JP2018203689A - Pharmaceutical composition - Google Patents

Abstract

To provide a pharmaceutical composition having a high elution rate of an active ingredient in the presence of herbal medicine or extract thereof.SOLUTION: A pharmaceutical composition contains (A) component: at least one selected from the group consisting of loperamide hydrochloride, berberine chloride, scopolamine, and a scopolamine derivative, (B) component: at least one selected from the group consisting of herbal medicine and extract thereof, and (C) component: an organic solvent for dissolving the component (A).SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition.

  There are various factors in the diseases that occur in people's lives. For example, diarrhea caused by overeating and drinking may cause complications such as indigestion due to a decrease in stomach and liver function in addition to diarrhea. Therefore, not only an antipruritic component as an active ingredient, but also, for example, a herbal medicine that normalizes the function of the stomach and liver is desired.

  Patent Document 1 proposes a pharmaceutical composition containing an antipruritic component and a crude drug.

Japanese Patent Laid-Open No. 10-109942

  However, depending on the type of active ingredient, when combined with a crude drug, the elution rate of the active ingredient is reduced, and as a result, absorption from the intestinal tract into the blood is also reduced. If the blood concentration of the active ingredient decreases, the effect may not be sufficiently obtained.

  This invention is made | formed in view of the said situation, and it aims at providing the pharmaceutical composition with a high elution rate of an active ingredient even in presence of a crude drug or its extract.

  The present inventors have intensively studied and found that the above problem can be solved by blending an organic solvent that dissolves an active ingredient.

That is, the pharmaceutical composition of the present invention includes the following aspects.
[1] Component (A): at least one selected from the group consisting of loperamide hydrochloride, berberine chloride, scopolamine, and scopolamine derivatives;
(B) component: at least one selected from the group consisting of herbal medicine and herbal extracts,
(C) component: The pharmaceutical composition containing the organic solvent which melt | dissolves said (A) component.
[2] The pharmaceutical composition according to [1], wherein the component (B) is at least one selected from the group consisting of turmeric, licorice, and glaze.
[3] The pharmaceutical composition according to [1] or [2], wherein the component (C) is at least one selected from the group consisting of propylene glycol, propylene glycol fatty acid ester, and ethanol.
[4] The pharmaceutical composition according to any one of [1] to [3], wherein the component (A) is loperamide hydrochloride.

  ADVANTAGE OF THE INVENTION According to this invention, when using an active ingredient and a crude drug together, the pharmaceutical composition with a high elution rate of an active ingredient can be provided even in presence of a crude drug or its extract.

≪Pharmaceutical composition≫
The pharmaceutical composition of the present invention comprises (A) component, (B) component, and (C) component.
<(A) component>
The component (A) is at least one active ingredient selected from the group consisting of loperamide hydrochloride, berberine chloride, scopolamine, and scopolamine derivatives. Examples of the scopolamine derivative include scopolamine hydrobromide, methyl scopolamine bromide, butyl scopolamine bromide and the like, and scopolamine hydrobromide is preferable. As the component (A), loperamide hydrochloride is particularly preferable.
(A) A component may be used individually by 1 type and may be used in combination of 2 or more type.
(A) As for the compounding quantity of a component, 0.1-100 mg is preferable as a single dose, 0.5-30 mg is more preferable, 0.5-5 mg is further more preferable. When the blending amount of the component (A) is not more than the above upper limit value, bitterness is suppressed and the dosing property is improved. When the blending amount of the component (A) is not less than the above lower limit, the pharmacological effect of the active component (component (A)) is improved.
(A) 0.01-35 mass% is preferable with respect to the total mass of a pharmaceutical composition, and, as for content of a component, 0.01-10 mass% is more preferable. The reason why the content of the component (A) is not more than the above upper limit value and not less than the above lower limit value is the same as the reason described in the blending amount (dosage).

<(B) component>
The component (B) is at least one selected from the group consisting of herbal medicines and herbal extracts. In the present invention, the component (B) functions as a gastrointestinal drug that normalizes the function of the stomach and liver. Herbal medicines include turmeric, glaze, and licorice, with turmeric and glaze being preferred.
Turmeric is a ginger family perennial herb that has an oval or cylindrical surface with a ring-shaped node 3-4 cm in diameter, and the inside has a yellow rhizome. It likes high temperature and humidity, and it is widely cultivated in tropical night and subtropics centering on Southeast Asia from India. In Japan, it is cultivated in Okinawa, Amami Oshima, etc., and the rhizome is used for medicinal, edible and dyestuffs. The main pharmacological actions include liver function improvement, antibacterial action, antioxidant action, and anti-inflammatory action. The turmeric used in the present invention is not particularly limited, and examples include turmeric powder, turmeric extract, turmeric extract, and dried turmeric extract, with turmeric powder being preferred.
Glaze is dried from the roots of the peony peony, and its main pharmacological actions are anti-inflammatory, analgesic, antibacterial, hemostatic, and anticonvulsant. Although it does not specifically limit as a glaze used by this invention, A peony dry extract, a peony stream extract, etc. are mentioned, A peony dry extract is preferable.
Licorice is a dried licorice root of legumes, and its main pharmacological actions are anti-peptic ulcer action, gastric epithelial growth promoting action, gastric mucosal damage prevention action, antitussive action, anti-inflammatory action, detoxification action, antibacterial action Many pharmacological actions have been reported, such as action, antispasmodic action. Although it does not specifically limit as a licorice used by this invention, A licorice extract, a licorice dry extract, a licorice flow extract, a licorice crude extract, etc. are mentioned, A licorice dry extract is preferable.

(B) A component may be used individually by 1 type and may be used in combination of 2 or more type.
(B) As for the compounding quantity of a component, 10-1000 mg is preferable as a single dose, 30-500 mg is more preferable, 30-300 mg is further more preferable. (B) When the compounding quantity of a component is below the said upper limit, the unpleasant taste accompanying a crude drug will decrease and dosing property will improve. (B) The effectiveness of a crude drug improves that the compounding quantity of a component is more than the said lower limit.
(B) As for content of a component, 1-60 mass% is preferable with respect to the total mass of a pharmaceutical composition, and 5-55 mass% is more preferable. The reason why the content of the component (B) is not more than the above upper limit value and not less than the above lower limit value is the same as the reason described in the blending amount (dosage).

20-400 are preferable and, as for mass ratio (henceforth B / A ratio) represented by (B) component / (A) component, 30-300 are more preferable.
By making the B / A ratio not more than the above upper limit value, the unpleasant taste derived from the component (B) can be suppressed.
By making B / A ratio more than the said lower limit, the effectiveness of a crude drug improves.

<(C) component>
Component (C) is an organic solvent that dissolves component (A). By mix | blending (C) component, the elution property of (A) component can be improved and an absorptivity can be improved. Here, “dissolved” means that after adding 200 parts by mass of component (C) to 1 part by mass of component (A) and stirring at room temperature or warming (70 to 80 ° C.), it is judged by visual observation. This means no state.
(C) As an ingredient, Preferably organic solvents, such as propylene glycol, propylene glycol fatty acid ester, and ethanol, are mentioned, More preferably, propylene glycol is mentioned.
Propylene glycol fatty acid ester is an ester of propylene glycol and a fatty acid. 8-18 are mentioned as carbon number of a fatty acid, and it is preferable that it is 8-10. Examples of the propylene glycol fatty acid ester include monoester type and diester type. Monoester type propylene glycol fatty acid monoesters are preferred. Specifically, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monopalmitate, propylene glycol monoisostearate, propylene glycol monostearate, propylene monooleate Glycol and the like, and propylene glycol monocaprylate is particularly preferable.

As the component (C), one type may be used alone, or two or more types may be used in combination.
(C) The compounding quantity of a component is 1-100 mg as a single dose, 3-100 mg is more preferable, 5-75 mg is further more preferable. When the blending amount of the component (C) is not more than the above upper limit value, the unpleasant taste derived from the component (C) can be suppressed, and a single dose can be reduced, and the dosage is improved. When the blending amount of the component (C) is not less than the above lower limit, the inhibition of the elution of the component (A) by the component (B) is improved, and the intestinal absorbability of the component (A) is improved.
(C) 0.1-35 mass% is preferable with respect to the total mass of a pharmaceutical composition, and, as for content of a component, 1-30 mass% is more preferable. The reason why the content of the component (C) is not more than the above upper limit value and not less than the above lower limit value is the same as the reason described in the blending amount (dosage).

1-110 are preferable and, as for mass ratio (henceforth C / A ratio) represented by (C) component / (A) component, 4-75 are more preferable. When the component (C) is propylene glycol alone, the C / A ratio is preferably 4-50. When the component (C) is ethanol alone, the C / A ratio is preferably 30 to 100. When the component (C) is a propylene glycol fatty acid ester alone, the C / A ratio is preferably 50 to 110.
By setting the C / A ratio to be equal to or less than the above upper limit value, the unpleasant taste derived from the component (C) can be suppressed, and a single dose can be reduced, and the dosage is improved. By making C / A ratio more than the said lower limit, the inhibition of the elution property of (A) component by (B) component is improved, and the intestinal absorptivity of (A) component improves.

The mass ratio represented by component (C) / component (B) (hereinafter also referred to as C / B ratio) is preferably 0.01 to 1, and more preferably 0.02 to 0.75.
By making the C / B ratio not more than the above upper limit value, the unpleasant taste derived from the component (C) can be suppressed, and the dose at one time can be reduced, and the dosage is improved.
By making C / B ratio more than the said lower limit, inhibition of the elution property of (A) component by (B) component is improved.

<Optional component>
In addition to the components (A) to (C) described above, the pharmaceutical composition of the present invention can be appropriately blended with known medicinal ingredients and optional ingredients as needed within a range not impairing the effects of the present invention. Examples of such components include various additives. The blending amount of these optional components can be appropriately set according to the purpose within a range not impeding the effects of the present invention.
Additives include various sweeteners (sucrose, fructose glucose liquid sugar, honey, erythritol, maltitol, fructose, reduced palatinose, xylitol, aspartame, acesulfame potassium, sucralose, etc.), stabilizers (sodium edetate, water-soluble high Molecules), solubilizers (anionic surfactants, nonionic surfactants, amphoteric surfactants, etc.), solvents (purified water, etc.), polyols (glycerin, polyethylene glycol, etc.), preservatives (ethyl paraoxybenzoate, Methyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), excipients (crystalline cellulose, lactose, mannitol, low-substituted hydroxypropylcellulose, crospovidone, etc.), binders (starch, crystalline cellulose, etc.), Film-forming agent (gelatin, grease Phosphorus, succinylated gelatin, pectin, etc.), bases (medium chain fatty acid triglycerides, rapeseed oil, etc.), suspending agents (salax beeswax, glycerin fatty acid esters, etc.), antioxidants, flavoring agents / fragrances, cooling agents ( Menthol, etc.), colorants, pH adjusters, buffers and the like.
In addition, the sum total of content of (A)-(C) component and an arbitrary component does not exceed 100 mass%.

≪Method for producing pharmaceutical composition≫
The pharmaceutical composition of the present invention can be obtained by mixing the (A) component, the (B) component, the (C) component, and optional components as necessary. In addition, when mix | blending water as an arbitrary component, it is preferable to mix (A) component and (C) component first, and to mix (B) component and another arbitrary component subsequently.

≪Formulation≫
The dosage form of the preparation containing the pharmaceutical composition of the present invention is preferably an internal medicine and includes tablets, powders, granules, soft capsules, and liquids.
In the case of soft capsules, the capsule film filled with the contents of the present invention is not particularly limited, and water-soluble polymers such as gelatin, succinylated gelatin, agar, sodium alginate, pullulan, glucomannan, Arabic Known film bases such as rubber, carrageenan, furseleran, Eugema algae, gellan gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone can be used.
Moreover, as a manufacturing method of a soft capsule agent, it can produce, for example using the rotary die type automatic soft capsule manufacturing machine which is the conventional capsule filling manufacturing method.

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description. In addition, the compounding quantity of the component used in each example is a pure conversion value unless there is particular notice.
In the table, the content of each component represents the amount (mg) used for one administration.

[Raw materials]
・ Loperamide hydrochloride: Trade name “Loperamide hydrochloride” (manufactured by Shiono Chemical Co., Ltd.)
・ Turmeric powder: Trade name “Turmeric powder” (manufactured by Nippon Powder Chemical Co., Ltd.)
・ Turmeric style extract: Trade name “Turmeric style extract” (manufactured by Nippon Powder Chemical Co., Ltd.)
・ Turmeric extract: Trade name “Turmeric extract-A” (manufactured by Nippon Powder Chemical Co., Ltd.)
・ Dried turmeric extract: Trade name “Dried turmeric extract” (Matsuura Pharmaceutical Co., Ltd.)
・ Peonies dried extract: Trade name “Peonies dried extract” (manufactured by Nippon Powder Chemical Co., Ltd.)
・ Citric acid: Trade name “Citric anhydride 100M” (manufactured by Komatsuya Co., Ltd.)
・ Propylene glycol: Trade name “Propylene glycol” (manufactured by ADEKA)
Propylene glycol fatty acid ester: trade name “sefsol-218” (manufactured by Nikko Chemicals), carbon number of fatty acid: 8
・ Ethanol: Trade name “Fermented alcohol 95 degrees” (manufactured by Nippon Alcohol Sales Co., Ltd.)
・ Medium-chain fatty acid triglyceride: Trade name “Coconard MT” (manufactured by Kao Corporation)
・ Glycerin fatty acid ester: Trade name “EMAX BW-36” (manufactured by Riken Vitamin Co., Ltd.)
Polysorbate 80: trade name “NIKKOL TO-10MV” (manufactured by Nikko Chemicals Co., Ltd.)
・ L-Menthol: Product name “Thin Cargo” (manufactured by Nagaoka Jitsugyo Co., Ltd.)
・ Aspartame: Product name “Aspartame” (manufactured by Ajinomoto Co., Inc.)
-Acesulfame potassium: trade name "Sanet Pharma Grade D" (manufactured by MC Food Specialty Co., Ltd.)
-Fragrance: Product name "Grapefruit Flavor MQ-9046" (manufactured by Takasago Fragrance Co., Ltd.)
Polyethylene glycol 400: trade name “Macrogor 400” (manufactured by NOF Corporation)
・ Polyoxyethylene hydrogenated castor oil 60: trade name “NIKKOL HCO-60” (manufactured by Nikko Chemicals Co., Ltd.)
・ Dried licorice extract: Trade name “Dried licorice extract” (manufactured by Alps Pharmaceutical Co., Ltd.)
・ Berberine chloride: Trade name “Berberine chloride hydrate” (manufactured by Alps Pharmaceutical Co., Ltd.)
・ Scopolamine: Trade name “Scopolamine hydrobromide hydrate” (manufactured by Alps Pharmaceutical Co., Ltd.)
-Light anhydrous silicic acid: Trade name "Cycilia 350" (manufactured by YK KY)
・ Cross popidone: Trade name “Koridon CL-SF” (manufactured by BASF Japan Ltd.)
・ D-mannitol: Trade name “Pearlitol 50C” (manufactured by Rocket Japan Co., Ltd.)
・ Corn starch: Trade name “Corn starch” (Matsuya Chemical Co., Ltd.)
・ Crystalline cellulose: Trade name “Theolas UF-702” (manufactured by Asahi Kasei Chemicals Corporation)
・ Sucrose: Product name “Granulated Sugar” (Mitsui Sugar Co., Ltd.)

<Preparation of soft capsule contents>
Glycerin fatty acid ester was added to medium chain fatty acid triglyceride, and the mixture was heated and mixed at 70 to 80 ° C. to obtain a mixture. Separately, the (A) component and the (C) component are dissolved at room temperature (when ethanol is added and mixed) or heated to 70 to 80 ° C. and mixed (when other than ethanol is added and mixed). Then it was added to the above mixture. Further, the remaining components were added and uniformly stirred with a general-purpose high-speed stirrer to prepare each pharmaceutical composition.

<Evaluation of dissolution rate>
After adjusting the contents of each soft capsule, after stirring for 30 minutes under the following elution conditions, component (A) was quantified by HPLC under the following conditions, and the elution rate was calculated and evaluated by the following formula. .
[Elution conditions]
・ Testing machine: NTR-6400 (manufactured by Toyama Sangyo Co., Ltd.)
・ Test solution: JP2 elution test second solution (pH 6.8) 900 mL
・ Rotation speed: Paddle 100rpm
・ Sample input amount: Total amount of soft capsule contents ・ Eluate collection amount: 10 mL
[Quantification of component (A)]
・ Tester: LC-2010CHT (Shimadzu Corporation)
Mobile phase: Triethylamine hydrochloride (1 → 180 solution) / acetonitrile / diluted phosphoric acid (1 → 10) mixed solution (54: 45: 1)
・ Column: ODS
-Column temperature: 40 ° C
・ Injection volume: 100 μL
[(A) component elution rate]
(Amount of component (A) eluted) / (Amount of component (A) in soft capsule content before dissolution test) × 100

The above test was repeated three times, and the average value was evaluated based on the following criteria. An elution rate of 65% or more (C or more) was considered acceptable.
[Criteria]
A: Elution rate is 80% or more.
B: The elution rate is 70% or more and less than 80%.
C: The elution rate is 65% or more and less than 70%.
D: The elution rate is less than 65%.

In Examples 1 to 18, the elution of the component (A) was good.
The comparative example 1 which does not contain (C) component was inferior in the elution property of (A) component.
The comparative examples 2-5 which changed the (C) component into the (C ') component were inferior in the elution property of the (A) component.
In Reference Examples 1 and 2, which did not contain the component (B), the elution of the component (A) was good. This is because (B) component does not show the elution suppression effect of component (A).

For example, the present invention can be applied to other internal medicines (tablets, soft capsules, liquids) as shown in the following prescription examples, and the effects of the described invention are exhibited.
<Soft capsule contents 1>
・ Loperamide hydrochloride: 0.5mg
・ Peonies dried extract: 24mg
・ Propylene glycol: 5mg
・ Medium chain fatty acid triglyceride: 130mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Soft capsule contents 2>
・ Loperamide hydrochloride: 0.5mg
・ Dried licorice extract: 24mg
・ Propylene glycol: 5mg
・ Medium chain fatty acid triglyceride: 130mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Soft capsule contents 3>
・ Berberine chloride: 100mg
・ Turmeric powder: 100mg
・ Propylene glycol: 50mg
・ Medium chain fatty acid triglyceride: 80mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Soft capsule contents 4>
・ Berberine chloride: 100mg
・ Peonies dried extract: 24mg
・ Propylene glycol: 50mg
・ Medium chain fatty acid triglyceride: 80mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate: 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Soft capsule contents 5>
・ Scopolamine: 0.1mg
・ Turmeric powder: 100mg
・ Propylene glycol: 5mg
・ Medium chain fatty acid triglyceride: 180mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Soft capsule contents 6>
・ Scopolamine: 0.1mg
・ Peonies dried extract: 24mg
・ Propylene glycol: 5mg
・ Medium chain fatty acid triglyceride: 180mg
・ Glycerin fatty acid ester: 10mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
<Tablet 1>
・ Loperamide hydrochloride: 0.5mg
・ Turmeric powder: 100mg
・ Propylene glycol: 5mg
・ Light anhydrous silicic acid: 30mg
・ Cross popidone: 5mg
・ D-mannitol: 150mg
・ L-Menthol: 5mg
・ Corn starch: 5mg
・ Crystalline cellulose: 60mg
<Internal solution 1>
・ Loperamide hydrochloride: 0.5mg
・ Turmeric powder: 100mg
・ Propylene glycol: 5mg
・ Polysorbate 80: 30mg
・ L-Menthol: 5mg
・ Citric acid: 3mg
・ Purified water: 100mg
・ Sucrose: 50mg

Claims (4)

(A) component: at least one selected from the group consisting of loperamide hydrochloride, berberine chloride, scopolamine, and derivatives of scopolamine,
(B) component: at least one selected from the group consisting of herbal medicine and herbal extracts,
(C) component: The pharmaceutical composition containing the organic solvent which melt | dissolves said (A) component.   The pharmaceutical composition according to claim 1, wherein the component (B) is at least one selected from the group consisting of turmeric, licorice, and glaze.   The pharmaceutical composition according to claim 1 or 2, wherein the component (C) is at least one selected from the group consisting of propylene glycol, propylene glycol fatty acid ester, and ethanol.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the component (A) is loperamide hydrochloride.