JP2019210262A - Orally disintegrating tablet - Google Patents

Abstract

To provide orally disintegrating tablets having excellent disintegration, hardness, and storage stability.SOLUTION: Provided are a preparation base comprising (A) a composite granulated material with a surface modified by covering the surface of mannitol with a low-substituted hydroxypropylcellulose having a hydroxypropoxy group substitution degree of 5 to 16 mass%, polyvinyl alcohol and mannitol; (B) one or more selected from starches and celluloses; and (C) stearic acid or a salt thereof, and one or more selected from sodium stearyl fumarate, and an orally disintegrating tablet comprising a preparation base the same and a drug (D).SELECTED DRAWING: None

Description

  The present invention relates to an orally disintegrating tablet and a base for an orally disintegrating tablet.

  Tablets, capsules, granules, powders, etc. are known as dosage forms for oral solid preparations in the fields of pharmaceuticals, foods, etc., but dosage forms that are easier to take for the elderly, children and patients who have difficulty swallowing Therefore, development of orally disintegrating tablets that rapidly disintegrate when contained in the mouth is expected.

  As an orally disintegrating tablet, there is a demand for an agent having an appropriate hardness so that the disintegration time in the oral cavity is short and the agent is not damaged at the time of production, transportation and use, as is the case with ordinary agents. Further, there is a demand for an agent having excellent storage stability that maintains high hardness and a short disintegration time even after being exposed to humidity after opening.

  Patent Documents 1 to 3 describe a tablet containing a composite granulated product in which the surface of mannitol is coated with a low-substituted hydroxypropyl cellulose, polyvinyl alcohol and mannitol and a drug.

Japanese Patent No. 6022410 Japanese Patent No. 6195957 Japanese Patent No. 6307417

  In order to meet the high demands for ease of swallowing of orally disintegrating tablets, moderate hardness, and stability, the present invention aims to provide an orally disintegrating tablet that is further excellent in disintegration, hardness, and storage stability. And

  The present inventors have intensively studied to solve the above problems. As a result, one or two or more kinds selected from a composite granulated product, a starch, and a cellulose, in which the surface of mannitol is coated with low-substituted hydroxypropylcellulose, polyvinyl alcohol, and mannitol, and the surface is modified. It has been found that an orally disintegrating tablet combining one or more selected from an acid or a salt thereof and sodium stearyl fumarate and a drug becomes an orally disintegrating tablet capable of solving the above problems. Based on such knowledge, the present invention has been completed.

That is, the gist of the present invention is as follows.
[1]
(A) a composite granulated product in which the surface of mannitol is coated and modified by low-substituted hydroxypropylcellulose having a hydroxypropoxy group substitution degree of 5 to 16% by mass, polyvinyl alcohol and mannitol,
(B) one or more selected from starches and celluloses, and
(C) stearic acid or a salt thereof, and one or more selected from stearyl sodium fumarate,
A pharmaceutical base comprising
[2]
An orally disintegrating tablet comprising the formulation base according to [1] and (D) a drug.

  The present invention provides an orally disintegrating tablet having a short disintegration time, an appropriate hardness, and high storage stability. Moreover, the base for formulation used for manufacture of such an orally disintegrating tablet is provided.

Hereinafter, embodiments of the present invention will be described in detail.
[Formulation base]
One form of the present invention is (A) a composite structure in which the surface of mannitol is coated and surface-modified with low-substituted hydroxypropyl cellulose having a hydroxypropoxy group substitution degree of 5 to 16% by mass, polyvinyl alcohol and mannitol. 1 type or 2 or more types selected from granules, (B) starches, and celluloses, and (C) 1 type or 2 or more types selected from stearic acid or a salt thereof, and sodium stearyl fumarate And a pharmaceutical base (hereinafter, also referred to as “the pharmaceutical base of the present invention”).

<Composite granulated product>
The pharmaceutical base of the present invention is a composite granulation in which the surface of mannitol is coated with a low-substituted hydroxypropyl cellulose having a hydroxypropoxy group substitution degree of 5 to 16% by mass, polyvinyl alcohol and mannitol, and the surface is modified. Including things.

The composite granulated product can be produced by a method described in literature (for example, Patent No. 6307417, Patent No. 6195957, Patent No. 6022410). Commercial products can also be used. Examples of commercially available products include SmartEX (registered trademark) (manufactured by Shin-Etsu Chemical Co., Ltd.).
Specifically, the composite granulated product is a core particle of an aqueous dispersion prepared by blending low-substituted hydroxypropyl cellulose, polyvinyl alcohol, D-mannitol (first mannitol) and water. -It can be produced by adding mannitol (second mannitol) by spraying, etc., granulating, and optionally drying.
The average particle size of the composite granulated product varies depending on the granulation conditions, but is preferably 50 to 300 μm.
The content of the composite granulated product in the preparation base is usually 1 to 99 per 100% by mass of the preparation base.
% By mass, preferably 20 to 99% by mass, more preferably 40 to 99% by mass.

(Low-substituted hydroxypropyl cellulose)
The basic skeleton of low-substituted hydroxypropylcellulose is cellulose, and a small amount of hydroxypropoxy group is introduced into the glucose ring. Hydroxypropoxy group substitution degree is 5
It is -16 mass%, More preferably, it is 5-9 mass%.
The average particle size of the low-substituted hydroxypropyl cellulose is preferably about 5 to 100 μm, more preferably about 20 to 60 μm.
Low substituted hydroxypropyl cellulose is 100 parts by mass of mannitol (total amount of the first mannitol in the aqueous dispersion and the second mannitol to which the aqueous dispersion is added) in the obtained composite granulated product. The amount is preferably 1 to 15 parts by mass, more preferably 2 to 10 parts by mass.

(Polyvinyl alcohol)
Polyvinyl alcohol having a degree of polymerization of about 500 to 2000 can be preferably used. As the polyvinyl alcohol, a commercially available product or a product produced based on a conventional method can be used.
Polyvinyl alcohol is 100 parts by mass of mannitol in the obtained composite granulated product,
Preferably it is 0.05-0.4 mass part, More preferably, it is 0.1-0.3 mass part.

(Mannitol)
In the present specification, mannitol means D-mannitol unless otherwise specified.
The average particle diameter of the first mannitol used by dissolving in the aqueous dispersion is not particularly limited as long as it can be dissolved.
The average particle size of the second mannitol to which the aqueous dispersion is added is preferably 5 to 100 μm.
More preferably, it is 10-50 micrometers.

The total amount of the first and second mannitols is preferably 80 to 98% by mass, more preferably 90 to 95% by mass, in the resulting composite granulated product.
The first mannitol added to the aqueous dispersion is preferably 1 to 50% by mass, more preferably 5 to 30% by mass, based on the total amount of mannitol in the obtained composite granulated product.

<Starches and celluloses>
The pharmaceutical base of the present invention contains one or more selected from starches and celluloses.
The starches are not particularly limited, but, for example, one or more selected from corn starch, potato starch, wheat starch, partially pregelatinized starch, hydroxypropyl starch, starch starch glycolate and the like, and derivatives thereof. Is mentioned. Preferably, corn starch etc. are mentioned. As the starches, those that have been granulated can also be used.
Examples of celluloses include, but are not limited to, carmellose or carmellose derivatives such as croscarmellose sodium, croscarmellose calcium, carmellose (carboxymethylcellulose), carmellose sodium, carmellose calcium, or salts thereof; hydroxypropyl cellulose, hydroxy One type or two or more types selected from celluloses such as propylmethylcellulose and methylcellulose, derivatives thereof or salts thereof may be used. Preferably, croscarmellose sodium, carmellose, etc. are mentioned.
The content of starches and celluloses (as a sum of them when two or more are used) in the formulation base is usually 1 to 30% by mass, preferably 1 to 100% by mass of the formulation base
-20% by mass, more preferably 1-10% by mass.
As the starches and celluloses, commercially available products or those manufactured based on a conventional method can be used.

<Stearic acid or its salt and sodium stearyl fumarate>
The pharmaceutical base of the present invention contains one or more selected from stearic acid or a salt thereof and sodium stearyl fumarate.
Although it does not specifically limit as stearic acid and its salt, For example, 1 type, or 2 or more types chosen from a stearic acid, magnesium stearate, a calcium stearate, etc. are mentioned. Preferably, a magnesium stearate etc. are mentioned.
The content of stearic acid or a salt thereof and sodium stearyl fumarate (in the case of using two or more kinds as a total thereof) in the formulation base is usually 0.1 to 5 with respect to 100% by mass of the formulation base. % By mass, preferably 0.2 to 3% by mass, more preferably 0.5 to 2% by mass.
As stearic acid and its salt, and sodium stearyl fumarate, commercially available products or those manufactured based on a conventional method can be used.

  The preparation base of the present invention is obtained by mixing the above (A) to (C). Mixing can be performed based on a conventional method.

[Oral disintegrating tablets]
A further aspect of the present invention provides an orally disintegrating tablet (D) comprising the above-mentioned pharmaceutical base and (D) a drug.
Hereinafter, it is also referred to as “an orally disintegrating tablet of the present invention”).

The orally disintegrating tablet of the present invention contains a drug.
The drug is not particularly limited in terms of use, type, etc., but is used for nervous system and sensory organ drugs (central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, etc.) and individual organ system drugs (circulatory organs). Drugs, respiratory organs, digestive organs, hormones, genitourinary organs, etc.), metabolic drugs (vitamins, nutrient tonics, blood and body fluids, etc.), tissue cell function agents (anti Tumor drugs, radiopharmaceuticals, antiallergic drugs, etc.), herbal medicines, Kampo medicines, drugs against pathogenic organisms (antibiotics, chemotherapeutics, etc.), diagnostic drugs, in vitro diagnostic drugs, and the like.
Preferably, hormonal agents are mentioned, and examples of the hormonal agents include prostaglandin derivatives, active vitamin D ₃ , corticosteroids, androgen agents, mestranol, ethinyl estradiol, and follicular hormone agents such as progesterone, norethisterone, It is a luteinizing hormone agent such as dienogest, or a mixed hormone agent thereof. Examples of the mixed hormone agent include a combination agent of male hormone and follicular hormone, a combination agent of follicular hormone and luteinizing hormone used for pills as oral contraceptives, and the like.

The orally disintegrating tablet of the present invention is obtained by mixing the above (A) to (D) and then tableting. The tableting method is not particularly limited. For example, using a tableting die, an upper punch and a lower punch for tableting, a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine, etc. A method is mentioned. Tableting is performed by adjusting so that the obtained tablet has an appropriate hardness and can be rapidly disintegrated as an orally disintegrating tablet. The tableting pressure is appropriately adjusted according to the tableting method, the device used for tableting, the size of the tablet, the drug as the active ingredient, and the like. For example, when tableting a tablet mass of 100 mg using the above device (φ6.5 mm 杵), it is usually 4 to 15 kN, preferably 5 to 10 kN. The obtained tablet may be further subjected to a predetermined coating using a coating agent.

The shape of the orally disintegrating tablet of the present invention produced as described above is not particularly limited, and examples thereof include a disc shape, a donut shape, a polygonal plate shape, a spherical shape, an oval shape, and a caplet shape.
The size is not particularly limited. The hardness is usually 20 to 150 N, preferably 20 to 100 N (or usually 2 to 15 kgf, preferably 2 to 10 kgf). The hardness can be measured using a tablet hardness meter or the like.
The disintegration time is usually within 15 seconds, preferably within 13 seconds, in the oral cavity when taken without water. The disintegration time can be measured using a disintegration tester or the like.
The content of the drug in the orally disintegrating tablet is usually 0.01 to 60% by mass, preferably 0.05 to 55% by mass, and more preferably 0.1 to 50% by mass with respect to 100% by mass of the orally disintegrating tablet.

The dose of the orally disintegrating tablet of the present invention can be appropriately determined with reference to the conventional dose of a drug as an active ingredient. Specifically, it can be appropriately determined depending on the condition of the patient to be administered, the drug, and the like, but it is preferable to administer about 0.1 μg / kg to about 1,000 mg / kg per patient body weight per day. The number of administrations may be single or multiple, and is preferably administered 1 to 4 times a day, more preferably once or twice a day.

<Optional component>
In addition to the components (A) to (D), the orally disintegrating tablet and the preparation base of the present invention may contain any pharmaceutically acceptable component as long as the effects of the present invention are not hindered.
Although it does not specifically limit as an arbitrary component, For example, a fluidizing agent, surfactant, antioxidant, binder, a foaming agent, a sour agent, a sweetener, a corrigent, a coloring agent, a fragrance | flavor, etc. are mentioned. Further, the orally disintegrating tablet and formulation base of the present invention include excipients other than the above component (A), disintegrants other than the above component (B), lubricants other than the above (C) component, and the like. May be included.
The optional components may be used alone or in combination of two or more.

Examples of excipients other than the component (A) that may be included in the orally disintegrating tablet and pharmaceutical preparation of the present invention include, but are not limited to, for example, monosaccharides such as glucose and fructose; maltose, lactose, Examples thereof include disaccharides such as sucrose and trehalose; sugar alcohols such as mannitol, erythritol, inositol and sorbitol. The excipients may be used alone or in combination of two or more.

  Although it does not specifically limit as a fluidizing agent which may be contained in the orally disintegrating tablet and formulation base of this invention, For example, a hydrous silicon dioxide, a talc, etc. are mentioned. The fluidizing agent may be used alone or in combination of two or more.

  The surfactant that may be contained in the orally disintegrating tablet and the formulation base of the present invention is not particularly limited, and examples thereof include polysorbate, polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, and sesquiolein. Examples include acid sorbitan. Surfactants may be used alone or in combination of two or more.

Although it does not specifically limit as an antioxidant which may be contained in the orally disintegrating tablet and formulation base of this invention, For example, cysteine hydrochloride, sodium hydrogen sulfite, sodium sulfite, sodium edetate, etc. are mentioned. Antioxidants may be used alone or in combination of two or more.

The binder that may be contained in the orally disintegrating tablet and the preparation base of the present invention is not particularly limited, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose, sugar, sugar alcohol and the like. The binders may be used alone or in combination of two or more.

  Although it does not specifically limit as an effervescent agent which may be contained in the orally disintegrating tablet and formulation base of this invention, For example, sodium bicarbonate, tartaric acid, anhydrous citric acid, etc. are mentioned. A foaming agent may be used independently and may be used in combination of 2 or more type.

  The sour agent that may be contained in the orally disintegrating tablet and the preparation base of the present invention is not particularly limited, and examples thereof include citric acid, tartaric acid, malic acid, and lactic acid. A sour agent may be used independently and may be used in combination of 2 or more type.

The sweetening agent that may be contained in the orally disintegrating tablet and the preparation base of the present invention is not particularly limited, and examples thereof include aspartame, stevia, glycyrrhizin dipotassium, and sucralose. Sweetening agents may be used alone or in combination of two or more.

  The taste-masking agent that may be contained in the orally disintegrating tablet and the preparation base of the present invention is not particularly limited, and examples thereof include sucralose, citric acid, and tartaric acid. A corrigent may be used independently and may be used in combination of 2 or more types.

The colorant that may be contained in the orally disintegrating tablet and the formulation base of the present invention is not particularly limited, but for example, food color such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, etc .; Examples include lake pigments, yellow ferric oxide, ferric oxide, and titanium oxide. The colorants may be used alone or in combination of two or more.

  Although it does not specifically limit as a fragrance | flavor which may be contained in the orally disintegrating tablet and formulation base of this invention, For example, mint, menthol, orange, lemon, strawberry, etc. are mentioned. A fragrance | flavor may be used independently and may be used in combination of 2 or more type.

The disintegrant other than the component (B) is not particularly limited, and examples thereof include crospovidone. The lubricant other than the component (C) is not particularly limited, and examples thereof include sucrose fatty acid ester and talc.

  As long as the effects of the present invention are not hindered, the content and content ratio of each optional component are not particularly limited, and can be appropriately determined by those skilled in the art.

The orally disintegrating tablet and formulation base of the present invention contain the above components (A) to (C), so that the disintegration time is short, the hardness is appropriate, and the oral disintegration has high storage stability. It becomes a base for tablets and preparations. As a mechanism having such characteristics, the addition of the component (B) is because disintegration is further enhanced while maintaining the hardness of the composite granulated product. In addition, the component (C) imparts moderate lubricity and improves moldability.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the embodiments of the following examples.

[Test method]
<Disintegration test>
According to the 17th revision of the Japanese Pharmacopoeia "Disintegration Test Method" The disintegration time of 6 samples was measured, and the average value was calculated.

<Hardness>
The tablet hardness of 10 tablets of each sample was measured using a tablet hardness meter (KHT-20N, manufactured by Fujiwara Seisakusho Co., Ltd.), and the average value was calculated.

<Stability test>
The tablets placed in the opened petri dish were stored for 1 week in an apparatus set under the following conditions of severe temperature and humidity, and then removed.

(Temperature and humidity conditions and set equipment)
40 ℃ 75% RH: SRH-15VEVJ2, manufactured by Nagano Science Co., Ltd.
25 ° C 75% RH: LH21-14M, manufactured by Nagano Science Co., Ltd.
60 ° C humidity rise: NDO-600SD, manufactured by Tokyo Rika Kikai Co., Ltd.

<Example 1>
An orally disintegrating tablet was produced according to the formulation shown in Table 1 below. In addition, a placebo tablet (base for formulation) containing no active ingredient (D) in the formulation shown in Table 1 was produced. Placebo tablets
In each case, the symbol p is appended to the example number or comparative example number. SmartEx QD-50 (manufactured by Shin-Etsu Chemical Co., Ltd.) was used as component (A), and dienogest drug substance was used as component (D).
Ingredients (A) to (D) were weighed as shown in the table below and mixed using an agate mortar. (Ingredient (D) was not added for the placebo tablet trial production.)
Tableting pressure is 6kN with the tableting machine (VIRGO 0512SS2AY, manufactured by Kikusui Seisakusho Co., Ltd.).
Then, tablets were compressed so that the tablet diameter was 6.5 mm and the mass was 100 mg, and tablets of Example 2 and Examples 1p to 4p and Comparative Example 1 and Comparative Example 1p were obtained. About the obtained tablet, the disintegration test, the hardness measurement, and the stability test were done by the said test method. The results are shown in Tables 2 and 3.

In Examples, by containing the components (A), (B), (C) or (A), (B), (C), (D), the comparative example was disintegrated while maintaining the hardness. It has been shown that the performance is improved. The examples also showed excellent stability.

  The present invention is useful as pharmaceuticals and pharmaceutical bases.

Claims (2)

(A) A composite granulated product in which the surface of mannitol is coated and modified by low-substituted hydroxypropylcellulose having a hydroxypropoxy group substitution degree of 5 to 16% by mass, polyvinyl alcohol and mannitol,
(B) one or more selected from starches and celluloses, and
(C) stearic acid or a salt thereof, and one or more selected from stearyl sodium fumarate,
A pharmaceutical base comprising   An orally disintegrating tablet comprising the formulation base according to claim 1 and (D) a drug.