 25 to 500 times that of component (A), and in step (II), the mass ratio of component (D) is preferably 1 to 500 times that of component (B). 50 times is preferable.

In any process, it can be produced at room temperature using a general-purpose liquid mixer. In the above step (III), for example, when adding solution (I) to dispersion (II), it is preferable to gradually add dispersion (II) while strongly stirring it with a stirring blade having a shearing ability.

[courage]

Examples of containers for filling the oral liquid pharmaceutical composition of the present invention include general bottle containers, resin containers (both bottle type and single-use type can be used), and glass bottles as bottle containers. As the material of the resin, common materials such as polyethylene, polypropylene, polyethylene terephthalate, and polyacrylonitrile can be used, and polyethylene, polypropylene, and polyethylene terephthalate are preferred. Packaging containers (pouches, etc.) made of a laminate of metal foil and resin film can be used. The above general materials can be used as the resin material, and in particular, polyethylene, polypropylene, polyethylene terephthalate, etc. can be used as the innermost layer. As the metal foil, aluminum foil or the like can be used. Among them, a resin pouch container is preferable because it is a liquid, so an appropriate amount can be consumed at once, and because of portability. The shape of the laminated packaging container can be freely formed into a three-dimensional structure by using pressured air or physical extrusion with a mold.

[Liquid pharmaceutical composition]

The liquid pharmaceutical composition of the present invention preferably has a viscosity (25°C) of 0.1 to 5 Pa·s, and more preferably 0.2 to 3 Pa·s. By maintaining this viscosity range, the amount retained in the esophagus can be improved and administration becomes easier. In addition, the viscosity was measured using a B-type viscometer (e.g., DV2T type, manufactured by Brookfield) at 60 rpm, 25°C, and the rotor was appropriately selected according to the viscosity (average value from three measurements). Additionally, the pH of the composition of the present invention is preferably 5 to 9.

The liquid pharmaceutical composition of the present invention is for oral use and includes aqueous solutions, suspensions, emulsions, etc. As a dosage form, any dosage form that falls under the general provisions of the Japanese Pharmacopoeia and oral liquid formulations can be used. They can also be used as hard capsules, soft capsules, jellies, and liquid-containing gummies. In that case, excipients, binders, disintegrants, etc. for each dosage form can be mixed. Among them, suspension and emulsion are preferable.

(Example)

Hereinafter, the present invention will be described in detail by showing examples and comparative examples, but the present invention is not limited to the following examples. In addition, in the examples below, unless otherwise specified, "%" in the composition represents mass%, ratio represents mass ratio, and the amount of each component in the table is the amount converted to net fraction.

[Examples, comparative examples]

The compositions shown in the table below were produced by the following method.

[Example 1]

(I) 20 g of component (A) and 4 g of component (C) were dissolved in 666 g of water (I) (D) (Three-one motor, 500 to 1,000 rpm, room temperature) to obtain solution (I).

(II) 400 g of (B) was dispersed in 2,000 g of water (II) (D) (Three-One Motor, 200-500 rpm, room temperature) to obtain dispersion (II).

(III) Solution (I) was slowly added to the dispersion (II) while stirring to dissolve it, and the remaining 1,910 g of water (D) was added and stirred to obtain a composition.

Other examples and comparative examples were prepared according to Example 1, and the obtained composition was evaluated as follows. The results are shown in the table. In addition, the compositions of the examples were all liquid, and the pH was in the range of 5 to 9. Additionally, 5 mL of the obtained composition was filled into a 5 mL aluminum laminate distribution container (manufactured by Fujimori Kogyo Co., Ltd., an alumina laminate film (polyethylene, aluminum, PET, polyethylene from the innermost layer)) to obtain a pharmaceutical product. Additionally, the table shows the composition of 5,000 mg (about 5 mL).

[Viscosity measurement]

The composition was placed in a 200 mL glass bottle and measured using a B-type viscometer (Brookfield, DV2T type, 60 rpm, 25°C, rotor appropriately selected according to viscosity).

[Uniformity]

Approximately 10 mL of the composition was charged into a 15 mL centrifuge tube. The properties and appearance after standing for 1 day were confirmed based on the evaluation criteria below.

[Evaluation standard]

4: Uniformly dispersed, no supernatant

3: There is some supernatant, but less than 10% by volume of the total, and is evenly dispersed by shaking.

2: The supernatant is more than 10% by volume of the total, but is uniformly dispersed by shaking.

1: There is supernatant or sediment and is not uniformly dispersed even when shaken.

A score of 2 or more was considered passing.

[Ease of taking and real feeling of stay]

Four panelists (healthy adult men and women) took 5 mL of the composition filled in a 5 mL aluminum laminated distribution container and evaluated the ease of taking and the feeling of retention after 3 minutes in 5 levels. The results are expressed as the average value of 4 people.

[Ease of taking evaluation criteria: Comprehensive evaluation of the feeling of swallowing, the feeling of remaining in the mouth when taking it, and the feeling of remaining in the mouth after swallowing]

5: Very easy to take: There is a definite feeling of swallowing and no residue in the mouth.

4: Easy to take: There is no definite feeling of swallowing, but it does not stick to the mouth and does not leave any residue.

3: Can't say either way: There's no definite feeling of swallowing, it sticks in the mouth, but doesn't leave a residue after swallowing.

2: Difficult to take: Sticks in the mouth and leaves a slight residual feeling even after swallowing.

1: Very difficult to take: It definitely remains in the mouth and there is a residual feeling even after swallowing.

The average score of 4 panelists was 3.0 or higher to pass.

[Feeling of stay: Evaluating mucosal irritation felt in the esophagus as feeling of stay]

5: I feel very strongly.

4: I feel strongly

3: Feel a little

2: I feel a little

1: Feel little or nothing

The average score of 4 panelists was 3.0 or higher to pass.

In addition, the panelists were previously explained about their experience of staying as follows.

Menthol: refreshing sensation, carvacrol, eugenol: warming sensation

The raw materials used in the above examples are shown below. In addition, unless otherwise specified, the amount of each component in the table is the pure amount converted.

Hydroxypropyl cellulose: Nippon Soda Co., Ltd. product, “HPC-L”

Carrageenan: Sansho Co., Ltd. product, “GENUVISCO J-J”

Sodium alginate: Kimikaze Co., Ltd., “Kimika Algin”

Polyvinyl alcohol: Wako Pure Chemical Industries, Ltd., “Polyvinyl alcohol (Wako Grade 1)”

Carboxymethyl cellulose: manufactured by Daicel Chemical Co., Ltd., “CMC Daicel 1160”

Xanthan gum: DSP Kokyo Food & Chemical Co., Ltd. product, “Eco Gum”

Hydroxypropyl Starch: Freund Industrial Co., Ltd. product, “HPS101”

Agar: Wako Pure Chemical Industries, Ltd., “Agar (Reagent Special Grade)”

Gelatin: Made by Nitta Gelatin Co., Ltd., “Gelatin AP-270”

Magnesium metasilicate aluminate: manufactured by Fuji Chemical Co., Ltd., “Noisirin NFL2N”

Magnesium aluminate silicate: Fuji Chemical Co., Ltd. product, “Noisirin A (AS)”

Magnesium carbonate: “Basic magnesium carbonate (heavy)” manufactured by Wako Pure Chemical Industries, Ltd.

Magnesium oxide: Wako Pure Chemical Industries, Ltd., “Magnesium oxide (reagent special grade)”

Aluminum hydroxide: Kyowa Chemical Co., Ltd. product, “Dried Aluminum Hydroxide Gel SN”

Synthetic hydrotalcite: Kyowa Chemical Co., Ltd., “Alcamac VF”

Menthol: Nagaoka Shitsugyo Co., Ltd. product, “Super Menthol 3003”

Carvacrol: Manufactured by Wako Pure Chemical Industries, Ltd., “Carvacrol”

Eugenol: “Eugenol” manufactured by Tokyo Kasei Kogyo Co., Ltd.

5mL aluminum laminate distribution container: Made by Fujimori Kogyo Co., Ltd., aluminum laminate film (polyethylene, aluminum, PET, polyethylene from the innermost layer) sealed on four sides.

Claims (9)

(A) at least one water-soluble polymer compound selected from the group consisting of hydroxypropyl cellulose, carrageenan, sodium alginate, polyvinyl alcohol, carboxymethyl cellulose, xanthan gum, hydroxypropyl starch, agar, and gelatin;
(B) at least one porous water-insoluble inorganic particle component selected from the group consisting of magnesium carbonate, magnesium oxide, and synthetic hydrotalcite;
(C) one or more mucosal irritant ingredients selected from the group consisting of menthol, carvacrol, and eugenol; and
(D) water;
Oral liquid formulation containing. delete delete delete According to claim 1,
The mass ratio of component (A) and component (B) represented by (A)/(B) is 0.01 to 0.4, and the mass ratio of component (A) and component (C) represented by (A)/(C) is 1.0. Oral liquid formulation with ~100 doses. According to claim 1,
An oral liquid preparation containing an association of component (A) and component (C). According to claim 1,
(I) A process of obtaining solution (I) by mixing component (A), component (C), and some of component (D) (component (D) of step (I)),
(II) a step of mixing the component (B) and some of the component (D) (component (D) of step (II)) to obtain dispersion (II), and
(III) Oral liquid preparation obtained by mixing the solution (I) and the dispersion (II). A method for producing the oral liquid formulation according to claim 1, comprising:
(I) A process of obtaining solution (I) by mixing component (A), component (C), and some of component (D) (component (D) of step (I)),
(II) a step of mixing the component (B) and some of the component (D) (component (D) of step (II)) to obtain dispersion (II), and
(III) A method for producing an oral liquid formulation comprising the step of mixing the solution (I) and the dispersion (II). A product filled with the oral liquid preparation according to claim 1 in a resin container made of polyethylene, polypropylene, or polyethylene terephthalate, or a glass bottle.