JP2008214334A - Coated medicine-containing particle and solid preparation containing particle - Google Patents
Coated medicine-containing particle and solid preparation containing particle Download PDFInfo
- Publication number
- JP2008214334A JP2008214334A JP2008019834A JP2008019834A JP2008214334A JP 2008214334 A JP2008214334 A JP 2008214334A JP 2008019834 A JP2008019834 A JP 2008019834A JP 2008019834 A JP2008019834 A JP 2008019834A JP 2008214334 A JP2008214334 A JP 2008214334A
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- drug
- weight
- parts
- coating
- containing particles
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 20
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- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 4
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- 150000001720 carbohydrates Chemical class 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
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Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
本発明は薬物含有粒子および該粒子を含む固形製剤に関するものである。具体的には、不快な味を有する薬物の口腔内での不快な味を低減させた薬物含有粒子、および該粒子を含む固形製剤であって、当該薬物の不快な味を実質的に感じず、且つ消化管内において溶出性のよい製剤に関する。 The present invention relates to drug-containing particles and solid preparations containing the particles. Specifically, a drug-containing particle in which an unpleasant taste in a mouth of a drug having an unpleasant taste is reduced, and a solid preparation containing the particle, wherein the unpleasant taste of the drug is not substantially felt In addition, the present invention relates to a preparation having good dissolution property in the digestive tract.
近年、高齢化社会が進み、生理的諸機能の低下または老人性痴呆症などにより、食物摂取機能（咀嚼、嚥下など）の低下したまたは障害のある高齢者が増加している。また、高齢者の中には夜尿症患者も多く存在し、このような患者に対して錠剤を水で服用させた場合、服用困難あるいは、夜尿の懸念等の問題が生じてきている。一方、忙しい現代社会において時間および場所を選ばずに服用することができるという利点から、服用時に水を必要としない経口製剤の開発が求められている。そこで、水なしでも服用可能な経口製剤の開発が種々なされており、その一つとして口腔内崩壊錠が盛んに開発されている。 In recent years, an aging society has progressed, and the number of elderly people with reduced or impaired food intake functions (such as mastication and swallowing) due to decreased physiological functions or senile dementia is increasing. In addition, there are many patients with nocturnal enuresis among elderly people, and when taking such patients with water, problems such as difficulty in taking or concern about nocturnal urine have arisen. On the other hand, because of the advantage that it can be taken at any time and place in a busy modern society, development of an oral preparation that does not require water at the time of taking is required. Therefore, various oral preparations that can be taken without water have been developed, and as one of them, orally disintegrating tablets have been actively developed.
しかしながら、医薬品に含まれる薬物には、苦味、渋味、辛味のごとき服用時に不快感を伴う成分が多い。薬物がこのような不快な味を伴う場合、口腔内崩壊錠として製する場合には、錠剤を口腔内の唾液水分で崩壊もしくは溶解させて服用するという口腔内崩壊錠の性質上、薬物の不快な味が口腔内に暴露され、服用に困難を伴う。そこで、薬物自体の不快な味を製剤中において遮蔽させることが製剤上の大きな課題となっている。 However, many drugs included in pharmaceutical products are accompanied by discomfort when taken such as bitter, astringent and pungent. When the drug has such an unpleasant taste, when it is manufactured as an orally disintegrating tablet, the discomfort of the drug is due to the nature of the orally disintegrating tablet, which is taken by dissolving or dissolving the tablet with saliva water in the oral cavity. The taste is exposed to the oral cavity and is difficult to take. Therefore, it is a major problem in formulation to shield the unpleasant taste of the drug itself in the formulation.
この課題を解決するために、即ち、服用時の薬物の不快な味をマスキングするために、従来から、甘味料や香料等を添加する方法が用いられているが、十分な苦味マスキングのためには甘味料の量を増加させる必要がある場合があった。また、水不溶性高分子基剤、たとえばエチルセルロース等を利用して薬物自体または薬物を含む顆粒等をコーティングする方法も行われている。しかし、この方法では、不快な味を有する薬物の味を抑えようとしてコーティング量を増大させると、水不溶性高分子が体内で溶解しないために服用時の薬物放出が極端に抑制され、十分な薬効を得られないという問題がある。 In order to solve this problem, that is, in order to mask the unpleasant taste of the drug at the time of taking, a method of adding a sweetener or a fragrance has been conventionally used. Sometimes it was necessary to increase the amount of sweetener. In addition, a method of coating the drug itself or granules containing the drug using a water-insoluble polymer base such as ethyl cellulose is also performed. However, in this method, if the amount of coating is increased in order to suppress the taste of drugs having an unpleasant taste, the water-insoluble polymer does not dissolve in the body, so that the drug release at the time of administration is extremely suppressed, and sufficient drug efficacy is achieved. There is a problem that cannot be obtained.
即ち、口腔内速崩壊錠においては、口腔内での崩壊性および消化管内における溶出性に優れた錠剤を生産することが望まれている。しかし、不快な味を呈する薬物を含有する口腔内速崩壊錠においては、口腔内での速やかな崩壊性という条件と口腔内での不快な味を低減するという条件とを担保することは相反することであり、さらに、口腔内での不快な味を低減するという条件と消化管内での優れた溶出性という条件を担保することも相反することであり、これら条件を同時に解決することは容易でなかった。 That is, in the intraoral quick disintegrating tablet, it is desired to produce a tablet excellent in disintegration property in the oral cavity and dissolution property in the digestive tract. However, in an intraoral rapidly disintegrating tablet containing a drug exhibiting an unpleasant taste, it is contradictory to guarantee the condition of rapid disintegration in the oral cavity and the condition of reducing the unpleasant taste in the oral cavity. Furthermore, it is also contradictory to guarantee the condition of reducing the unpleasant taste in the oral cavity and the excellent dissolution property in the digestive tract, and it is easy to solve these conditions at the same time. There wasn't.
これまで薬物を造粒又は被覆して得られる粒子（または顆粒）を製剤に配合することは知られており、例えば、特許文献１においては、「薬物および糖類を含有してなる口腔内速崩壊錠において苦味を有する薬物および／または流動性の劣る薬物と、製剤用担体とからなる、噴霧乾燥されてなる、平均粒子径約５０〜約２５０μｍ、かつ見掛け比重約０．５〜約１．２の薬物含有粒子を配合することを特徴とする口腔内速崩壊錠」を開示している。ここにおいて、製剤用担体としては、水不溶性高分子、胃溶性高分子、腸溶性高分子、ワックス状物質および糖類が例示されている。 しかしながら、特許文献１においては、薬物に被覆するのではなく薬物とともに噴霧乾燥している点、被覆組成物中に崩壊剤や凝集防止剤を添加していない点等で以下に示す本願発明とは異なる。 It has been known so far to blend particles (or granules) obtained by granulating or coating a drug into a preparation. For example, in Patent Document 1, “intraoral rapid disintegration comprising a drug and a saccharide” An average particle size of about 50 to about 250 μm and an apparent specific gravity of about 0.5 to about 1.2. Orally rapidly disintegrating tablets characterized by containing the drug-containing particles of Here, examples of the carrier for formulation include water-insoluble polymers, gastric polymers, enteric polymers, wax-like substances and saccharides. However, in Patent Document 1, the invention of the present application shown below is that it is spray-dried together with the drug instead of being coated with the drug, the disintegrating agent and the aggregation inhibitor are not added to the coating composition, and the like. Different.
特許文献２においては、（１）不快な味を有する薬物、（２）メチルセルロースおよび（３）マンニトールを混合し粒子化した薬物の不快な味を低減した薬物含有粒子を開示しており、味のマスキングに関して、被覆造粒することは開示していない。 Patent Document 2 discloses drug-containing particles in which (1) a drug having an unpleasant taste, (2) methylcellulose, and (3) a drug obtained by mixing and granulating mannitol to reduce the unpleasant taste of the drug. With respect to masking, no covering granulation is disclosed.
また、薬物を被覆した粒子として、例えば、特許文献３では、急速に放出し、且つ味を隠蔽する医薬剤型として、薬物、低置換ヒドロキシプロピルセルロースおよび微結晶セルロースを含む中核に水溶性ポリマーを含有する内側被覆層、さらにその上に唾液に不溶性のポリマーの外側被覆層を有する剤型について開示されている。このように中核に微結晶セルロースおよび低置換度ヒドロキシプロピルセルロースを添加することを必須としている点で、以下に示す本願発明とは異なるものである。 In addition, as a drug-coated particle, for example, in Patent Document 3, as a pharmaceutical dosage form that rapidly releases and conceals the taste, a water-soluble polymer is added to the core containing the drug, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose. Disclosed is a dosage form having an inner coating layer containing, and further having an outer coating layer of a polymer insoluble in saliva thereon. Thus, it is different from the present invention shown below in that it is essential to add microcrystalline cellulose and low-substituted hydroxypropyl cellulose to the core.
特許文献４では、苦味を有する薬物粒子と、水難溶性高分子化合物と、可塑剤とを含有する薬物含有造粒粒子を、さらに水難溶性高分子化合物および可塑剤の膜で被覆し、被覆造粒薬物粒子を製造する方法が開示されている。 しかしながら、特許文献４では、水難溶性高分子の被膜に崩壊剤や凝集防止剤を添加することについて開示も示唆もされていない。 In Patent Document 4, drug-containing granulated particles containing drug particles having a bitter taste, a poorly water-soluble polymer compound, and a plasticizer are further coated with a film of poorly water-soluble polymer compound and a plasticizer, and coated granulation is performed. A method for producing drug particles is disclosed. However, Patent Document 4 does not disclose or suggest the addition of a disintegrant or an anti-aggregation agent to a film of a poorly water-soluble polymer.
一方で、特許文献５では、平均粒子径 100 μｍ以下である不快な味を有する原薬粒子を、水難溶性高分子物質を用いて造粒した造粒物を打錠してなるチュアブル錠を製する方法が開示されている。 しかしながら、特許文献５では、水難溶性高分子の被膜に崩壊剤や凝集防止剤を添加することについて開示も示唆もされていない。 On the other hand, in Patent Document 5, a chewable tablet is produced by tableting a granulated product obtained by granulating a drug substance particle having an unpleasant taste having an average particle diameter of 100 μm or less using a poorly water-soluble polymer substance. A method is disclosed. However, Patent Document 5 does not disclose or suggest the addition of a disintegrant or an aggregation inhibitor to a film of a poorly water-soluble polymer.
特許文献６では、口腔内崩壊錠に利用する不快な味を低減した薬物含有粒子の製造方法に関して、賦形剤と混合した不快な味を有する薬物をエチルセルロースで造粒もしくは被覆してなる薬物含有顆粒について開示されている。 しかしながら、該文献は腸溶性コーティングについては開示していない。 Patent Document 6 relates to a method for producing drug-containing particles with reduced unpleasant taste used for orally disintegrating tablets, and contains a drug having an unpleasant taste mixed with an excipient granulated or coated with ethyl cellulose. Granules are disclosed. However, the document does not disclose enteric coatings.
特許文献７には、味がマスクされ、活性成分を即時放出する、被覆された顆粒の製造方法として、少なくとも活性成分を含む粉末と顆粒崩壊剤の成分が、最初に乾燥混合され；ついで、得られた粉末が、粒子を互いに結合させて顆粒とすることができる少なくとも一の結合剤を含む賦形剤混合物の存在下で、造粒され；ついで、形成された顆粒が、少なくとも一の被覆剤と膜崩壊剤を含む懸濁液で噴霧することにより被覆され；最後に、得られた被覆された顆粒が乾燥される、方法を開示している。該文献の段落番号００２２には、「被覆により活性成分の味のマスキングを達成するが、同時に活性成分の溶解を遅らせないことを可能にするものであって、顆粒レベル及び膜レベルの両方において、各々、結合剤及び被覆剤のみでなく、（顆粒及び膜）崩壊剤も導入することによって、行うものである。」との記載がある。即ち、該発明は、薬物、顆粒崩壊剤及び結合剤を含む顆粒を被覆剤及び膜崩壊剤を含む懸濁液で被膜することで達成されることを開示するものである。
上記のように、不快な味を有する薬物を含有する口腔内速崩壊製剤において、不快な味を有する薬物の不快な味のマスキングおよび消化管内での速溶性を実現した口腔内速崩壊製剤が望まれていた。 As described above, in the oral rapid disintegrating preparation containing a drug having an unpleasant taste, an oral disintegrating preparation that realizes masking of an unpleasant taste of an unpleasant taste drug and fast solubility in the digestive tract is desired. It was rare.
このような状況において、本発明者らは、薬物の不快な味を低減するために腸溶性フィルム基剤で薬物を被覆することに着目した。しかしながら、腸溶性フィルム基剤を用いて被覆した粒子を含む固形製剤であっては、酸性領域では溶出せず、また中性領域では粒子同士が凝集し、速溶性を示さないことが判明した。そこで、さらに種々検討した結果、腸溶性フィルム基剤に凝集防止剤と崩壊剤とを併用することによって、不快な味のマスキングを維持したままで、酸性領域では速溶性を示し、また中性領域では粒子同士が凝集することなく速溶性を示すことを見出し、上記課題を解決することに成功し、本発明を完成した。本発明は下記の各種の態様の発明を提供するものである。 Under such circumstances, the inventors have focused on coating the drug with an enteric film base to reduce the unpleasant taste of the drug. However, it was found that a solid preparation containing particles coated with an enteric film base does not elute in the acidic region and aggregates in the neutral region and does not exhibit fast solubility. Therefore, as a result of various investigations, the combination of an anti-aggregation agent and a disintegrating agent with the enteric film base maintained an unpleasant taste masking while exhibiting fast solubility in the acidic region, and neutral region. Then, it discovered that a particle | grain showed quick solubility, without aggregating, succeeded in solving the said subject, and completed this invention. The present invention provides the following various aspects of the invention.
項１： 不快な味を有する薬物を含む薬物含有組成物を、下記の成分を含む被覆組成物で被覆造粒した薬物含有粒子：
（１）腸溶性高分子、（２）崩壊剤および（３）凝集防止剤。
Item 1: Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components:
(1) Enteric polymer, (2) disintegrant and (3) anti-aggregation agent.
項２： 凝集防止剤（３）が、酸化チタン、ステアリン酸またはその金属塩、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウム、硬化油およびタルクからなる群から選択される少なくとも１種である項１記載の薬物含有粒子。 Item 2: The aggregation preventing agent (3) is at least one selected from the group consisting of titanium oxide, stearic acid or a metal salt thereof, sucrose fatty acid ester, sodium stearyl fumarate, hydrogenated oil, and talc. Drug-containing particles.
項３： 被覆組成物が、腸溶性高分子（１）１００重量部に対して、凝集防止剤（３）を０．１〜２６０重量部の割合で含む、項１または２に記載の薬物含有粒子。 Item 3: The drug-containing product according to Item 1 or 2, wherein the coating composition contains 0.1 to 260 parts by weight of the aggregation inhibitor (3) with respect to 100 parts by weight of the enteric polymer (1). particle.
項４： 凝集防止剤（３）が、タルクを含む項２又は３に記載の薬物含有粒子。 Item 4: The drug-containing particles according to Item 2 or 3, wherein the aggregation inhibitor (3) contains talc.
項５： 被覆組成物が、腸溶性高分子（１）１００重量部に対して、タルクを３５〜２６０重量部の割合で含む、項４に記載の薬物含有粒子。 Item 5: The drug-containing particle according to Item 4, wherein the coating composition contains 35 to 260 parts by weight of talc with respect to 100 parts by weight of the enteric polymer (1).
項６： 被覆組成物が、腸溶性高分子（１）１００重量部に対して、崩壊剤（２）を５〜４０重量部の割合で含む、項１〜５のいずれかに記載の薬物含有粒子。 Item 6: The drug content according to any one of Items 1 to 5, wherein the coating composition contains 5 to 40 parts by weight of the disintegrant (2) with respect to 100 parts by weight of the enteric polymer (1). particle.
項７： 崩壊剤（２）が、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、でんぷん類、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロースおよびクロスポビドンからなる群から選択される少なくとも１種である項６記載の薬物含有粒子。 Item 7: The disintegrant (2) is selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, starches, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose and crospovidone Item 7. The drug-containing particle according to Item 6, which is at least one kind.
項８： 崩壊剤（２）が、クロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロース或いはこれらの混合物である項７記載の薬物含有粒子。 Item 8: The drug-containing particle according to Item 7, wherein the disintegrant (2) is croscarmellose sodium, low-substituted hydroxypropylcellulose, or a mixture thereof.
項９： 腸溶性高分子（１）が、腸溶性セルロース誘導体類および腸溶性アクリル酸系共重合体類からなる群から選択される少なくとも１種である項１〜８のいずれかに記載の薬物含有粒子。 Item 9: The drug according to any one of Items 1 to 8, wherein the enteric polymer (1) is at least one selected from the group consisting of enteric cellulose derivatives and enteric acrylic copolymers. Containing particles.
項１０： 腸溶性高分子（１）が、腸溶性アクリル酸系共重合体類からなる群から選択される少なくとも１種である項９に記載の薬物含有粒子。 Item 10: The drug-containing particle according to Item 9, wherein the enteric polymer (1) is at least one selected from the group consisting of enteric acrylic copolymers.
項１１： 腸溶性アクリル酸系共重合体類が、メタクリル酸コポリマーである項１０に記載の薬物含有粒子。 Item 11: The drug-containing particle according to Item 10, wherein the enteric acrylic copolymers are methacrylic acid copolymers.
項１２： 不快な味を有する薬物を含む薬物含有組成物を、下記成分を下記割合で含む被覆組成物で被覆造粒した薬物含有粒子：
（１）メタクリル酸コポリマー、
（２）メタクリル酸コポリマー１００重量部に対して、３５〜２６０重量部の割合のタルクおよび
（３）メタクリル酸コポリマー１００重量部に対して、５〜４０重量部の割合のクロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロース或いはこれらの混合物。
Item 12: Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components in the following proportions:
(1) methacrylic acid copolymer,
(2) 35 to 260 parts by weight of talc with respect to 100 parts by weight of methacrylic acid copolymer and (3) 5 to 40 parts by weight of croscarmellose sodium or low with respect to 100 parts by weight of methacrylic acid copolymer Degree of substitution hydroxypropylcellulose or a mixture thereof.
項１３： 凝集防止剤（３）が、ステアリン酸またはその金属塩を含む項２又は３に記載の薬物含有粒子。 Item 13: The drug-containing particle according to Item 2 or 3, wherein the aggregation inhibitor (3) contains stearic acid or a metal salt thereof.
項１４： 被覆組成物が、腸溶性高分子（１）１００重量部に対して、ステアリン酸またはその金属塩を０．１〜１５重量部の割合で含む、項１３に記載の薬物含有粒子。 Item 14: The drug-containing particle according to Item 13, wherein the coating composition contains 0.1 to 15 parts by weight of stearic acid or a metal salt thereof with respect to 100 parts by weight of the enteric polymer (1).
項１５： 不快な味を有する薬物を含む薬物含有組成物を、下記成分を下記割合で含む被覆組成物で被覆造粒した薬物含有粒子：
（１）メタクリル酸コポリマー、
（２）メタクリル酸コポリマー１００重量部に対して、０．１〜１５重量部の割合のステアリン酸またはその金属塩および
（３）メタクリル酸コポリマー１００重量部に対して、５〜４０重量部の割合のクロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロース或いはこれらの混合物。
Item 15: Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components in the following proportions:
(1) methacrylic acid copolymer,
(2) 0.1 to 15 parts by weight of stearic acid or a metal salt thereof with respect to 100 parts by weight of methacrylic acid copolymer and (3) 5 to 40 parts by weight with respect to 100 parts by weight of methacrylic acid copolymer Croscarmellose sodium or low substituted hydroxypropylcellulose or a mixture thereof.
項１６： 平均粒子径が３００μｍ以下である項１〜１５のいずれかに記載の薬物含有粒子。 Item 16: The drug-containing particle according to any one of Items 1 to 15, wherein the average particle size is 300 μm or less.
項１７： 項１〜１６のいずれかに記載の薬物含有粒子と他の製剤化成分を含む固形製剤。 Item 17: A solid preparation comprising the drug-containing particles according to any one of Items 1 to 16 and other formulation ingredients.
項１８： 固形製剤が錠剤状製剤または粒状製剤である項１７に記載の固形製剤。 Item 18: The solid preparation according to Item 17, wherein the solid preparation is a tablet-like preparation or a granular preparation.
項１９： 錠剤状製剤が錠剤または丸剤である項１８に記載の固形製剤。 Item 19: The solid preparation according to Item 18, wherein the tablet-form preparation is a tablet or a pill.
項２０： 粒状製剤が、顆粒剤、細粒剤または散剤である項１８に記載の固形製剤。 Item 20: The solid preparation according to Item 18, wherein the granular preparation is a granule, a fine granule or a powder.
項２１： 固形製剤が口腔内速崩壊製剤である項１７〜２０のいずれかに記載の固形製剤。 Item 21: The solid preparation according to any one of Items 17 to 20, wherein the solid preparation is an intraoral rapidly disintegrating preparation.
項２２： 口腔内速崩壊製剤が錠剤である項２１に記載の固形製剤。 Item 22: The solid preparation according to Item 21, wherein the intraoral rapidly disintegrating preparation is a tablet.
項２３： 口腔内速崩壊製剤が粒状製剤である項２１に記載の固形製剤。 Item 23: The solid preparation according to Item 21, wherein the intraoral rapidly disintegrating preparation is a granular preparation.
項２４： 不快な味を有する薬物を含む薬物含有組成物に、（１）腸溶性高分子、（２）崩壊剤および（３）凝集防止剤を含む被覆組成物並びに水または含水溶媒を含有する被覆コーティング分散液を用いて、被覆造粒して粒子化することを特徴とする薬物の不快な味を低減した薬物含有粒子の製造方法。 Item 24: A drug-containing composition containing a drug having an unpleasant taste contains (1) an enteric polymer, (2) a disintegrating agent, and (3) a coating composition containing an aggregation inhibitor and water or a hydrous solvent. A method for producing drug-containing particles with reduced unpleasant taste of a drug, characterized in that the granulation is performed by coating granulation using a coating coating dispersion.
本発明によれば、薬物の苦味等の不快な味を低減した薬物含有粒子を提供できる。また、該粒子を含むことにより、消化管内、即ち、酸性領域から中性領域にかけて速溶性を実現できる製剤、さらには、口腔内崩壊製剤にあっては、不快な味のマスキングを維持し服用感のよい製剤を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the drug containing particle | grains which reduced unpleasant tastes, such as a bitter taste of a drug, can be provided. In addition, in the preparations that can achieve fast solubility in the digestive tract, that is, from the acidic region to the neutral region by containing the particles, and in the oral disintegrating preparations, the masking of unpleasant taste is maintained and the feeling of ingestion is maintained. A good formulation can be provided.
本特許請求の範囲および本明細書において「平均粒子径」とは、特にことわらない限り、粉体粒子の体積基準測定における累積50％平均粒径Ｄ50（体積基準平均粒径）を意味する。かかる平均粒子径は、レーザー回折式粒度分布測定装置(島津製作所製、ＳＡＬＤ3000)で体積基準により測定する。また、粒度分布についても、同様にレーザー回折式粒度分布測定装置により測定される。 In the present claims and the present specification, the “average particle diameter” means a cumulative 50% average particle diameter D50 (volume reference average particle diameter) in volume-based measurement of powder particles, unless otherwise specified. The average particle diameter is measured on a volume basis with a laser diffraction particle size distribution measuring apparatus (SALD3000, manufactured by Shimadzu Corporation). Similarly, the particle size distribution is measured by a laser diffraction type particle size distribution measuring apparatus.
本明細書における「薬物の量」とは、一般的に薬剤として採用されている「医薬活性成分」の形態を基準とするものである。すなわち、塩の形態をとっている薬物の場合には、その塩を加えた量を基準とする。但し、薬物が結晶水を有する場合は、当該結晶水相当量を減じた量を基準とする。 The “amount of drug” in the present specification is based on the form of “pharmaceutical active ingredient” generally employed as a drug. That is, in the case of a drug in the form of a salt, the amount added with the salt is used as a reference. However, when the drug has water of crystallization, the amount obtained by subtracting the amount corresponding to the water of crystallization is used as a reference.
本特許請求の範囲および本明細書における「腸溶性高分子１００重量部」とは、腸溶性高分子の固形分の重量を基準として１００重量部とするものである。 The term “100 parts by weight of enteric polymer” in the claims and the present specification refers to 100 parts by weight based on the solid content of the enteric polymer.
本発明の薬物含有粒子は、本質的には、不快な味を有する薬物を含む薬物含有組成物を、下記の成分：
（１）腸溶性高分子、（２）崩壊剤および（３）凝集防止剤を含む被覆組成物で被覆造粒した薬物含有粒子であり、以下に各成分、組成物、薬物含有粒子、および該粒子を含む固形製剤について説明する。
The drug-containing particles of the present invention essentially comprise a drug-containing composition containing a drug having an unpleasant taste, and the following components:
(1) Enteric polymer, (2) disintegrating agent and (3) drug-containing particles coated and granulated with a coating composition containing an anti-aggregation agent, each component, composition, drug-containing particle, and A solid preparation containing particles will be described.
不快な味を有する薬物
本発明に用いられる「不快な味を有する薬物」としては、医薬活性成分として疾患の治療や予防に供されるものであり、苦味、渋味、辛味のごとき不快な味を有するものであれば、特に制限されない。かかる薬物としては、解熱鎮痛消炎剤、キノロン系抗菌剤、抗生物質、抗ガン剤、胃腸薬、止しゃ剤、抗うつ剤、抗てんかん剤、降圧剤、抗ヒスタミン剤、循環器用剤等が挙げられる。例えば、以下に示すクエン酸モサプリド、ファモチジン、硫酸キニーネ、硫酸モルヒネ、塩酸モルヒネ、エテンザミド、リン酸コデイン、リン酸ジヒドロコデイン、塩化ベルベリン、アクリノール、ゾニサミド、塩酸ロペラミド、ガチフロキサシン、スパルフロキサシン、アラセプリル、クラリスロマイシン、塩酸アロチノロール、インドメタシン、クエン酸ペントキシベリン、塩酸メトホルミン、イブプロフェン、ケトプロフェン、アスピリン、アセトアミノフェン、カフェイン、イソプロピルアンチピリン、塩酸ジフェニルピラリン、マレイン酸クロルフェニラミン、塩酸イソチペンジル、塩酸フェニレフリン、塩酸プロカインアミド、硫酸キニジン、イソソルビド、スルピリド、ジアゼパム、バルプロ酸、炭酸リチウム、セファレキシン、アンピシリンなどが例示できる。上述のごとく、本薬物は、塩フリーのものであってもよいし、塩の形態であってもよい。さらに、それらの水和物であってもよい。
Drug having an unpleasant taste The “drug having an unpleasant taste” used in the present invention is used for treating or preventing a disease as a pharmaceutically active ingredient, and has an unpleasant taste such as a bitter taste, astringency, and pungent taste. If it has, it will not be restrict | limited in particular. Examples of such drugs include antipyretic analgesic / anti-inflammatory agents, quinolone antibacterial agents, antibiotics, anticancer agents, gastrointestinal agents, antitussives, antidepressants, antiepileptic agents, antihypertensive agents, antihistamines, cardiovascular agents, and the like. For example, mosapride citrate, famotidine, quinine sulfate, morphine sulfate, morphine hydrochloride, etheneamide, codeine phosphate, dihydrocodeine phosphate, berberine chloride, acrinol, zonisamide, loperamide hydrochloride, gatifloxacin, sparfloxacin, alaspril , Clarithromycin, arotinolol hydrochloride, indomethacin, pentoxyberine citrate, metformin hydrochloride, ibuprofen, ketoprofen, aspirin, acetaminophen, caffeine, isopropylantipyrine, diphenylpyraline hydrochloride, chlorpheniramine maleate, isothipentyl hydrochloride, phenylephrine hydrochloride , Procainamide hydrochloride, quinidine sulfate, isosorbide, sulpiride, diazepam, valproic acid, lithium carbonate, cephalex , Ampicillin, and others. As described above, the drug may be salt-free or in the form of a salt. Furthermore, those hydrates may be sufficient.
薬物は１種でもよいし、２種以上であってもよい。また、苦味等の不快な味を有しない薬物を追加してもよい（該薬物は粒子内、特に薬物含有組成物中にあっても、粒子外に添加してもよい）。本発明においては、塩基性の薬物に適用することによって、より優れた効果を発揮する。 The drug may be one type or two or more types. In addition, a drug that does not have an unpleasant taste such as a bitter taste may be added (the drug may be added inside the particle, particularly in the drug-containing composition, or outside the particle). In the present invention, by applying to a basic drug, a more excellent effect is exhibited.
薬物含有組成物
本発明における薬物含有組成物は、上記薬物単独であってもよいし、他の成分（添加剤）との混合物であってもよい。薬物含有組成物中に含まれる不快な味の薬物の量としては、１０〜１００重量％程度、好ましくは、５０〜９９．９重量％程度である。
Drug-containing composition The drug-containing composition in the present invention may be the drug alone or a mixture with other components (additives). The amount of unpleasant-tasting drug contained in the drug-containing composition is about 10 to 100% by weight, preferably about 50 to 99.9% by weight.
混合されうる添加剤としては、ステアリン酸、ステアリン酸マグネシウムやステアリン酸カルシウムなどのステアリン酸の金属塩、フマル酸ステアリルナトリウム、タルク、ショ糖脂肪酸エステル、軽質無水ケイ酸、含水二酸化ケイ素などの流動化剤、賦形剤、崩壊剤、結合剤、滑沢剤、甘味剤、香料、安定化剤、可塑剤、着色剤、矯味剤などが挙げられる。これらの添加剤は、一種または二種以上を組み合わせて適宜適量添加される。 Additives that can be mixed include fluidizing agents such as stearic acid, metal salts of stearic acid such as magnesium stearate and calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid ester, light anhydrous silicic acid, hydrous silicon dioxide , Excipients, disintegrants, binders, lubricants, sweeteners, fragrances, stabilizers, plasticizers, colorants, flavoring agents and the like. These additives are appropriately added in an appropriate amount by one or a combination of two or more.
本発明における薬物含有組成物は、上述のごとく、薬物単独でもあってもよく、公知の製剤工程によって得られるもの、例えば、他の添加剤と混合して得られるものや、造粒して得られる造粒物であってもよい。造粒する方法としては、例えば、攪拌造粒法、押出し造粒法、流動層造粒法、乾式造粒法などの慣用の造粒法が例示できる。 As described above, the drug-containing composition in the present invention may be a drug alone, obtained by a known formulation process, for example, obtained by mixing with other additives, or obtained by granulation. It may be a granulated product. Examples of the granulation method include conventional granulation methods such as stirring granulation method, extrusion granulation method, fluidized bed granulation method, and dry granulation method.
本発明における薬物含有組成物の平均粒子径について、薬物単独、他の添加剤と混合して得られるものの場合は、薬物の平均粒子径をもって該組成物の平均粒子径とし、薬物を含んだ造粒物の場合は、造粒物自身の平均粒子径をもって該組成物の平均粒子径とする。それらの上限としては、平均粒子径２５０μｍ以下、好ましくは２００μｍ以下、さらに好ましくは１５０μｍ以下、最も好ましくは１２５μｍ以下が挙げられる。これ以上大きい粒子径であると、被覆後の粒子径が粗大となり、口に含んだときにザラつきを感じる。 Regarding the average particle size of the drug-containing composition in the present invention, when the drug is obtained by mixing the drug alone or other additives, the average particle size of the drug is defined as the average particle size of the composition, In the case of granules, the average particle size of the granulated product itself is taken as the average particle size of the composition. The upper limit thereof includes an average particle diameter of 250 μm or less, preferably 200 μm or less, more preferably 150 μm or less, and most preferably 125 μm or less. If the particle diameter is larger than this, the particle diameter after coating becomes coarse and feels rough when it is put in the mouth.
（１）腸溶性高分子
本発明で使用する「腸溶性高分子」としては、特に限定されないがセルロースアセテートプロピオネート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルエチルセルロースフタレート、カルボキシメチルエチルセルロース、セルロースアセテートフタレート等の腸溶性セルロース誘導体類、メタクリル酸コポリマーＬＤ（例えば、商品名：オイドラギットＬ30Ｄ-55、エボニック デグサ ジャパン株式会社製、商品名：ポリキッドＰＡ-30、ポリキッドPA-30Ｓ、三洋化成社製、商品名：コリコートＭＡＥ30ＤＰ、ＢＡＳＦ社製）、メタクリル酸コポリマーＬ（例えば、商品名：オイドラギットＬ、エボニック デグサ ジャパン株式会社製）、メタクリル酸コポリマーＳ（例えば、商品名：オイドラギットＳ、オイドラギットＳ１００、オイドラギットＦＳ３０Ｄ、エボニック デグサ ジャパン株式会社製）などの腸溶性アクリル酸系共重合体等が挙げられる。
(1) Enteric polymer “Enteric polymer” used in the present invention is not particularly limited, but is cellulose acetate propionate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethyl. Enteric cellulose derivatives such as ethyl cellulose and cellulose acetate phthalate, methacrylic acid copolymer LD (for example, trade name: Eudragit L30D-55, manufactured by Evonik Degussa Japan, trade name: Polykid PA-30, Polykid PA-30S, Sanyo Chemical Product name: Kollicoat MAE30DP, manufactured by BASF), methacrylic acid copolymer L (for example, product name: Eudragit L, manufactured by Evonik Degussa Japan Co., Ltd.), Examples include enteric acrylic copolymers such as tacrylic acid copolymer S (for example, trade names: Eudragit S, Eudragit S100, Eudragit FS30D, manufactured by Evonik Degussa Japan).
好ましい腸溶性高分子としては、腸溶性アクリル酸系共重合体、より好ましくは、メタクリル酸コポリマーであり、例えば、メタクリル酸コポリマーＬＤ（例えば、商品名：オイドラギットＬ30Ｄ-55、エボニック デグサ ジャパン株式会社製、商品名：ポリキッドＰＡ-30、ポリキッドPA-30Ｓ、三洋化成社製、商品名：コリコートＭＡＥ30ＤＰ、ＢＡＳＦ社製）、メタクリル酸コポリマーＬ（例えば、商品名：オイドラギットＬ、エボニック デグサ ジャパン株式会社製）、メタクリル酸コポリマーＳ（例えば、商品名：オイドラギットＳ、オイドラギットＳ１００、オイドラギットＦＳ３０Ｄ、エボニック デグサ ジャパン株式会社製）等が挙げられる。 The enteric polymer is preferably an enteric acrylic copolymer, more preferably a methacrylic acid copolymer, such as a methacrylic acid copolymer LD (for example, trade name: Eudragit L30D-55, manufactured by Evonik Degussa Japan Co., Ltd.). , Trade name: Polykid PA-30, Polykid PA-30S, Sanyo Kasei Co., Ltd., trade name: Kollicoat MAE30DP, BASF Co.), methacrylic acid copolymer L (for example, trade name: Eudragit L, Evonik Degussa Japan Co., Ltd.) Methacrylic acid copolymer S (for example, trade name: Eudragit S, Eudragit S100, Eudragit FS30D, manufactured by Evonik Degussa Japan Co., Ltd.) and the like.
これら高分子は１種または２種以上混合して用いてもよい。腸溶性高分子の被覆量としては、薬物含有組成物１００重量部に対して、固形分重量として１０〜２００重量部、好ましくは２５〜１５０重量部、より好ましくは、３５〜１００重量部程度である。 These polymers may be used alone or in combination. The coating amount of the enteric polymer is 10 to 200 parts by weight, preferably 25 to 150 parts by weight, more preferably about 35 to 100 parts by weight as the solid content with respect to 100 parts by weight of the drug-containing composition. is there.
（２）崩壊剤
本発明で使用する崩壊剤としては、例えば、クロスカルメロースナトリウム；カルボキシメチルスターチナトリウム；トウモロコシデンプン、部分α化デンプン、バレイショデンプン、コメデンプンなどのでんぷん類；カルボキシメチルセルロース（カルメロース）；カルボキシメチルセルロースナトリウム（カルメロースナトリウム）；カルボキシメチルセルロースカルシウム（カルメロースカルシウム）；低置換度ヒドロキシプロピルセルロース；クロスポビドン等が例示でき、これらの中から１種又は２種以上混合して用いてもよい。好ましくは、クロスカルメロースナトリウム；カルボキシメチルスターチナトリウム；トウモロコシデンプン、部分α化デンプン、バレイショデンプン、コメデンプンなどのでんぷん類；低置換度ヒドロキシプロピルセルロース、より好ましくは、クロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロースである。崩壊剤の配合量としては、腸溶性高分子１００重量部（ただし、これは固形分重量を意味する）に対して、５〜４０重量部程度、好ましくは１０〜３７重量部程度である。また、使用する崩壊剤は、微粉砕したものを用いてもよい。
（３）凝集防止剤
本発明の被覆組成物に使用される凝集防止剤としては、酸化チタン、ステアリン酸またはその金属塩、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウム、硬化油、タルク等が例示でき、これら１種または２種以上を混合して用いることができる。好ましくは、ステアリン酸またはその塩やタルクである。凝集防止剤の配合量としては、腸溶性高分子１００重量部（ただし、これは固形分重量を意味する）に対して、０．１〜２６０重量部程度であるが、一般的には好ましくは１０〜２１０重量部程度、より好ましくは、２０〜１６０重量部程度、特に好ましくは３５〜１６０重量部程度である。タルクを用いる場合には、好ましくは、３５〜２６０重量部程度である。一方、ステアリン酸又はその塩を用いる場合には、好ましくは０．１〜１６０重量部、より好ましくは、０．１〜１５重量部、特に好ましくは、１〜１０重量部である。
(2) Disintegrating agent Examples of the disintegrating agent used in the present invention include croscarmellose sodium; carboxymethyl starch sodium; starches such as corn starch, partially pregelatinized starch, potato starch and rice starch; carboxymethylcellulose (carmellose) Carboxymethylcellulose sodium (carmellose sodium); carboxymethylcellulose calcium (carmellose calcium); low-substituted hydroxypropylcellulose; crospovidone and the like, and one or a mixture of two or more of these may be used. . Preferably, croscarmellose sodium; sodium carboxymethyl starch; starches such as corn starch, partially pregelatinized starch, potato starch, rice starch; low-substituted hydroxypropylcellulose, more preferably croscarmellose sodium or low-substituted Hydroxypropyl cellulose. The compounding amount of the disintegrant is about 5 to 40 parts by weight, preferably about 10 to 37 parts by weight with respect to 100 parts by weight of the enteric polymer (however, this means the solid content weight). The disintegrant used may be finely pulverized.
(3) Anti-flocculating agent Examples of the anti-flocculating agent used in the coating composition of the present invention include titanium oxide, stearic acid or a metal salt thereof, sucrose fatty acid ester, sodium stearyl fumarate, hydrogenated oil, talc and the like. These 1 type (s) or 2 or more types can be mixed and used. Preferably, it is stearic acid or its salt, and talc. The blending amount of the aggregation inhibitor is about 0.1 to 260 parts by weight with respect to 100 parts by weight of the enteric polymer (however, this means the solid content weight), but is generally preferably About 10 to 210 parts by weight, more preferably about 20 to 160 parts by weight, and particularly preferably about 35 to 160 parts by weight. When talc is used, it is preferably about 35 to 260 parts by weight. On the other hand, when stearic acid or a salt thereof is used, it is preferably 0.1 to 160 parts by weight, more preferably 0.1 to 15 parts by weight, and particularly preferably 1 to 10 parts by weight.
被覆組成物
被覆組成物は、上記（１）〜（３）の各成分を含有するものであり、必要に応じて下記可塑剤（４）を含有していてもよい。
Coating composition The coating composition contains the above components (1) to (3), and may contain the following plasticizer (4) as necessary.
（４）可塑剤
本発明の被覆組成物に使用してもよい可塑剤としては、例えば、トリアセチン、クエン酸トリエチル、セバシン酸ジブチル、アセチル化モノグリセリド、プロピレングリコール、ポリソルベート80、ポリエチレングリコール、ラウリル硫酸ナトリウム等の日本薬局方および医薬添加物規格等の公定書に記載のものが挙げられる。
(4) Plasticizer Plasticizers that may be used in the coating composition of the present invention include, for example, triacetin, triethyl citrate, dibutyl sebacate, acetylated monoglyceride, propylene glycol, polysorbate 80, polyethylene glycol, sodium lauryl sulfate And those described in Japanese pharmacopoeia such as the Japanese Pharmacopoeia and official standards such as pharmaceutical additive standards.
可塑剤の配合量としては、腸溶性高分子１００重量部（ただし、これは固形分重量を意味する）に対して、５〜４５重量部程度、好ましくは５〜３５重量部程度、より好ましくは、１０〜３０重量部程度である。 As a compounding quantity of a plasticizer, it is about 5-45 weight part with respect to 100 weight part of enteric polymers (however, this means solid content weight), Preferably it is about 5-35 weight part, More preferably 10 to 30 parts by weight.
この被覆組成物には、更に、ｐＨ調整剤、着色剤、矯味剤、香料等が含まれていてもよい。 This coating composition may further contain a pH adjuster, a colorant, a corrigent, a fragrance and the like.
ｐＨ調整剤としては、水酸化ナトリウム、メグルミン、アルギニン、リジン等が挙げられる。該調整剤によって、例えば、被覆組成物を水又は含水溶媒を加えて被覆コーティング分散液としたときのｐＨが通常、４〜８、好ましくは、５〜７程度になるように調整される。 Examples of the pH adjuster include sodium hydroxide, meglumine, arginine, lysine and the like. For example, the pH of the coating composition when adjusted to a coating coating dispersion by adding water or a water-containing solvent to the coating composition is usually adjusted to 4 to 8, preferably about 5 to 7.
また、本発明の効果を損なわない範囲において、他の高分子を１種または２種以上混合してもよい。例えば、水溶性高分子、水不溶性高分子、胃溶性高分子および熱可塑性物質（ワックス状物質）等が挙げられる。 Moreover, in the range which does not impair the effect of this invention, you may mix 1 type (s) or 2 or more types of other polymer | macromolecule. Examples thereof include water-soluble polymers, water-insoluble polymers, gastric polymers, and thermoplastic substances (wax-like substances).
薬物含有粒子
本発明の薬物含有粒子は、上記薬物含有組成物に、上記被覆組成物と水または含水溶媒を含有する被覆コーティング分散液を用いて被覆造粒して粒子化することで得ることができる。
Drug-containing particles The drug-containing particles of the present invention can be obtained by coating and granulating the drug-containing composition with a coating coating dispersion containing the coating composition and water or a water-containing solvent. it can.
本発明における「薬物含有粒子」は、１個の薬物（や薬物の造粒物）のまわりが被覆組成物によって得られる被覆層によって被膜されている状態だけでなく、複数の薬物（や薬物の造粒物）が被覆組成物を介して結合し、最終的に、被覆組成物によって得られる被覆層で被膜されている状態も含む。 The “drug-containing particles” in the present invention are not limited to a state in which a single drug (or a granulated product of drug) is coated with a coating layer obtained by a coating composition, but also a plurality of drugs (and drug drugs). It includes a state in which the granulated product) is bonded through the coating composition and is finally coated with a coating layer obtained by the coating composition.
被覆するための装置としては、一般的な流動層造粒機（転動流動層造粒機、ワースター型流動層造粒機等を含む）が挙げられるが、工程中の粒子の粗大化を抑えるために、側面からの強制循環装置を備えるワースター法を改良した流動層造粒機（例えばパウレック社製 GPCG-SPCなど）や整粒解砕機構(スクリーン・インペラ方式やブレード・ステータ方式、クロススクリュー、ランプブレーカなど)付き複合型流動層造粒機（例えば、パウレック社製 微粒子コーティング・造粒装置MP-01SFPなど）、回転流動層造粒機（例えば、奈良機械製作所製 オムニテックス など）が好ましい。 Examples of the apparatus for coating include general fluidized bed granulators (including rolling fluidized bed granulators, Wurster type fluidized bed granulators, etc.), but suppress the coarsening of particles during the process. For this purpose, a fluidized bed granulator (such as GPCG-SPC manufactured by POWREC Co., Ltd.) with an improved Wurster method equipped with a forced circulation device from the side and a particle size crushing mechanism (screen impeller method, blade stator method, cross screw) Composite fluidized bed granulators (for example, a fine particle coating / granulating device MP-01SFP manufactured by POWREC) and rotating fluidized bed granulators (for example, Omnitex manufactured by Nara Machinery Co., Ltd.) are preferable. .
本発明の薬物含有粒子は、平均粒子径が３００μｍを超えると、添加量もしくは噴霧固形分量が少なく抑えられるものの、口腔内でのザラつきや異物感を感じてしまうことがある。そのため、平均粒子径が３００μｍ以下であることが好ましく、より好ましくは２５０μｍ以下、さらに好ましくは２００μｍ以下が挙げられ、最も好ましくは１７５μｍ以下が挙げられる。一方、粒子径の小さな粒子が多いと薬物含有粒子の比表面積が大きいため、苦味等の不快な味の抑制が充分でない場合がある。このため平均粒子径は３０μｍ以上であることが好ましい。その平均粒子径は、不快な味のマスキング効果と共に、服用感や溶出性も考慮して適宜粒子の大きさを決定することができる。 When the average particle diameter of the drug-containing particles of the present invention exceeds 300 μm, the addition amount or the amount of spray solid content can be suppressed to a small level, but there may be a feeling of roughness in the oral cavity or a foreign body feeling. Therefore, the average particle size is preferably 300 μm or less, more preferably 250 μm or less, still more preferably 200 μm or less, and most preferably 175 μm or less. On the other hand, when the number of particles having a small particle size is large, the specific surface area of the drug-containing particles is large, and therefore, suppression of unpleasant taste such as bitterness may not be sufficient. For this reason, it is preferable that an average particle diameter is 30 micrometers or more. The average particle size can appropriately determine the size of the particles in consideration of the feeling of ingestion and dissolution as well as an unpleasant taste masking effect.
本願発明は、上述の口腔内でのざらつき、異物感を回避するため、平均粒子径が３００μｍ以下の薬物含有粒子であっても、不快な味を低減させ、溶出性のよい粒子が得られることを目的として見出したものであり、特に、上記（１）〜（３）を含む被覆組成物で被覆造粒した場合に達成できることを見出したものである。 In the present invention, in order to avoid the above-described roughness in the oral cavity and the sensation of foreign matter, even if the drug-containing particles have an average particle size of 300 μm or less, unpleasant taste is reduced and particles having good elution properties can be obtained. In particular, it has been found that it can be achieved when coating granulation with a coating composition containing the above (1) to (3).
本発明の固形製剤
本発明の薬物含有粒子を用いて、固形製剤を製造することができる。適用できる剤型としては、例えば、錠剤状製剤または粒状製剤が例示できる。錠剤状製剤としては、錠剤や丸剤が、粒状製剤としては、顆粒剤、細粒剤または散剤が例示できる。また、固形製剤は、口腔内速崩壊製剤であってもよく、これには錠剤（口腔内速崩壊錠）や粒状製剤（口腔内速崩壊顆粒や口腔内速崩壊散）が含まれる。
Solid preparation of the present invention A solid preparation can be produced using the drug-containing particles of the present invention. Applicable dosage forms include, for example, tablet-like preparations and granular preparations. Examples of tablet preparations include tablets and pills, and examples of granular preparations include granules, fine granules, and powders. The solid preparation may be an intraoral rapidly disintegrating preparation, and includes tablets (orally disintegrating tablets) and granular preparations (orally disintegrating granules or rapidly disintegrating oral cavity).
本発明の固形製剤には、通常、薬物含有粒子に加えて、特に支障のない限り、固形医薬製剤の製造に用いられる薬学的に許容される製剤化成分を配合され、このような「製剤化成分」としては、配合しても不都合がなく、且つ、配合の必要性があるものならばいずれでもよく、例えば、賦形剤、結合剤、滑沢剤、崩壊剤等が挙げられる。 In the solid preparation of the present invention, in addition to the drug-containing particles, a pharmaceutically acceptable formulation component used for the production of a solid pharmaceutical preparation is usually blended unless otherwise hindered. As the “component”, any component may be used as long as it is not inconvenient even if it is blended and needs to be blended, and examples thereof include excipients, binders, lubricants, and disintegrants.
賦形剤の例としては、たとえば、乳糖、ショ糖、Ｄ−マンニトール、デンプン、結晶セルロース、エリスリトール、トレハロース、無水リン酸水素カルシウム、硫酸カルシウムなどが例示できる。また、結合剤としては、アラビアゴム、でんぷん類、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、プルラン、ゼラチン、エチルセルロース、メチルセルロース、カルメロースナトリウム、デキストリン、ポリビニルピロリドンなどが挙げられる。 Examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, erythritol, trehalose, anhydrous calcium hydrogen phosphate, calcium sulfate and the like. Examples of the binder include gum arabic, starches, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, pullulan, gelatin, ethylcellulose, methylcellulose, carmellose sodium, dextrin, and polyvinylpyrrolidone.
また、滑沢剤として、例えば、ステアリン酸やステアリン酸マグネシウム、ステアリン酸カルシウムなどのステアリン酸金属塩、タルク、コロイドシリカ、ショ糖脂肪酸エステル、硬化油、ポリエチレングリコール、フマル酸ステアリルナトリウムなど、崩壊剤として、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルメロースカルシウム、クロスポビドン、カルボキシメチルスターチナトリウム、カルメロースなどが用いられる。 As a lubricant, for example, stearic acid, magnesium stearate, stearic acid metal salts such as calcium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, etc. Low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, crospovidone, sodium carboxymethyl starch, carmellose and the like are used.
また、必要に応じて、安定化剤（エデト酸ナトリウム、トコフェロール、Ｌ−アスコルビン酸、Ｌ−システイン、亜硫酸塩など）、流動化剤（軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウムなど）、界面活性剤（ラウリル硫酸ナトリウム、ポリソルベート、など）、防腐剤、着色剤（食用色素、三二酸化鉄、カルミンなど）、香料（ストロベリーを含む種々の果実香料並びにヨーグルト、ミント、メントールなど）、矯味剤等を加えてもよい。 If necessary, stabilizers (sodium edetate, tocopherol, L-ascorbic acid, L-cysteine, sulfite, etc.), fluidizing agents (light anhydrous silicic acid, magnesium metasilicate aluminate, etc.), surface activity Agents (sodium lauryl sulfate, polysorbate, etc.), preservatives, coloring agents (food dyes, ferric oxide, carmine, etc.), flavors (various fruit flavors including strawberry, yogurt, mint, menthol, etc.), flavoring agents, etc. May be added.
矯味剤としては、ネオテーム、ソーマチン（タウマチン）、アスパルテーム、ステビア、サッカリンナトリウム、グルタミン酸ナトリウムなどが挙げられ、これらは単品で使用してもよいが、二種または数種の併用であってもよい。 Examples of the corrigent include neotame, thaumatin (thaumatin), aspartame, stevia, saccharin sodium, sodium glutamate, and the like. These may be used alone or in combination of two or more.
本発明の固形製剤は、製剤分野において慣用の方法を用いて製造することができる。例えば本発明の薬物含有粒子に上述のような諸成分を均一に混合したのち、その混合物を公知手段で製剤化することができる。例えば錠剤、丸剤、散剤、顆粒剤、細粒剤などの経口投与に適した各種固形製剤に製剤化することができる。例えば、錠剤の場合は、薬物含有粒子と賦形剤、崩壊剤等を加え、混合し、結合剤を加えて造粒を行って顆粒とし、これに滑沢剤を加えて打錠して錠剤とすることができる。又は、薬物含有粒子と賦形剤および崩壊剤等の製剤化成分を、混合機を用いて混合し、これを打錠してもよいし、製剤化成分の混合物を造粒したのち薬物含有粒子を混合し、これを打錠してもよい。 The solid preparation of the present invention can be produced using a method commonly used in the pharmaceutical field. For example, after the above-mentioned components are uniformly mixed in the drug-containing particles of the present invention, the mixture can be formulated by a known means. For example, it can be formulated into various solid preparations suitable for oral administration such as tablets, pills, powders, granules and fine granules. For example, in the case of tablets, drug-containing particles, excipients, disintegrants, etc. are added, mixed, added with a binder, granulated to form granules, and then added with a lubricant and compressed into tablets. It can be. Alternatively, the drug-containing particles may be mixed with pharmaceutical ingredients such as excipients and disintegrants using a mixer and compressed into tablets, or the drug-containing particles may be granulated after granulating the mixture of the pharmaceutical ingredients. May be mixed and tableted.
また、顆粒剤においても錠剤とほぼ同様な方法の流動層造粒を行なうか、攪拌造粒を行うことにより製造することができる。散剤等も同様な方法で製造できる。 Also, granules can be produced by fluidized bed granulation in the same manner as tablets or by stirring granulation. A powder etc. can be manufactured by the same method.
本発明においては、薬物含有粒子を口腔内速崩壊製剤に適用することもできる。適用できる剤型としては、錠剤（口腔内速崩壊錠）や粒状製剤（口腔内速崩壊顆粒や口腔内速崩壊散）が含まれる。 In the present invention, the drug-containing particles can also be applied to an intraoral rapidly disintegrating preparation. Applicable dosage forms include tablets (intraoral rapidly disintegrating tablets) and granular preparations (intraoral rapidly disintegrating granules and intraoral rapidly disintegrating powders).
本発明の口腔内速崩壊製剤は、製剤分野において慣用の方法を用いて製造することができる。例えば本発明の薬物含有粒子に上述のような諸成分を均一に混合したのち、その混合物を公知手段で製剤化することができる。例えば、錠剤の場合は、薬物含有粒子と賦形剤、崩壊剤等を加え、混合し、結合剤を加えて造粒を行って顆粒とし、これに滑沢剤を加えて打錠して錠剤とすることができる。又は、薬物含有粒子と賦形剤および崩壊剤等の製剤化成分を、混合機を用いて混合し、これを打錠してもよいし、製剤化成分の混合物を造粒したのち薬物含有粒子を混合し、これを打錠してもよい。また、顆粒剤においても錠剤とほぼ同様な方法の流動層造粒を行なうか、攪拌造粒を行うことにより製造することができる。散剤等も同様な方法で製造できる。 The intraoral rapidly disintegrating preparation of the present invention can be produced using a method commonly used in the pharmaceutical field. For example, after the above-mentioned components are uniformly mixed in the drug-containing particles of the present invention, the mixture can be formulated by a known means. For example, in the case of tablets, drug-containing particles, excipients, disintegrants, etc. are added, mixed, added with a binder, granulated to form granules, and then added with a lubricant and compressed into tablets. It can be. Alternatively, the drug-containing particles may be mixed with pharmaceutical ingredients such as excipients and disintegrants using a mixer and compressed into tablets, or the drug-containing particles may be granulated after granulating the mixture of the pharmaceutical ingredients. May be mixed and tableted. In addition, granules can be produced by fluidized bed granulation in the same manner as tablets or by stirring granulation. A powder etc. can be manufactured by the same method.
例えば、ＷＯ00/047233（薬物、デンプンおよび水溶性賦形剤をデンプン結合液で造粒し、打錠）、特開平11-263723(水溶性の高い糖と水溶性結合剤の混合液で薬物を造粒、乾燥後打錠しエージング)、ＷＯ99/47124(薬物、糖類、および非晶質糖類を打錠後加湿乾燥)、特開平08-291051号(薬物、水溶性結合剤および水溶性賦形剤の混合物を低圧成形後、加湿乾燥)、特開平05-271054(薬物と糖類の混合物で、糖類の粒子表面が湿る条件で打錠)、特開平9-71523(崩壊剤に低置換度ヒドロキシプロピルセルロース、賦形剤に結晶セルロース、これと滑沢剤を混合・打錠)に、開示された製造方法などが挙げられる。 For example, WO00 / 047233 (drug, starch and water-soluble excipient are granulated with a starch binding solution and tableting), JP-A-11-263723 (drug is mixed with a mixture of a highly water-soluble sugar and a water-soluble binder) Granulation, tableting and aging after drying), WO99 / 47124 (humidity drying after tableting of drug, sugar and amorphous sugar), JP 08-291051 (drug, water-soluble binder and water-soluble shaping) After low-pressure molding of the mixture of agents, humidified and dried), JP 05-271054 (tablet under conditions where the sugar particle surface is moistened with a mixture of drug and saccharide), JP 9-71523 (disintegrant with low substitution degree) Hydroxypropyl cellulose, crystalline cellulose as an excipient, and this and a lubricant are mixed and tableted), and the disclosed production method and the like can be mentioned.
本発明における「口腔内速崩壊製剤」とは、製剤を服用するために水を摂取することなく、口腔内で主として唾液により６０秒以内に崩壊する製剤を意味し、通常、４０秒以内、好ましくは３５秒以内で崩壊する。 In the present invention, the “orally disintegrating preparation in the oral cavity” means a preparation that disintegrates within 60 seconds mainly by saliva in the oral cavity without ingesting water for taking the preparation, and usually within 40 seconds, preferably Collapses within 35 seconds.
かくして得られる本発明の固形製剤は、口腔内で薬物に由来する不快な味を感じさせることなく、消化管内での溶出性もよく、日本薬局方第１５改正に記載の溶出試験（３７℃、溶媒：溶出Ｉ液、II液およびマッキュルベイン（ＭｃＩｌｖａｉｎｅ）緩衝液（ｐＨ２〜９）、第２法（５０回転／分））において、速溶性を示すものである。なお、粒状製剤においては製剤の特性に応じて第１法（５０回転／分）においても速溶性を示す。 The solid preparation of the present invention thus obtained has good dissolution in the digestive tract without causing an unpleasant taste derived from the drug in the oral cavity, and the dissolution test described in the Japanese Pharmacopoeia 15th revision (37 ° C., Solvent: Eluent I, II and McIlvaine buffer (pH 2-9), second method (50 rotations / min)) exhibit fast solubility. In addition, the granular preparation exhibits fast solubility in the first method (50 rotations / minute) according to the characteristics of the preparation.
以下に、実施例を挙げて本発明をさらに詳しく説明するが、本発明はこれらに限定されない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
尚、以下の実施例および比較例において、クエン酸モサプリド・２水和物とは、（±）４−アミノ−５−クロロ−２−エトキシ−Ｎ−[[４−（４−フルオロベンジル）−２−モルホリニル]メチル]ベンズアミド クエン酸塩・２水和物であって、大日本住友製薬（株）のものを使用する（平均粒子径約８μｍ）。 In the following Examples and Comparative Examples, mosapride citrate dihydrate is (±) 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl)- 2-Morpholinyl] methyl] benzamide citrate dihydrate, used by Dainippon Sumitomo Pharma Co., Ltd. (average particle size of about 8 μm).
また、ファモチジンとは、Ｎ−スルファモイル−３−（２−グアニジノ−チアゾール−４−イル−メチルチオ）−プロピオンアミジンであって、三洋化学研究所（株）のものを使用する（平均粒子径約１４μｍ）。 Famotidine is N-sulfamoyl-3- (2-guanidino-thiazol-4-yl-methylthio) -propionamidine, which is used by Sanyo Chemical Research Co., Ltd. (average particle size of about 14 μm). ).
本発明で使用するポリソルベート80は、日本油脂株式会社製の日局ポリソルベート80（HX）を使用した。タルクは、林化成株式会社製のものを、ステアリン酸マグネシウムは、太平化学産業株式会社製のものを、クロスカルメロースナトリウムは、FMC BioPolymer社製のAc-Di-Solを、低置換度ヒドロキシプロピルセルロース（LH-21）は、信越化学工業株式会社製のものを、メタクリル酸コポリマーLDは、三洋化成工業株式会社製のポリキッドPA-30Sを使用した。軽質無水ケイ酸は、日本アエロジル株式会社製のアエロジール200を、コーンスターチは、日本食品化工株式会社製のコーンスターチ(XX16)Wを、Ｄ−マンニトールは、ロケット社製のPEARLITOLを使用した。フマル酸ステアリルナトリウムは、JRS pharma社製のPRUVを使用した。 As the polysorbate 80 used in the present invention, JP Polysorbate 80 (HX) manufactured by NOF Corporation was used. Talc is manufactured by Hayashi Kasei Co., Ltd., magnesium stearate is manufactured by Taihei Chemical Industrial Co., Ltd., croscarmellose sodium is Ac-Di-Sol manufactured by FMC BioPolymer, low-substituted hydroxypropyl Cellulose (LH-21) was manufactured by Shin-Etsu Chemical Co., Ltd., and methacrylic acid copolymer LD was Polykid PA-30S manufactured by Sanyo Chemical Industries. The light silicic acid used was Aerosil 200 manufactured by Nippon Aerosil Co., Ltd., the corn starch used was Corn Starch (XX16) W manufactured by Nippon Shokuhin Kako Co., Ltd., and D-mannitol used PEARLITOL manufactured by Rocket. For sodium stearyl fumarate, PRUV manufactured by JRS pharma was used.
実施例１
下記仕込み量に従って、被覆コーティング分散液を調製した。即ち、精製水（５６７ｇ）にポリソルベート８０を加え、十分に混和させた後、タルク、クロスカルメロースナトリウムを加え、十分に攪拌した（第１液）。これとは別に、水酸化ナトリウムを精製水（６７．６５ｇ）に溶解させた溶液を、メタクリル酸コポリマーＬＤに徐々に加え、攪拌した（第２液）。第１液に第２液を加え懸濁させ、１７７μｍ開口径のメッシュ網で篩過し、被覆コーティング分散液とした。
Example 1
A coating coating dispersion was prepared according to the following charge amount. That is, after adding polysorbate 80 to purified water (567 g) and mixing thoroughly, talc and croscarmellose sodium were added and stirred sufficiently (first liquid). Separately, a solution obtained by dissolving sodium hydroxide in purified water (67.65 g) was gradually added to the methacrylic acid copolymer LD and stirred (second liquid). The second liquid was added to the first liquid, suspended, and sieved through a mesh screen having an opening diameter of 177 μm to obtain a coating coating dispersion.
クエン酸モサプリド・２水和物３４６．５ｇと軽質無水ケイ酸 ３．５ｇを５００μｍ開口径のメッシュ網で篩過してポリエチレン袋内で十分に混合し、薬物含有組成物を調製後、強制循環装置付ワースター型流動層造粒機（改良ワースター型流動層造粒機、ＭＰ−０１ ＳＰＣ），株式会社パウレック製）に入れ、上記の被覆コーティング分散液を噴霧した。噴霧時は給気温度を約８０〜９０℃、排気温度を約２６〜３０℃に保ち、ボトムスプレーで噴霧液流量１０〜１２ｇ／ｍｉｎ、スプレーエア流量８０Ｌ／ｍｉｎ、スプレーエアー圧力０．２〜０．３ＭＰａ、サイドエアー圧力０．２〜０．２５ＭＰａ、給気風量約０．３０〜０．５５ｍ３／ｍｉｎで製造を行った。被覆コーティング分散液の噴霧量が約１３０６ｇの時点でコーティングを終了し、排気温度が４２℃になるまで乾燥した。得られた粒子を３２メッシュ（目開き５００μｍ）の篩で篩過し、平均粒子径が約９８μｍの薬物含有粒子を得た。 Silane mosapride dihydrate 346.5g and light anhydrous silicic acid 3.5g are sifted through a mesh screen of 500μm opening diameter and mixed well in a polyethylene bag to prepare a drug-containing composition, followed by forced circulation It put into the Wurster type fluidized-bed granulator with an apparatus (Improved Wurster type fluidized-bed granulator, MP-01 SPC, the product made from POWREC Co., Ltd.), and sprayed said coating coating dispersion liquid. During spraying, the supply air temperature is maintained at about 80 to 90 ° C., the exhaust temperature is maintained at about 26 to 30 ° C., the spray liquid flow rate is 10 to 12 g / min, the spray air flow rate is 80 L / min, and the spray air pressure is 0.2 to 0.2 ° C. Manufacture was performed at 0.3 MPa, a side air pressure of 0.2 to 0.25 MPa, and a supply air volume of about 0.30 to 0.55 m 3 / min. When the spray amount of the coating coating dispersion was about 1306 g, the coating was completed and the coating was dried until the exhaust temperature reached 42 ° C. The obtained particles were sieved with a sieve of 32 mesh (aperture 500 μm) to obtain drug-containing particles having an average particle diameter of about 98 μm.
実施例２
実施例１と同様にして、下記表２の仕込み量に記載の被覆コーティング分散液を調製した。得られた被覆コーティング分散液を用いて、実施例１と同様にして、薬物含有粒子を製造した(平均粒子径 約７９μｍ)。なお、コーティングに使用した液量は、表２に示すとおりである。
Example 2
In the same manner as in Example 1, coating coating dispersions described in Table 2 below were prepared. Using the resulting coating coating dispersion, drug-containing particles were produced in the same manner as in Example 1 (average particle size of about 79 μm). The amount of liquid used for coating is as shown in Table 2.
実施例３〜４
下記表３に示す仕込み量で、実施例１および２で各々得られた薬物含有粒子を、D-マンニトール、コーンスターチ、およびフマル酸ステアリルナトリウムと混合し、打錠圧12kNで打錠し、１錠重量１５０ｍｇ、直径７．５ｍｍの錠剤を製造した。
Examples 3-4
In the amounts shown in Table 3 below, the drug-containing particles obtained in Examples 1 and 2 were mixed with D-mannitol, corn starch, and sodium stearyl fumarate, and tableted with a tableting pressure of 12 kN. A tablet having a weight of 150 mg and a diameter of 7.5 mm was produced.
実施例５
ファモチジン３４６．５ｇと軽質無水ケイ酸 ３．５ｇを５００μｍ開口径のメッシュ網で篩過してポリエチレン袋内で十分に混合し、薬物含有組成物を調製後、実施例１の被覆コーティング分散液を用いて、実施例１と同様にして、平均粒子径が約１６５μｍの薬物含有粒子を得た。
Example 5
346.5 g of famotidine and 3.5 g of light anhydrous silicic acid are sieved through a mesh network having an opening diameter of 500 μm and thoroughly mixed in a polyethylene bag to prepare a drug-containing composition, and then the coating coating dispersion of Example 1 is prepared. In the same manner as in Example 1, drug-containing particles having an average particle size of about 165 μm were obtained.
実施例６
下記表４に示す仕込み量で、実施例５で得られた薬物含有粒子を、D-マンニトール、コーンスターチ、およびフマル酸ステアリルナトリウムと混合し、打錠圧12kNで打錠し、１錠重量１５０ｍｇ、直径７．５ｍｍの錠剤を製造した。
Example 6
In the amount shown in Table 4 below, the drug-containing particles obtained in Example 5 were mixed with D-mannitol, corn starch, and sodium stearyl fumarate, and tableted with a tableting pressure of 12 kN. Tablets with a diameter of 7.5 mm were produced.
比較例１
下記表５に記載の仕込み量に従って、被覆コーティング分散液を調製した。即ち、精製水（１８８．５ｇ）にポリソルベート８０を加え、十分に混和させた後、メタクリル酸コポリマーＬＤに徐々に加え、攪拌し、１７７μｍ開口径のメッシュ網で篩過し、被覆コーティング分散液とした。
Comparative Example 1
A coating coating dispersion was prepared according to the charge amounts listed in Table 5 below. That is, after adding polysorbate 80 to purified water (188.5 g) and mixing well, it is gradually added to methacrylic acid copolymer LD, stirred, and sieved through a mesh network having an opening diameter of 177 μm, did.
その後、クエン酸モサプリド・２水和物３４６．５ｇと軽質無水ケイ酸 ３．５ｇを５００μｍ開口径のメッシュ網で篩過してポリエチレン袋内で十分に混合し、薬物含有組成物を調製後、得られた被覆コーティング分散液を用いて実施例１と同様にして薬物含有粒子を製造した（平均粒子径：約１０４μｍ）。なお、コーティングに使用した液量は、表５に示すとおりである。 Thereafter, 346.5 g of mosapride citrate dihydrate and 3.5 g of light anhydrous silicic acid are sieved through a mesh network having an opening diameter of 500 μm and thoroughly mixed in a polyethylene bag to prepare a drug-containing composition. Using the obtained coating coating dispersion, drug-containing particles were produced in the same manner as in Example 1 (average particle size: about 104 μm). The amount of liquid used for coating is as shown in Table 5.
比較例２および３
実施例１と同様にして下記表６に記載の被覆コーティング分散液を調製した。該被覆コーティング分散液を用いて、実施例１と同様にして、薬物含有粒子を製造した(平均粒子径：比較例２（約１４６μｍ）、比較例３（約５３μｍ）)。なお、コーティングに使用した液量は、表６に示すとおりであり、この粒子は、被覆組成物にタルクまたはクロスカルメロースナトリウムが配合されていない点において、本発明とは区別される。
Comparative Examples 2 and 3
In the same manner as in Example 1, the coating coating dispersion described in Table 6 below was prepared. Using the coating coating dispersion, drug-containing particles were produced in the same manner as in Example 1 (average particle size: Comparative Example 2 (about 146 μm), Comparative Example 3 (about 53 μm)). The amount of liquid used for coating is as shown in Table 6. This particle is distinguished from the present invention in that talc or croscarmellose sodium is not blended in the coating composition.
比較例４〜６
下記表７に示す仕込み量で、比較例１〜３で各々得られた薬物含有粒子を、D-マンニトール、コーンスターチ、およびフマル酸ステアリルナトリウムと混合し、打錠圧12kNで打錠し、１錠重量１５０ｍｇ、直径７．５ｍｍの錠剤を製造した。
Comparative Examples 4-6
In the amount shown in Table 7 below, the drug-containing particles obtained in Comparative Examples 1 to 3 were mixed with D-mannitol, corn starch, and sodium stearyl fumarate, and tableted with a tableting pressure of 12 kN. A tablet having a weight of 150 mg and a diameter of 7.5 mm was produced.
実施例７〜１０
実施例１と同様にして、下記表８の仕込み量に記載の被覆コーティング分散液を調製した。得られた被覆コーティング分散液を用いて、実施例１と同様にして、薬物含有粒子を製造した(平均粒子径：実施例７（約９０μｍ）、実施例８（約８４μｍ）、実施例９（約４７μｍ）、実施例１０（約６０μｍ）)。なお、コーティングに使用した液量は、表８に示すとおりである。
Examples 7-10
In the same manner as in Example 1, coating coating dispersions described in Table 8 below were prepared. Using the obtained coating coating dispersion, drug-containing particles were produced in the same manner as in Example 1 (average particle size: Example 7 (about 90 μm), Example 8 (about 84 μm), Example 9 ( About 47 μm), Example 10 (about 60 μm)). The amount of liquid used for coating is as shown in Table 8.
実施例１１〜１４
下記表９に示す仕込み量で、実施例７〜１０で各々得られた薬物含有粒子を、D-マンニトール、コーンスターチ、およびフマル酸ステアリルナトリウムと混合し、打錠圧12kNで打錠し、１錠重量１５０ｍｇ、直径７．５ｍｍの錠剤を製造した。
Examples 11-14
The drug-containing particles obtained in Examples 7 to 10 were mixed with D-mannitol, corn starch, and sodium stearyl fumarate in the amounts shown in Table 9 below, and tableted at a tableting pressure of 12 kN. A tablet having a weight of 150 mg and a diameter of 7.5 mm was produced.
実施例１５
実施例１と同様にして、下記表１０の仕込み量に記載の被覆コーティング分散液を調製した。得られた被覆コーティング分散液を用いて、実施例１と同様にして、薬物含有粒子を製造した(平均粒子径：約９８μｍ)。なお、コーティングに使用した液量は、表１０に示すとおりである。
Example 15
In the same manner as in Example 1, coating coating dispersions described in Table 10 below were prepared. Using the resulting coating coating dispersion, drug-containing particles were produced in the same manner as in Example 1 (average particle size: about 98 μm). The amount of liquid used for coating is as shown in Table 10.
実施例１６
下記表１１に示す仕込み量で、実施例１５で得られた薬物含有粒子を、D-マンニトール、コーンスターチ、およびフマル酸ステアリルナトリウムと混合し、打錠圧12kNで打錠し、１錠重量１５０ｍｇ、直径７．５ｍｍの錠剤を製造した。
Example 16
The drug-containing particles obtained in Example 15 were mixed with D-mannitol, corn starch, and sodium stearyl fumarate in the amounts shown in Table 11 below, and tableted at a tableting pressure of 12 kN. Tablets with a diameter of 7.5 mm were produced.
試験例１
各実施例及び各比較例で製造された薬物含有粒子および錠剤の特性を調べ、表１２及び表１３の結果を得た。なお、薬物含有粒子については不快な味の遮蔽度を、錠剤については、不快な味の遮蔽度、服用感、および溶出試験をおこなった。表１２は、各実施例及び各比較例で製造された薬物含有粒子の不快な味の遮蔽度、錠剤の不快な味の遮蔽度および服用感、表１３は、日本薬局方第１５改正に記載の溶出Ｉ液、マッキュルベイン（ＭｃＩｌｖａｉｎｅ）緩衝液（ｐＨ５．０）、溶出II液での錠剤の溶出試験の結果を示す。なお、各溶出試験については、日本薬局方第１５改正の記載に従って行った。
Test example 1
The characteristics of the drug-containing particles and tablets produced in each Example and each Comparative Example were examined, and the results shown in Table 12 and Table 13 were obtained. The drug-containing particles were subjected to an unpleasant taste shielding degree, and the tablets were subjected to an unpleasant taste shielding degree, a feeling of taking, and a dissolution test. Table 12 shows the unpleasant taste shielding degree of the drug-containing particles produced in each Example and each Comparative Example, the unpleasant taste shielding degree and feeling of taking of the tablet, and Table 13 describes the 15th revision of the Japanese Pharmacopoeia. The results of the dissolution test of the tablet with the dissolution solution I, McIlvaine buffer solution (pH 5.0) and dissolution solution II are shown. In addition, about each elution test, it carried out according to the description of Japanese Pharmacopoeia 15th revision.
このように、本願発明の薬物含有粒子は、不快な味をマスキングし、さらに、該粒子を含む製剤は、粒子同士の凝集を回避し、膜成分の溶解を促進できることにより、酸性〜中性領域において優れた溶出性を示した。 As described above, the drug-containing particles of the present invention mask an unpleasant taste, and furthermore, the preparation containing the particles can avoid the aggregation of the particles and promote the dissolution of the membrane component, thereby causing an acidic to neutral region. Excellent elution was exhibited.
本発明の薬物含有粒子は、薬物の苦味等の不快な味の低減を図ることができ、さらに、該粒子を含む製剤は不快な味のマスキングおよび消化管内での速溶性を実現することができる。 The drug-containing particles of the present invention can reduce an unpleasant taste such as a bitter taste of the drug, and the preparation containing the particles can realize an unpleasant taste masking and a fast solubility in the digestive tract. .
Claims (24)
（１）腸溶性高分子、
（２）崩壊剤および
（３）凝集防止剤。 Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components:
(1) Enteric polymer,
(2) disintegrant and (3) anti-agglomeration agent.
（１）メタクリル酸コポリマー、
（２）メタクリル酸コポリマー１００重量部に対して、３５〜２６０重量部の割合のタルクおよび
（３）メタクリル酸コポリマー１００重量部に対して、５〜４０重量部の割合のクロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロース或いはこれらの混合物。 Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components in the following proportions:
(1) methacrylic acid copolymer,
(2) 35 to 260 parts by weight of talc with respect to 100 parts by weight of methacrylic acid copolymer and (3) 5 to 40 parts by weight of croscarmellose sodium or low with respect to 100 parts by weight of methacrylic acid copolymer Degree of substitution hydroxypropylcellulose or a mixture thereof.
（１）メタクリル酸コポリマー、
（２）メタクリル酸コポリマー１００重量部に対して、０．１〜１５重量部の割合のステアリン酸またはその金属塩および
（３）メタクリル酸コポリマー１００重量部に対して、５〜４０重量部の割合のクロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロース或いはこれらの混合物。 Drug-containing particles obtained by coating and granulating a drug-containing composition containing a drug having an unpleasant taste with a coating composition containing the following components in the following proportions:
(1) methacrylic acid copolymer,
(2) 0.1 to 15 parts by weight of stearic acid or a metal salt thereof with respect to 100 parts by weight of methacrylic acid copolymer and (3) 5 to 40 parts by weight with respect to 100 parts by weight of methacrylic acid copolymer Croscarmellose sodium or low substituted hydroxypropylcellulose or a mixture thereof.
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| JP7182356B2 (en) | 2017-07-05 | 2022-12-02 | 日本ケミファ株式会社 | Orally disintegrating tablet and manufacturing method thereof |
| WO2019039420A1 (en) | 2017-08-21 | 2019-02-28 | ニプロ株式会社 | Pharmaceutical composition particles, orally disintegrating preparation containing same, and method for producing pharmaceutical composition particles |
| WO2019131891A1 (en) * | 2017-12-28 | 2019-07-04 | 大日本住友製薬株式会社 | Bitterness-masked drug-containing particles and formulation containing said drug-containing particles |
| JP2020105173A (en) * | 2018-12-27 | 2020-07-09 | 日本ケミファ株式会社 | Orally disintegrating tablet containing two or more drugs and method for producing the same |
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