JP2001322927A - Solid preparation including hydroxypropyl cellulose of low substitution degree and method for preparation of the same - Google Patents

Solid preparation including hydroxypropyl cellulose of low substitution degree and method for preparation of the same

Info

Publication number
JP2001322927A
JP2001322927A JP2000139536A JP2000139536A JP2001322927A JP 2001322927 A JP2001322927 A JP 2001322927A JP 2000139536 A JP2000139536 A JP 2000139536A JP 2000139536 A JP2000139536 A JP 2000139536A JP 2001322927 A JP2001322927 A JP 2001322927A
Authority
JP
Japan
Prior art keywords
bulk density
solid preparation
sugar
weight
low
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2000139536A
Other languages
Japanese (ja)
Inventor
Fumie Tanno
史枝 丹野
Sakae Ohara
栄 尾原
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shin Etsu Chemical Co Ltd
Original Assignee
Shin Etsu Chemical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shin Etsu Chemical Co Ltd filed Critical Shin Etsu Chemical Co Ltd
Priority to JP2000139536A priority Critical patent/JP2001322927A/en
Priority to KR1020010025732A priority patent/KR20010104268A/en
Publication of JP2001322927A publication Critical patent/JP2001322927A/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Abstract

PROBLEM TO BE SOLVED: To provide a solid preparation quickly collapsing in the oral cavity by saliva in the oral cavity or taking with a small amount of water, easy to prepare, having a proper strength capable of retaining its molding property in preparation and in distribution process. SOLUTION: This solid preparation includes a hydroxypropyl cellulose of low substitution degree having volume average particle size <=25 mμ measured by a dry laser diffraction method, bulk density of 0.35 g/mL in loosely packed state and 0.60 g/mL of bulk density in a tightly packed state and a sugar/sugar alcohol, and its preparative method.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【発明の属する技術分野】本発明は、口腔内の唾液又は
少量の水により速やかに口腔内で崩壊する固形製剤に関
するものである。TECHNICAL FIELD The present invention relates to a solid preparation which is rapidly disintegrated in the oral cavity by saliva or a small amount of water in the oral cavity.

【０００２】[0002]

【従来の技術】近年、高齢化社会が進むにつれて、高齢
者にとって服用しやすい形態の製剤が望まれており、す
でに幾つかの剤形が提案されてきたが、現状としては未
だ経口製剤の多くは通常の錠剤やカプセル剤であり、高
齢者にとって必ずしも服用が容易ではない。また、これ
らの通常の製剤は、小児などの嚥下能力の低い患者にと
っても服用が困難な場合も多い。また、小型錠剤や顆粒
剤では、取り扱いが困難であり、高齢者や小児患者にと
っては満足できるものではない。このような問題を解決
する目的で、すでに提案されている剤形の一つとして口
腔内崩壊錠があるが、水なしあるいは少量の水により口
中で速やかに崩壊する特性を有し、かつ製法によっては
通常の製剤システムの使用が可能なため、実用性が高い
と考えられている。2. Description of the Related Art In recent years, as the aging society progresses, preparations in a form that is easy for the elderly to take have been desired, and several dosage forms have already been proposed. Are ordinary tablets and capsules, which are not always easy for the elderly to take. In addition, these usual preparations are often difficult to take even for patients with low swallowing ability such as children. In addition, small tablets and granules are difficult to handle and are not satisfactory for elderly or pediatric patients. For the purpose of solving such problems, there is an orally disintegrating tablet as one of the dosage forms that have been already proposed, but it has the property of rapidly disintegrating in the mouth without water or with a small amount of water, and depending on the manufacturing method. Is considered to be highly practical because it allows the use of normal formulation systems.

【０００３】一般的な設備で口腔内崩壊錠を調製する方
法としては、特開平９−７１５２３号公報がある。薬物
と崩壊剤に低置換度ヒドロキシプロピルセルロース、賦
形剤として結晶セルロース及び滑沢剤からなる混合物
を、低圧で打錠した口腔内崩壊性錠剤が提案されている
が、セルロース系の添加剤を多く使用するため、錠剤の
崩壊性、味、舌触りにおいて実用上劣るという欠点を有
する。As a method for preparing an orally disintegrating tablet with general equipment, there is JP-A-9-71523. Orally disintegrating tablets have been proposed in which a mixture of low-substituted hydroxypropylcellulose as a drug and a disintegrant, microcrystalline cellulose as an excipient and a lubricant is compressed at a low pressure, but a cellulose-based additive is used. Since it is frequently used, it has a disadvantage that the tablet is practically inferior in disintegration, taste and texture.

【０００４】特開平１１−４３４２９号公報には、薬
物、糖及び置換度の限定された低置換度ヒドロキシプロ
ピルセルロースからなる口腔内崩壊錠剤が提案されてい
るが、錠剤の舌触り、味の改善において充分ではない。JP-A-11-43429 proposes an orally disintegrating tablet comprising a drug, a sugar and a low-substituted hydroxypropylcellulose having a limited degree of substitution. Not enough.

【０００５】[0005]

【発明が解決しようとする課題】本発明は、口腔内の唾
液又は少量の水と共に服用することにより、口腔内で味
の不快感を感じることなく速やかに崩壊し、製造工程が
容易でかつ製造時や流通過程において成形性を保持しう
る適度な強度を有する固形製剤及びその製造方法を提供
することを目的とする。DISCLOSURE OF THE INVENTION The present invention is intended to provide a method for disintegrating quickly without taking any unpleasant taste in the oral cavity by taking it with saliva or a small amount of water in the oral cavity. It is an object of the present invention to provide a solid preparation having an appropriate strength capable of maintaining the formability during time and a distribution process, and a method for producing the same.

【０００６】[0006]

【課題を解決するための手段】本発明者らは、乾式レー
ザー回折法による体積平均粒子径が２５ミクロン以下、
ゆるめ嵩密度が０．３５ｇ／ｍＬ以上で、かつ固め嵩密
度が０．６０ｇ／ｍＬ以上である低置換度ヒドロキシプ
ロピルセルロース及び糖・糖アルコールを含有する固形
製剤を用いることにより、固形製剤に適度な強度を与え
ると共に口腔内で味の不快感を感じることなく、速やか
に薬物が崩壊することを見出し、本発明をなすに至った
ものである。すなわち、乾式レーザー回折法による体積
平均粒子径が２５ミクロン以下、ゆるめ嵩密度が０．３
５ｇ／ｍＬ以上で、かつ固め嵩密度が０．６０ｇ／ｍＬ
以上である低置換度ヒドロキシプロピルセルロース及び
糖・糖アルコールを含有することを特徴とする固形製剤
及びその製造方法を提供する。Means for Solving the Problems The present inventors have found that the volume average particle diameter by dry laser diffraction method is 25 microns or less,
The use of a solid preparation containing low-substituted hydroxypropylcellulose having a loose bulk density of 0.35 g / mL or more and a solid bulk density of 0.60 g / mL or more and sugar / sugar alcohol makes it suitable for a solid preparation. The present inventors have found that the drug is rapidly disintegrated without giving an unpleasant taste in the oral cavity while giving a high strength, and the present invention has been accomplished. That is, the volume average particle diameter by dry laser diffraction method is 25 microns or less, and the loose bulk density is 0.3
5g / mL or more, and the bulk density is 0.60g / mL
A solid preparation characterized by containing the above-mentioned low-substituted hydroxypropylcellulose and sugar / sugar alcohol, and a method for producing the same are provided.

【０００７】[0007]

【発明の実施の形態】本発明における「ゆるめ嵩密度」
とは、疎充填の状態の嵩密度をいい、直径５．０３cm、
高さ５．０３cm（容積１００ｍＬ）の円筒容器（材質：
ステンレス）へ試料をＪＩＳの２２メッシュ（７１０μ
ｍ）のふるいを通して、上方２３cmから均一に供給し、
上面をすり切って秤量することによって測定される。一
方、「固め嵩密度」とは、これにタッピングを加えて密
充填にした場合の嵩密度をいう。ここで、タッピングと
は、試料を充填した容器を一定高さから繰り返し落下さ
せて底部に軽い衝撃を与え、試料を密充填にする操作を
いう。実際には、ゆるめ嵩密度を測定する際、上面をす
り切って秤量した後、さらにこの容器の上にキャップ
（下記ホソカワミクロン社製パウダーテスターの備品）
をはめ、この上縁まで粉体を加えてタップ高さ１．８cm
のタッピングを１８０回行う。終了後、キャップを外し
て容器の上面で粉体をすり切って秤量し、この状態の嵩
密度を固め嵩密度とする。また、「圧縮度」とは上記の
固め嵩密度とゆるめ嵩密度を用いて、次式から算出され
る。 圧縮度＝｛（固め嵩密度−ゆるめ嵩密度）/ 固め嵩密
度｝×１００ これらの操作は、例えばホソカワミクロン社製パウダー
テスター（ＰＴ−Ｄ）を使用することにより測定でき
る。BEST MODE FOR CARRYING OUT THE INVENTION "Loose bulk density" in the present invention
The term “bulk density” refers to bulk density in a loosely packed state, with a diameter of
5.03 cm (100 mL) cylindrical container (Material:
Transfer the sample to JIS 22 mesh (710μ)
m) through the sieve of m), feed uniformly from above 23cm,
It is measured by scraping the top surface and weighing. On the other hand, the “solid bulk density” refers to the bulk density in the case where tapping is added to the material to make it densely packed. Here, tapping refers to an operation in which a container filled with a sample is repeatedly dropped from a certain height to give a light impact to the bottom portion to tightly fill the sample. In practice, when measuring the loose bulk density, the top surface was cut off and weighed, and then a cap was placed on this container (supplied with a powder tester manufactured by Hosokawa Micron Corporation).
And add the powder to the upper edge, tap height 1.8cm
Is performed 180 times. After completion, the cap is removed and the powder is ground and weighed on the upper surface of the container, and the bulk density in this state is hardened to obtain the bulk density. The “compression degree” is calculated from the following equation using the above-mentioned solid bulk density and loose bulk density. Compressibility = {(solid bulk density-loose bulk density) / solid bulk density} × 100 These operations can be measured by using, for example, a powder tester (PT-D) manufactured by Hosokawa Micron Corporation.

【０００８】本発明の低置換度ヒドロキシプロピルセル
ロースは、乾式レーザー回折法による平均体積粒子径が
２５ミクロン以下、ゆるめ嵩密度が０．３５ｇ／ｍＬ以
上かつ固め嵩密度が０．６０ｇ／ｍＬ以上の低置換度ヒ
ドロキシプロピルセルロースである。なお、粉砕工程
は、常法に従って行われ、例えばボールミル、ナイフミ
ル、ジェットミルなどの粉砕機を用いることができる。
なお、乾式レーザー回折法とは、圧縮空気で粉体サンプ
ルを噴出させたものにレーザー光を照射し、その回折強
度により体積平均径を測定する方法をいう。例えば、Ro
dos & Helos 社のレーザー回折式粒度測定機が挙げられ
る。体積平均粒径は、例えば「改訂増補粉体物性図説」
粉体工学会・日本粉体工業技術協会編、日経技術図書、
１９８５年、第８８頁に記載されているように、式｛Σ
(ｎＤ3)／Σｎ｝1/3を用いて計算される。式中、Ｄは粒
子の直径、ｎはその直径の粒子数、Σｎは全粒子数を表
す。The low-substituted hydroxypropylcellulose of the present invention has an average volume particle size of 25 μm or less, a loose bulk density of 0.35 g / mL or more, and a solid bulk density of 0.60 g / mL or more measured by a dry laser diffraction method. It is a low-substituted hydroxypropyl cellulose. The pulverizing step is performed according to a conventional method, and for example, a pulverizer such as a ball mill, a knife mill, and a jet mill can be used.
The dry laser diffraction method refers to a method of irradiating a laser beam onto a powder sample ejected with compressed air and measuring the volume average diameter based on the diffraction intensity. For example, Ro
Dos & Helos laser diffraction particle size analyzer. The volume average particle size is, for example, "Revised supplementary powder physical properties illustration"
Japan Society of Powder Technology, Japan Society of Powder Technology, Nikkei Technical Books,
As described on page 88 of 1985, the formula
Calculated using (nD 3 ) / {n} 1/3 . In the formula, D is the diameter of the particle, n is the number of particles of that diameter, and Δn is the total number of particles.

【０００９】本発明に用いる低置換度ヒドロキシプロピ
ルセルロースは、セルロースエーテルの一種であり、結
合剤として汎用されるヒドロキシプロピルセルロースと
類似するが、その性質を異にする。前者と後者の本質的
な違いは、ヒドロキシプロポキシル基の含有量にあり、
その値は、前者が５．０〜１６．０重量％であるのに対
し、後者が５３．４〜７７．５重量％である。この値
は、日本薬局方「低置換度ヒドロキシプロピルセルロー
ス」のモノグラフで明確に規定されている。すなわち、
低置換度ヒドロキシプロピルセルロースのヒドロキシプ
ロポキシル基の含有量は、５．０〜１６．０重量％であ
る。The low-substituted hydroxypropylcellulose used in the present invention is a kind of cellulose ether and is similar to hydroxypropylcellulose generally used as a binder, but has different properties. The essential difference between the former and the latter lies in the content of hydroxypropoxyl groups,
The value of the former is 5.0 to 16.0% by weight, while the value of the latter is 53.4 to 77.5% by weight. This value is clearly defined in the monograph of the Japanese Pharmacopoeia "Low-substituted hydroxypropylcellulose". That is,
The content of hydroxypropoxyl groups in the low-substituted hydroxypropylcellulose is 5.0 to 16.0% by weight.

【００１０】ゆるめ嵩密度が０．３５ｇ／ｍＬ以上、か
つ固め嵩密度が０．６０ｇ／ｍＬ以上のヒドロキシプロ
ピルセルロースは、以下に示す方法により製造すること
ができる。すなわち、パルプをアルカリ溶液に浸漬し
て、アルカリセルロースとし、これを酸化プロピレンな
どのヒドロキシプロピル化剤と反応させる。この後の工
程において、生成物を水又はアルカリ性に調節した水に
投入して、完全溶解させ、ほとんど均一に透明なスラリ
ー状にしてから、塩酸で中和して析出された低置換度ヒ
ドロキシプロピルセルロースを回収後、水で洗浄し乾燥
して粉砕する。ここでいう完全溶解状態とは、生成物が
その形状をほぼ完全に失う状態を意味する。すなわち、
完全に透明になることはもとより、不透明のスラリー状
態や３リットルのスラリー中に５〜１０個の割合で生成
小塊の残留が認められる程度も含む。溶解した後の状態
は、高粘度のスラリー状であり、ニーダーなどの攪拌力
の強い練合機が必要である。この後、塩酸等の酸で中和
することにより、低置換度ヒドロキシプロピルセルロー
スが析出し、このものを回収して洗浄、乾燥、粉砕して
製品とする。Hydroxypropylcellulose having a loose bulk density of 0.35 g / mL or more and a hardened bulk density of 0.60 g / mL or more can be produced by the following method. That is, the pulp is immersed in an alkali solution to form alkali cellulose, which is reacted with a hydroxypropylating agent such as propylene oxide. In the subsequent step, the product is put into water or water adjusted to be alkaline, completely dissolved, turned into a nearly uniformly transparent slurry, and then neutralized with hydrochloric acid to precipitate a low-substituted hydroxypropyl. After collecting the cellulose, it is washed with water, dried and pulverized. The term "completely dissolved state" as used herein means a state in which the product almost completely loses its shape. That is,
In addition to being completely transparent, this includes the degree of opaque slurry and the degree to which 5 to 10 small particles remain in 3 liters of slurry. The state after dissolution is a slurry of high viscosity, and requires a kneader or other kneading machine with strong stirring power. Thereafter, the mixture is neutralized with an acid such as hydrochloric acid to precipitate hydroxypropylcellulose having a low degree of substitution, which is collected, washed, dried and pulverized to obtain a product.

【００１１】本発明における低置換度ヒドロキシプロピ
ルセルロースの添加量は、固形製剤１００重量部に対し
て１〜９９重量部、好ましくは、５〜５０重量部であ
る。低置換度ヒドロキシプロピルセルロースの添加量が
１重量部未満だと、錠剤の強度が不十分で取り扱いが困
難となるおそれがあり、９９重量部を越えると錠剤強度
は得られるが、口腔内での崩壊が遅延するおそれがあ
る。The amount of the low-substituted hydroxypropylcellulose used in the present invention is 1 to 99 parts by weight, preferably 5 to 50 parts by weight, per 100 parts by weight of the solid preparation. If the amount of low-substituted hydroxypropylcellulose is less than 1 part by weight, tablet strength may be insufficient and handling may be difficult. If it exceeds 99 parts by weight, tablet strength may be obtained, but in the oral cavity, Collapse may be delayed.

【００１２】本発明において、糖・糖アルコールとは、
糖アルコールを含めた広い意味の糖である。糖は、糖類
のうち水溶性で甘味を持つものの総称であり、単糖類と
大多数の少糖類が含まれる。糖アルコールは、糖のカル
ボニル基が還元された鎖状の多価アルコールを指し、類
似の性質を持つ環式糖アルコール（シクリトール）を含
む。本発明において、糖・糖アルコールとしては、好ま
しくはエリスリトール、ソルビトール、トレハロース、
キシリトール、マンニトール、グルコース、白糖などが
挙げられ、特に好ましくは、エリスリトール又はソルビ
トール、トレハロース、キシリトールが挙げられ、これ
らは、単独又は２種以上混合して使用することもでき
る。これらの糖・糖アルコールは、結晶又は粉末で用い
られるが、特に平均粒子径が５００ミクロン以下のもの
を用いると、成形性、崩壊性、舌触りの点で優れた特性
を示す。In the present invention, sugar / sugar alcohol is
It is a sugar in a broad sense, including sugar alcohols. Sugar is a generic name for water-soluble and sweet saccharides, and includes monosaccharides and most oligosaccharides. Sugar alcohol refers to a linear polyhydric alcohol in which the carbonyl group of the sugar is reduced, and includes a cyclic sugar alcohol (cyclitol) having similar properties. In the present invention, the sugar / sugar alcohol is preferably erythritol, sorbitol, trehalose,
Xylitol, mannitol, glucose, sucrose and the like are mentioned, and erythritol or sorbitol, trehalose and xylitol are particularly preferable. These can be used alone or in combination of two or more kinds. These sugars / sugar alcohols are used in the form of crystals or powders. When the sugars / sugar alcohols have an average particle diameter of 500 μm or less, they exhibit excellent properties in terms of moldability, disintegration, and texture.

【００１３】糖・糖アルコールの添加量は、固形製剤１
００重量部に対して１〜９９重量部好ましくは、１０〜
９０重量部である。糖・糖アルコールの添加量が、１重
量部未満だと口腔内での崩壊に時間を要するおそれがあ
り、９９重量部を越えると充分な製剤の強度が得られな
くなるおそれがある。[0013] The amount of sugar or sugar alcohol to be added depends on the solid preparation 1
1 to 99 parts by weight, preferably 10 to 100 parts by weight
90 parts by weight. If the amount of the sugar or sugar alcohol is less than 1 part by weight, it may take time to disintegrate in the oral cavity, and if it exceeds 99 parts by weight, sufficient strength of the preparation may not be obtained.

【００１４】また、本発明の固形製剤に加える主成分
は、医薬品であれば解熱鎮痛剤、抗生物質、抗炎症剤、
ビタミンや栄養物など特に限定はされない。さらに、他
の成分として例えば滑沢剤、結合剤、安定化剤、着色
剤、矯味剤などを添加しても良い。[0014] The main components to be added to the solid preparation of the present invention are drugs, such as antipyretic analgesics, antibiotics, anti-inflammatory agents,
There is no particular limitation on vitamins and nutrition. Further, as other components, for example, a lubricant, a binder, a stabilizer, a coloring agent, a flavoring agent, and the like may be added.

【００１５】本発明の固形製剤の製造方法については、
前記の組成物を混合して直接打錠あるいは乾式打錠する
か、乾式造粒、流動層造粒あるいは湿式造粒等いずれの
方法も適用される。また、錠剤を製造するための打錠方
法は、一般に錠剤を成形又は造粒するための装置を用い
て行われ、例えば単発打錠機、ロータリー打錠機、タブ
レッティングテスターなどがあげられる。打錠の際の成
形圧力は、通常５０〜３００ＭＰａ、好ましくは８０〜
２００ＭＰａである。成形圧力が５０ＭＰａより低いと
錠剤硬度が不足する場合があり、取り扱いが困難とな
り、３００ＭＰａより高いと崩壊が遅延する場合があ
る。Regarding the method for producing the solid preparation of the present invention,
Any method such as mixing the above composition and directly tableting or dry tableting, dry granulation, fluidized bed granulation or wet granulation can be applied. A tableting method for producing tablets is generally performed using a device for forming or granulating tablets, and examples thereof include a single-shot tableting machine, a rotary tableting machine, and a tableting tester. The molding pressure during tableting is usually 50 to 300 MPa, preferably 80 to 300 MPa.
It is 200 MPa. If the molding pressure is lower than 50 MPa, tablet hardness may be insufficient, and handling may be difficult. If the molding pressure is higher than 300 MPa, disintegration may be delayed.

【００１６】上記のようにして製造された本発明の固形
製剤、特に口腔内崩壊錠剤は口腔内での崩壊性にすぐ
れ、かつ適度な成形性（強度）を保持する。すなわち、
本発明の固形製剤の口腔内崩壊時間（健康な成人の口腔
内の唾液で錠剤が完全に崩壊するまでの時間）は、通常
１〜６０秒、好ましくは１〜４０秒、さらに好ましくは
１〜３０秒である。また、錠剤硬度（錠剤硬度計によ
る）は、通常２〜１５ｋｇｆ、好ましくは３〜１０kgｆ
である。The solid preparation of the present invention, particularly an orally disintegrating tablet, produced as described above is excellent in disintegration in the oral cavity and maintains an appropriate moldability (strength). That is,
The oral disintegration time of the solid preparation of the present invention (the time required for the tablet to completely disintegrate with the saliva in the oral cavity of a healthy adult) is usually 1 to 60 seconds, preferably 1 to 40 seconds, more preferably 1 to 40 seconds. 30 seconds. The tablet hardness (based on a tablet hardness tester) is usually 2 to 15 kgf, preferably 3 to 10 kgf.
It is.

【００１７】本発明における固形製剤には、錠剤、顆粒
剤、細粒剤、カプセル剤などが含まれる。The solid preparation of the present invention includes tablets, granules, fine granules, capsules and the like.

【００１８】[0018]

【実施例】以下に本発明の実施例及び比較例を示すが、
本発明はこれら実施例の内容のみに限定されるものでは
ない。 実施例１ エリスリトール（日研化学社製）を卓上ミルで粉砕し、
目開き３５５ミクロンのふるいで篩下した粉体を７０重
量部、本発明の低置換度ヒドロキシプロピルセルロース
（乾式レーザー法での体積平均粒子径が１６ミクロン、
ゆるめ嵩密度０．３８ｇ／ｍＬ、固め嵩密度が０．６３
ｇ／ｍＬ、ヒドロキシプロポキシル基含有量１１．０重
量％）３０重量部を混合し、流動層造粒機（パウレック
社製マルチプレックスＭＰ−１）を用いて、精製水を噴
霧し、流動層造粒を行った。得られた造粒末に、０．３
重量部の割合でステアリン酸マグネシウムを配合し、ロ
ータリー打錠機（菊水製作所製、Ｖｅｒｇｏ５１２ＳＳ
２ＡＶ）を用いて打錠圧１．０ｔ（予圧０．３ｔ）で１
０ｍｍφＡＲ、１錠４００ｍｇの固形製剤を得た。EXAMPLES Examples and comparative examples of the present invention are shown below.
The present invention is not limited only to the contents of these examples. Example 1 Erythritol (manufactured by Niken Kagaku Co., Ltd.) was pulverized with a desktop mill,
70 parts by weight of the powder sieved with a sieve having an opening of 355 microns was mixed with the low-substituted hydroxypropylcellulose of the present invention (having a volume average particle diameter of 16 microns by a dry laser method,
Loose bulk density 0.38 g / mL, hardened bulk density 0.63
g / mL, 30 parts by weight of hydroxypropoxyl group content (11.0% by weight) were mixed, and purified water was sprayed using a fluidized bed granulator (Multiplex MP-1 manufactured by Powrex) to form a fluidized bed. Granulation was performed. In the obtained granulated powder, 0.3
Magnesium stearate was blended in parts by weight and a rotary tableting machine (Vergo 512SS, manufactured by Kikusui Seisakusho)
2AV) using a tableting pressure of 1.0 t (preload 0.3 t).
A solid preparation of 0 mmφAR, 400 mg per tablet was obtained.

【００１９】実施例２ 実施例１の低置換度ヒドロキシプロピルセルロースを、
（乾式レーザー法での体積平均粒子径が１９ミクロン、
ゆるめ嵩密度０．４６ｇ／ｍＬ、固め嵩密度が０．６７
ｇ／ｍＬ、ヒドロキシプロポキシル基含有量５．７重量
％）の低置換度ヒドロキシプロピルセルロースに変えた
以外は、同様の操作を行い、固形製剤を得た。Example 2 The low-substituted hydroxypropylcellulose of Example 1 was
(The volume average particle diameter by dry laser method is 19 microns,
Loose bulk density 0.46 g / mL, hardened bulk density 0.67
g / mL, hydroxypropoxyl group content of 5.7% by weight), except that the composition was changed to a low-substituted hydroxypropylcellulose to obtain a solid preparation.

【００２０】比較例１ エリスリトール（日研化学社製）を卓上ミルで粉砕し、
目開き３５５ミクロンのふるいで篩下した粉体を、流動
層造粒機（パウレック社製マルチプレックスＭＰ−１）
を用いて、精製水を噴霧し、流動層造粒を行った。得ら
れた造粒末に０．３重量部の割合でステアリン酸マグネ
シウムを配合し、ロータリー打錠機（菊水製作所製、Ｖ
ｅｒｇｏ５１２ＳＳ２ＡＶ）を用いて打錠圧１．０ｔ
（予圧０．３ｔ）で、１０ｍｍφＡＲ、１錠４００ｍｇ
の固形製剤を得た。Comparative Example 1 Erythritol (manufactured by Niken Kagaku Co., Ltd.) was pulverized with a table mill.
Fluid bed granulator (Multiplex MP-1 manufactured by Powrex Co.)
And purified water was sprayed to perform fluidized bed granulation. Magnesium stearate was added to the obtained granulated powder at a ratio of 0.3 parts by weight, and a rotary tableting machine (Kikusui Seisakusho, V
tablet pressure 1.0t using ergo512SS2AV)
(Preload 0.3t), 10mmφAR, 400mg per tablet
Was obtained.

【００２１】比較例２ エリスリトール（日研化学社製）を卓上ミルで粉砕し、
目開き３５５ミクロンのふるいで篩下した粉体を７０重
量部、本発明の低置換度ヒドロキシプロピルセルロース
（信越化学工業社製 ＬＨ−３１、乾式レーザー法での
体積平均粒子径が１７ミクロン、ゆるめ嵩密度０．３２
ｇ／ｍＬ、固め嵩密度０．６２ｇ／ｍＬ、ヒドロキシプ
ロポキシル基含有量が１０．９重量％）３０重量部を混
合し、流動層造粒機（パウレック社製マルチプレックス
ＭＰ−１）を用いて、精製水を噴霧し、流動層造粒を行
った。得られた造粒末に０．３重量部の割合でステアリ
ン酸マグネシウムを配合し、ロータリー打錠機（菊水製
作所製、Ｖｅｒｇｏ５１２ＳＳ２ＡＶ）を用いて打錠圧
１．０ｔ（予圧０．３ｔ）で１０ｍｍφＡＲ、１錠４０
０ｍｇの固形製剤を得た。Comparative Example 2 Erythritol (manufactured by Niken Kagaku Co., Ltd.) was pulverized with a table mill.
70 parts by weight of a powder sieved with a sieve having an opening of 355 microns, the low-substituted hydroxypropylcellulose of the present invention (LH-31 manufactured by Shin-Etsu Chemical Co., Ltd .; volume average particle diameter by dry laser method: 17 microns, loose) Bulk density 0.32
g / mL, a consolidated bulk density of 0.62 g / mL, and a hydroxypropoxyl group content of 10.9% by weight) and 30 parts by weight, and using a fluidized-bed granulator (Pourec's Multiplex MP-1). And purified water was sprayed to perform fluidized bed granulation. Magnesium stearate was added to the obtained granulated powder in a ratio of 0.3 part by weight, and a rotary tableting machine (manufactured by Kikusui Seisakusho, Vergo 512SS2AV) was used to produce a 10 mmφ AR at a tableting pressure of 1.0 t (preload 0.3 t). , One tablet 40
0 mg of a solid preparation was obtained.

【００２２】比較例３ 比較例２の低置換度ヒドロキシプロピルセルロースを
（信越化学工業社製 LH-３２、乾式レーザー法での体
積平均粒子径が１８ミクロン、ゆるめ嵩密度０．３１ｇ
／ｍＬ、固め嵩密度０．５８ｇ／ｍＬ、ヒドロキシプロ
ポキシル基含有量が８．３重量％）に変えた以外は同様
の方法で口腔内崩壊錠を得た。Comparative Example 3 The low-substituted hydroxypropylcellulose of Comparative Example 2 was used (LH-32 manufactured by Shin-Etsu Chemical Co., Ltd., having a volume average particle diameter of 18 μm by a dry laser method and a loose bulk density of 0.31 g).
/ ML, solidified bulk density 0.58 g / mL, and hydroxypropoxyl group content of 8.3% by weight) to obtain orally disintegrating tablets.

【００２３】実施例３ ビタミンＣ（武田薬品工業社製、ＶＣ−９７）８０重量
部、実施例１で用いた造粒末２０重量部を混合後、ステ
アリン酸マグネシウム０．３重量部を配合し、ロータリ
ー打錠機（菊水製作所製、Ｖｅｒｇｏ５１２ＳＳ２Ａ
Ｖ）を用いて打錠圧１．０ｔ（予圧０．３ｔ）で、１０
ｍｍφＡＲ、１錠４００ｍｇの固形製剤を得た。Example 3 After mixing 80 parts by weight of vitamin C (VC-97, manufactured by Takeda Pharmaceutical Co., Ltd.) and 20 parts by weight of the granulated powder used in Example 1, 0.3 part by weight of magnesium stearate was blended. , Rotary tableting machine (Kikusui Seisakusho, Vergo512SS2A)
V) with a tableting pressure of 1.0 t (preload 0.3 t) and 10
A solid preparation of mmφAR, 400 mg per tablet was obtained.

【００２４】実施例４ 実施例３の造粒末を実施例２の造粒末に変えた以外は、
同様の方法にて固形製剤を得た。Example 4 Except that the granulated powder of Example 3 was changed to the granulated powder of Example 2,
A solid preparation was obtained in the same manner.

【００２５】比較例４ ビタミンＣ（武田薬品工業社製、ＶＣ−９７）８０重量
部に、比較例２の造粒末２０部を混合後、ステアリン酸
マグネシウム０．３重量部を配合し、ロータリー打錠機
（菊水製作所製、Ｖｅｒｇｏ５１２ＳＳ２ＡＶ）を用い
て、打錠圧１．０ｔ（予圧０．３ｔ）で、１０ｍｍφ、
１錠４００ｍｇの固形製剤を得た。Comparative Example 4 20 parts by weight of the granulated powder of Comparative Example 2 were mixed with 80 parts by weight of vitamin C (manufactured by Takeda Pharmaceutical Company Limited, VC-97), and 0.3 part by weight of magnesium stearate was blended. Using a tableting machine (manufactured by Kikusui Seisakusho, Vergo512SS2AV), a tableting pressure of 1.0 t (preload 0.3 t), 10 mmφ,
A solid preparation of 400 mg per tablet was obtained.

【００２６】比較例５ ビタミンＣ（武田薬品工業社製、ＶＣ−９７）８０重量
部に、比較例３の造粒末２０重量部を混合後、ステアリ
ン酸マグネシウム０．３重量部を配合し、ロータリー打
錠機（菊水製作所製、Ｖｅｒｇｏ５１２ＳＳ２ＡＶ）を
用いて、打錠圧１．０ｔ（予圧０．３ｔ）で、１０ｍｍ
φＡＲ、１錠４００ｍｇの固形製剤を得た。Comparative Example 5 After mixing 20 parts by weight of the granulated powder of Comparative Example 3 with 80 parts by weight of vitamin C (manufactured by Takeda Pharmaceutical Company Limited, VC-97), 0.3 part by weight of magnesium stearate was added. Using a rotary tableting machine (Vergo 512SS2AV, manufactured by Kikusui Seisakusho), a tableting pressure of 1.0 t (preload 0.3 t) and 10 mm
A solid preparation of φAR, 400 mg per tablet was obtained.

【００２７】実施例１〜４及び比較例１〜５の口腔内崩
壊錠剤の硬度と崩壊時間とを測定し、その結果を表１に
示す。なお、口腔内崩壊錠剤の硬度は、錠剤硬度計（エ
ルヴェカ硬度計）を用い、崩壊時間の測定には日本薬局
方崩壊試験器（試験液：水、３７℃）を使用し、ｎ＝６
（ｎは試料数を示す）で測定を行った。口腔内崩壊時間
は、健康な成人男女２名で試験し、口腔内で錠剤を噛ま
ずに、軽く口に含んだ状態で、錠剤が完全に溶解又は崩
壊するまでの時間を測定し、平均値を算出した。また、
この時の服用感も合わせて評価した。評価は、良好
（○）、ふつう（△）、不良（×）の３段階とした。表
１の結果から、硬度と崩壊時間の関係において、本発明
の固形製剤は、崩壊時間が速く、口腔内の服用感も良好
なものが得られた。The hardness and disintegration time of the orally disintegrating tablets of Examples 1 to 4 and Comparative Examples 1 to 5 were measured, and the results are shown in Table 1. The hardness of the orally disintegrating tablet was measured using a tablet hardness tester (Elveca hardness tester), and the disintegration time was measured using a Japanese Pharmacopoeia disintegration tester (test solution: water, 37 ° C.), n = 6.
(N indicates the number of samples). Oral disintegration time is tested by two healthy adult males and females, and without chewing the tablet in the oral cavity, the time it takes for the tablet to completely dissolve or disintegrate while lightly in the mouth is measured, and the average value Was calculated. Also,
The feeling of taking at this time was also evaluated. The evaluation was made in three stages: good (○), normal (△), and poor (x). From the results shown in Table 1, in the relationship between the hardness and the disintegration time, it was found that the solid preparation of the present invention had a fast disintegration time and a good feeling in taking in the oral cavity.

【００２８】[0028]

【発明の効果】本発明の固形製剤によれば、成形性及び
崩壊性に優れた特徴を有するため、嚥下力の弱い高齢者
や小児が容易に服用することができる。EFFECTS OF THE INVENTION The solid preparation of the present invention has characteristics excellent in moldability and disintegration property, so that it can be easily taken by elderly people and children with weak swallowing power.

【００２９】[0029]

【表１】 [Table 1]

───────────────────────────────────────────────────── フロントページの続き Ｆターム(参考） 4C076 AA31 AA37 BB01 CC01 CC04 CC24 CC32 CC40 DD38B DD41C DD41H DD67B EE32A FF04 FF06 FF07 FF09 GG04 GG12 GG14  ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA31 AA37 BB01 CC01 CC04 CC24 CC32 CC40 DD38B DD41C DD41H DD67B EE32A FF04 FF06 FF07 FF09 GG04 GG12 GG14

Claims (6)

【特許請求の範囲】[Claims] 【請求項１】 乾式レーザー回折法により測定される体
積平均粒子径が２５ミクロン以下、ゆるめ嵩密度が０．
３５ｇ／ｍＬ以上かつ固め嵩密度が０．６０ｇ／ｍＬ以
上である低置換度ヒドロキシプロピルセルロース及び糖
・糖アルコールを含有することを特徴とする固形製剤。1. A method according to claim 1, wherein the volume average particle diameter measured by a dry laser diffraction method is 25 μm or less, and the loose bulk density is 0.1 μm.
A solid preparation comprising low-substituted hydroxypropylcellulose having a bulk density of at least 35 g / mL and a bulk density of at least 0.60 g / mL, and sugar / sugar alcohol. 【請求項２】 上記糖・糖アルコールが、エリスリトー
ル、ソルビトール、トレハロース、キシリトール、マン
ニトール、グルコース、白糖からなる一群から選ばれる
一以上であることを特徴とする請求項１に記載の固形製
剤。2. The solid preparation according to claim 1, wherein the sugar / sugar alcohol is at least one selected from the group consisting of erythritol, sorbitol, trehalose, xylitol, mannitol, glucose, and sucrose. 【請求項３】 上記糖・糖アルコールの平均粒子径が、
５００ミクロン以下である請求項１又は請求項２に記載
の固形製剤。3. The sugar / sugar alcohol has an average particle diameter of:
3. The solid preparation according to claim 1, which has a size of 500 microns or less. 【請求項４】 上記低置換度ヒドロキシプロピルセルロ
ースのヒドロキシプロポキシル基含有量が、５．０〜１
６．０重量％であることを特徴とする請求項１〜３のい
ずれかに記載の固形製剤。4. The low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content of 5.0 to 1
The solid preparation according to any one of claims 1 to 3, which is 6.0% by weight. 【請求項５】 上記低置換度ヒドロキシプロピルセルロ
ースの圧縮度が４２．０以下であることを特徴とする請
求項１〜４のいずれかに記載の固形製剤。5. The solid preparation according to claim 1, wherein the compression degree of the low-substituted hydroxypropylcellulose is 42.0 or less. 【請求項６】 固形製剤の製造方法において、乾式レー
ザー回折法による体積平均粒子径が２５ミクロン以下
で、ゆるめ嵩密度が０．３５ｇ／ｍＬ以上で、かつ固め
嵩密度が０．６０ｇ／ｍＬ以上である低置換度ヒドロキ
シプロピルセルロースと糖・糖アルコールを用いること
を特徴とする固形製剤の製造方法。6. A method for producing a solid preparation, wherein the volume average particle diameter by dry laser diffraction method is 25 μm or less, the loose bulk density is 0.35 g / mL or more, and the solid bulk density is 0.60 g / mL or more. Using a low-substituted hydroxypropylcellulose and a sugar / sugar alcohol.
JP2000139536A 2000-05-12 2000-05-12 Solid preparation including hydroxypropyl cellulose of low substitution degree and method for preparation of the same Pending JP2001322927A (en)

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WO2011027729A1 (en) 2009-09-02 2011-03-10 日本曹達株式会社 Hydroxypropyl cellulose particles
WO2011065350A1 (en) * 2009-11-24 2011-06-03 日本曹達株式会社 Hydroxyalkylcellulose microparticles
WO2013047353A1 (en) 2011-09-26 2013-04-04 日本曹達株式会社 Orally disintegrating tablet containing hydroxyalkyl cellulose fine particles
JP2013087170A (en) * 2011-10-17 2013-05-13 Nippon Soda Co Ltd Hydroxypropyl cellulose fine particle
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