JP4439499B2 - Amlodipine-containing particles and orally disintegrating tablets comprising the same - Google Patents
Amlodipine-containing particles and orally disintegrating tablets comprising the same Download PDFInfo
- Publication number
- JP4439499B2 JP4439499B2 JP2006209050A JP2006209050A JP4439499B2 JP 4439499 B2 JP4439499 B2 JP 4439499B2 JP 2006209050 A JP2006209050 A JP 2006209050A JP 2006209050 A JP2006209050 A JP 2006209050A JP 4439499 B2 JP4439499 B2 JP 4439499B2
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- Prior art keywords
- amlodipine
- orally disintegrating
- disintegrating tablet
- containing particles
- weight
- 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.)
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Description
本発明はアムロジピンまたはその薬学上許容される塩(以下、アムロジピン量の測定などの特定量やアムロジピン・ベシル酸塩等の特定の塩を意味する場合以外はアムロジピンまたはその薬学上許容される塩をアムロジピンと総称する)を含有し、アムロジピンの苦味を抑制した薬物含有粒子に関する。また、この粒子を含有する、実用的な硬度を有し、口腔内崩壊時間が短く、バイオアベイラビリティを損なうことなく、苦味・ザラつきを感じない等の優れた特性を有する服用感の良好なアムロジピン口腔内崩壊錠に関する。 The present invention relates to amlodipine or a pharmaceutically acceptable salt thereof (unless it means a specific amount such as measurement of amlodipine or a specific salt such as amlodipine besylate) And a drug-containing particle that suppresses the bitter taste of amlodipine. In addition, this particle contains amlodipine with a practical hardness, a short disintegration time in the oral cavity, an excellent characteristic such as no bitterness or roughness, without impairing bioavailability, etc. It relates to an orally disintegrating tablet.
ジヒドロピリジン系Ca拮抗薬であるアムロジピンは充分かつ恒常的な血管拡張作用と頻脈をきたし難い性質から、降圧療法の中心的な役割を果たしている。また、アムロジピンは独特の苦味を有することが知られている。
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。
しかしながら、苦味を有する薬物を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、薬物の苦味が口腔内に暴露され、服用に困難を伴う。これを解決するために、口腔内崩壊錠などの水なしで服用する経口固形製剤における、薬物の苦味を抑制する方法が種々検討されている。
Amlodipine, which is a dihydropyridine Ca antagonist, plays a central role in antihypertensive therapy because of its sufficient and constant vasodilatory effect and the property of not causing tachycardia. Amlodipine is also known to have a unique bitter taste.
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.
However, when a drug having a bitter taste is produced as an orally disintegrating tablet, the bitter taste of the drug is exposed to the oral cavity due to the nature of the orally disintegrating tablet, which is taken by dissolving or dissolving the tablet with saliva moisture in the oral cavity. It is difficult to take. In order to solve this, various methods for suppressing the bitter taste of drugs in oral solid preparations taken without water such as orally disintegrating tablets have been studied.
例えば、特許文献1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。
特許文献2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及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。
一方で、特許文献3では、平均粒子径100μm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。
特許文献4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。
上記特許文献1〜4には製剤中の薬物含有粒子の含有量は明示されておらず、実施例として記載されている製剤について計算するとそれぞれ27〜86%、31〜50%、45〜61%、33%といずれも高い比率で薬物含有粒子を含有していた。本発明者らはアムロジピン含有粒子を用いた場合、このようにアムロジピン含有粒子の製剤中含有量が多いと通常使用される硬度の錠剤を作製すると口腔内崩壊時間が長くなってしまうという課題を見出した。このように特許文献1〜4の製剤は、アムロジピンに応用した場合、硬度と口腔内崩壊性を両立した口腔内崩壊錠を製造することは困難であった。
また、薬物含有粒子の粒子径について、特許文献2では実施例に210〜290μmであったことが記載されているのみであり、特許文献3については具体的な記載はなく本発明者らが追試すると210〜290μm前後となり口腔内崩壊錠とした場合に服用時にザラツキを感じてしまい服用に困難が生じるという課題を本発明者らは見出した。
また、特許文献4の方法をアムロジピンに適用したところ、被覆操作中にエタノールにアムロジピンが溶解することで粒子表面にアムロジピンが多く存在してしまい、苦味を隠蔽することができないという問題点を本発明者らは見出した。
このように、苦味を隠蔽したアムロジピン含有口腔内崩壊錠を製造する場合において、従来技術では以上のような問題点があった。
また、これら文献にはアムロジピン含有粒子を含有する口腔内崩壊錠であって、当該口腔内崩壊錠及び薬物含有粒子が5錠分を注射筒正倒立法で試験した際に37℃、10mlの水におけるアムロジピンの溶出量が30秒で800μg/mL以下であり、当該アムロジピン含有粒子がアムロジピンまたはその薬学上許容される塩を含有し、かつ当該アムロジピン含有粒子の平均粒子径が50〜200μmである口腔内崩壊錠の具体的記載はない。
For example, Patent Document 1 discloses an inner coating layer containing a water-soluble polymer in the core containing a drug, a low-substituted hydroxypropyl cellulose and a microcrystalline cellulose as a pharmaceutical dosage form that rapidly releases and conceals the taste, Discloses a dosage form having an outer coating layer of a polymer that is insoluble in saliva.
In Patent Document 2, 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.
On the other hand, in Patent Document 3, a chewable tablet is produced by tableting a granulated product obtained by granulating drug substance particles 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.
Patent Document 4 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.
In the above Patent Documents 1 to 4, the content of the drug-containing particles in the preparation is not clearly described, and 27 to 86%, 31 to 50%, and 45 to 61% are calculated for the preparations described as examples. , 33% contained drug-containing particles at a high ratio. When the amlodipine-containing particles are used, the present inventors have found a problem that when the amlodipine-containing particles are contained in a large amount in the preparation as described above, a tablet having a hardness that is usually used results in a long oral disintegration time. It was. As described above, when the preparations of Patent Documents 1 to 4 are applied to amlodipine, it has been difficult to produce an orally disintegrating tablet having both hardness and orally disintegrating properties.
In addition, with regard to the particle size of the drug-containing particles, Patent Document 2 only describes that it was 210 to 290 μm in the Examples, and Patent Document 3 has no specific description, and the inventors have made additional tests. Then, the present inventors have found a problem that when the tablet is orally disintegrating and becomes an orally disintegrating tablet, it feels rough at the time of taking, resulting in difficulty in taking.
Further, when the method of Patent Document 4 is applied to amlodipine, the amlodipine is dissolved in ethanol during the coating operation, so that amlodipine is present on the particle surface, and the bitterness cannot be masked. They found out.
Thus, when manufacturing the amlodipine containing orally disintegrating tablet which concealed the bitter taste, there existed the above problems in the prior art.
In addition, these documents are orally disintegrating tablets containing amlodipine-containing particles, and when the orally disintegrating tablets and drug-containing particles are tested for 5 tablets by a syringe upside-down method at 37 ° C., 10 ml of water. The amlodipine elution amount is 800 μg / mL or less in 30 seconds, the amlodipine-containing particles contain amlodipine or a pharmaceutically acceptable salt thereof, and the average particle size of the amlodipine-containing particles is 50 to 200 μm There is no specific description of the internally disintegrating tablet.
本発明が解決しようとする課題は、アムロジピンまたはその薬学上許容される塩を含有する口腔内崩壊錠において、実用的な硬度を有し、口腔内崩壊時間が短く、服用時に苦味やザラつき等の不快感を感じず、バイオアベイラビリティを損なわない等の特性を有するアムロジピン口腔内崩壊錠を提供することを目的とする。 The problem to be solved by the present invention is an orally disintegrating tablet containing amlodipine or a pharmaceutically acceptable salt thereof, which has practical hardness, has a short oral disintegration time, and has a bitter taste or roughness when taken. It is an object of the present invention to provide an amlodipine orally disintegrating tablet having such characteristics as not feeling uncomfortable and not impairing bioavailability.
本発明者らは、苦味を有するアムロジピンを口腔内崩壊錠に適用すべく検討したところ、アムロジピン原薬は苦味が著しく、香料、甘味剤等の添加剤等による官能的な苦味マスキング方法では十分な苦味マスキングの効果は得られなかった。また、前記以外の方法として連続層形成担体により原薬または原薬含有組成物を被覆する方法が知られているが、有機溶媒系での連続層形成担体・原薬の溶解/分散液を用いることは作業者や周辺環境への影響などから好ましくない。さらに、前記特許文献4の実施例のようにエタノール90%溶液での噴霧をアムロジピンに適用すると、同文献の実施例で使用するエタノールに難溶なファモチジンとは異なり、エタノールに易溶なアムロジピンは噴霧中にエチルセルロース皮膜内に浸出してしまい、苦味抑制が困難であった。
このようにアムロジピンの苦味抑制は公知の製剤技術では達成できなかった。
The present inventors studied to apply amlodipine having a bitter taste to orally disintegrating tablets, and the amlodipine drug substance has a significant bitter taste, and a functional bitterness masking method using additives such as a fragrance and a sweetener is sufficient. The effect of bitterness masking was not obtained. Further, as a method other than the above, a method of coating a drug substance or a drug substance-containing composition with a continuous layer-forming carrier is known. This is not preferable because of the influence on the worker and the surrounding environment. Further, when spraying with a 90% ethanol solution is applied to amlodipine as in the example of Patent Document 4, unlike famotidine which is hardly soluble in ethanol used in the example of the document, amlodipine which is easily soluble in ethanol is During spraying, it leached into the ethyl cellulose film, and it was difficult to suppress bitterness.
Thus, the suppression of the bitter taste of amlodipine could not be achieved by a known formulation technique.
本発明者らは、これらのことに鑑み、鋭意検討を行った結果、下記〔1〕〜〔22〕に記載する口腔内崩壊錠が、実用的な硬度を有し、口腔内崩壊時間が短く、苦味・ザラつき等の不快感を感じず、バイオアベイラビリティを損なわない等の優れた性質を有することを見出した。さらに、そのようなアムロジピン含有粒子は、好ましくはアムロジピンに水系コーティングを行うことで得られることを見出した。水系コーティングには、通常連続層形成担体を分散してコーティングするために界面活性剤を使用する。従って水系コーティングにより得られるアムロジピン含有粒子はアムロジピン、連続層形成担体及び界面活性剤を含有するという特徴を有する。 As a result of intensive studies in view of the above, the present inventors have found that the orally disintegrating tablets described in [1] to [22] below have practical hardness and a short oral disintegration time. The present inventors have found that it has excellent properties such as not feeling unpleasantness such as bitterness and roughness and not impairing bioavailability. Furthermore, it has been found that such amlodipine-containing particles are preferably obtained by subjecting amlodipine to an aqueous coating. In the aqueous coating, a surfactant is usually used to disperse and coat the continuous layer forming carrier. Therefore, the amlodipine-containing particles obtained by water-based coating are characterized by containing amlodipine, a continuous layer forming carrier and a surfactant.
すなわち、本発明は、以下のものに関する。
〔1〕 アムロジピン含有粒子を2〜25%(重量/重量)含有する口腔内崩壊錠であって、当該アムロジピン含有粒子が、アムロジピンまたはその薬学上許容される塩を、連続層形成担体を含有する組成物で被覆してなるものであり、該連続層形成担体が (1)腸溶性高分子単独であるか、あるいは(2)水溶性高分子、水不溶性高分子、胃溶性高分子、及び熱可塑性物質からなる群より選ばれる1種以上と腸溶性高分子である、口腔内崩壊錠。
〔2〕 アムロジピン含有粒子がさらに界面活性剤を含有する、〔1〕記載の口腔内崩壊錠。
〔3〕 アムロジピン含有粒子中の連続層形成担体の含有量が20〜50%(重量/重量)である、〔1〕又は〔2〕記載の口腔内崩壊錠。
〔4〕 アムロジピン含有粒子の被覆層が単層である、〔1〕〜〔3〕のいずれかに記載の口腔内崩壊錠。
〔5〕 アムロジピン含有粒子の含有量が3〜20%(重量/重量)である、〔1〕〜〔4〕のいずれかに記載の口腔内崩壊錠。
〔6〕 アムロジピン含有粒子の含有量が5〜15%(重量/重量)である、〔1〕〜〔4〕のいずれかに記載の口腔内崩壊錠。
〔7〕 アムロジピン含有粒子の平均粒子径が50〜200μmである、〔1〕〜〔6〕のいずれかに記載の口腔内崩壊錠。
〔8〕 連続層形成担体がアムロジピンまたはその薬学上許容される塩の含有量に対し、30〜100%(重量/重量)である、〔1〕〜〔7〕のいずれかに記載の口腔内崩壊錠。
〔9〕 アムロジピン含有粒子の平均粒子径が175μm以下である、〔1〕〜〔8〕のいずれかに記載の口腔内崩壊錠。
〔10〕 5錠の当該口腔内崩壊錠を注射筒正倒立法で試験した際に37℃、10mlの水におけるアムロジピンの溶出量が30秒で800μg/mL以下であり、かつ当該アムロジピン含有粒子の平均粒子径が50〜200μmである、〔1〕〜〔9〕のいずれかに記載の口腔内崩壊錠。
〔11〕 日局パドル法において、アムロジピン5mg相当量分の製剤が水900ml、回転数75rpmの条件下、30分で70%以上の溶出率を示す、〔1〕〜〔10〕のいずれかに記載の口腔内崩壊錠。
〔12〕 アムロジピンまたはその薬学上許容される塩が、ベシル酸アムロジピンである、〔1〕〜〔11〕のいずれかに記載の口腔内崩壊錠。
〔13〕 連続層形成担体中の腸溶性高分子の含有量が80%(重量/重量)以上である、〔1〕〜〔12〕のいずれかに記載の口腔内崩壊錠。
〔14〕 腸溶性高分子が腸溶性アクリル酸系共重合体である、〔1〕〜〔13〕のいずれかに記載の口腔内崩壊錠。
〔15〕 腸溶性高分子がメタクリル酸コポリマーLDである、〔1〕〜〔13〕のいずれかに記載の口腔内崩壊錠。
That is, the present invention relates to the following.
[1] An orally disintegrating tablet containing 2 to 25% (weight / weight) of amlodipine-containing particles, wherein the amlodipine-containing particles contain amlodipine or a pharmaceutically acceptable salt thereof and a continuous layer-forming carrier. The continuous layer-forming carrier is (1) an enteric polymer alone, or (2) a water-soluble polymer, a water-insoluble polymer, a gastric polymer, and a heat An orally disintegrating tablet which is an enteric polymer and at least one selected from the group consisting of plastic substances .
[2] Amlodipine-containing particles further contain a surfactant, [1] Symbol mounting oral disintegrating tablet.
[3] The orally disintegrating tablet according to [1] or [2] , wherein the content of the continuous layer-forming carrier in the amlodipine-containing particles is 20 to 50% (weight / weight).
[4] The orally disintegrating tablet according to any one of [1] to [3] , wherein the coating layer of the amlodipine-containing particles is a single layer.
[5] The orally disintegrating tablet according to any one of [1] to [4] , wherein the content of the amlodipine-containing particles is 3 to 20% (weight / weight).
[6] The orally disintegrating tablet according to any one of [1] to [4] , wherein the content of the amlodipine-containing particles is 5 to 15% (weight / weight).
[7] The orally disintegrating tablet according to any one of [1] to [6] , wherein the average particle size of the amlodipine-containing particles is 50 to 200 μm.
[8] The oral cavity according to any one of [1] to [7] , wherein the continuous layer-forming carrier is 30 to 100% (weight / weight) with respect to the content of amlodipine or a pharmaceutically acceptable salt thereof. Disintegrating tablets.
[9] The orally disintegrating tablet according to any one of [1] to [8] , wherein the average particle size of the amlodipine-containing particles is 175 μm or less.
[10] 37 ° C. when the orally disintegrating tablet of 5 tablets were tested in syringe positive inverted method, the eluted amount of amlodipine in 10ml of water of not more than 800 [mu] g / mL in 30 seconds, or One the amlodipine-containing particles The orally disintegrating tablet according to any one of [1] to [9], wherein the average particle size is 50 to 200 μm.
[11] In the JP paddle method, a formulation corresponding to 5 mg of amlodipine exhibits an elution rate of 70% or more in 30 minutes under the condition of 900 ml of water and 75 rpm, according to any one of [1] to [10] The orally disintegrating tablet described.
[12] The orally disintegrating tablet according to any one of [1] to [11], wherein the amlodipine or a pharmaceutically acceptable salt thereof is amlodipine besylate .
[13] The orally disintegrating tablet according to any one of [1] to [12], wherein the content of the enteric polymer in the continuous layer-forming carrier is 80% (weight / weight) or more .
[14] The orally disintegrating tablet according to any one of [1] to [13], wherein the enteric polymer is an enteric acrylic copolymer .
[15] The orally disintegrating tablet according to any one of [1] to [13], wherein the enteric polymer is methacrylic acid copolymer LD .
本発明によって、苦味を感じず、実用的な硬度を有し、口腔内崩壊時間が短く、服用時にザラつき等の異物感がなく、バイオアベイラビリティーの確保された等の優れた特性を有するアムロジピンの口腔内崩壊錠を提供することが可能である。これによって小児や高齢者等の嚥下能の低い患者及び脳卒中後遺症等の嚥下自体が困難な患者にとって易服用性となるだけではなく、腎機能障害患者、透析患者などの水分摂取が制限されている患者にとっては水を同時に摂取しなくても服用が可能になったり、多忙な社会生活を送る人々が手軽に携帯し、どのような場面においてもアムロジピンを容易に服用することが可能となった。 According to the present invention, amlodipine which has excellent characteristics such as no bitterness, practical hardness, short disintegration time in the oral cavity, no feeling of foreign matter such as roughness when taken, and ensuring bioavailability It is possible to provide an orally disintegrating tablet. This not only makes it easy to take for patients with low swallowing ability such as children and the elderly, and patients with difficulty in swallowing such as sequelae of stroke, but also restricts water intake in patients with renal impairment and dialysis patients. For patients, it became possible to take water without taking water at the same time, and people with busy social life could easily take it and take amlodipine easily in any situation.
以下、本発明につき、さらに詳しく説明する。
『アムロジピン』の化学名は2−(2−アミノエトキシメチル)−4−(2−クロルフェニル)−1,4−ジヒドロ−6−メチルピリジン−3,5−ジカルボン酸 3−エチル 5−メチルであり、この化合物は光学活性中心を有するため、(S)−(−)−体および(R)−(+)体が存在するが、本発明にはそれらのいずれかまたは混合物を用いることができる。好ましくは(S)−(−)−体およびラセミ体が用いられる。
アムロジピンの薬学上許容される塩としては、塩酸、臭化水素酸、硫酸、リン酸、酢酸、マレイン酸、フマル酸、乳酸、酒石酸、クエン酸、グルコン酸、コハク酸、サリチル酸、メタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸との塩が挙げられる。好ましくはベンゼンスルホン酸との塩、即ちベシル酸アムロジピンが挙げられる。
Hereinafter, the present invention will be described in more detail.
The chemical name of “amlodipine” is 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate 3-ethyl 5-methyl Yes, since this compound has an optically active center, (S)-(−)-and (R)-(+) isomers exist, and any or a mixture thereof can be used in the present invention. . Preferably, the (S)-(-)-isomer and the racemate are used.
Examples of pharmaceutically acceptable salts of amlodipine include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, succinic acid, salicylic acid, methanesulfonic acid, Examples thereof include salts with benzenesulfonic acid and toluenesulfonic acid. Preferred is a salt with benzenesulfonic acid, that is, amlodipine besylate.
本発明において『口腔内崩壊錠』とは、口腔内の唾液のみで90秒以内、好ましくは60秒以内、さらに好ましくは30秒以内に崩壊し、水を摂取することなく口腔内で崩壊させて服用が可能な錠剤を意味する。また、この『口腔内崩壊錠』は、錠剤のPTP取出し時において、割れ・欠けを生じない程度の錠剤硬度を有するものがよい。具体的には、7mm径の錠剤において、硬度が25 N以上、好ましくは30 N以上、さらに好ましくは35 N以上、最も好ましくは40 N以上である口腔内崩壊錠が挙げられる。さらに好ましくは、25℃相対湿度75%下1週間の条件で保存後の硬度が25 N以上、好ましくは30 N以上、さらに好ましくは35 N以上、最も好ましくは40 N以上である口腔内崩壊錠が挙げられる。 In the present invention, the “orally disintegrating tablet” means disintegrating within 90 seconds, preferably within 60 seconds, more preferably within 30 seconds with only saliva in the oral cavity, and disintegrating in the oral cavity without ingesting water. It means tablets that can be taken. The “orally disintegrating tablet” preferably has a tablet hardness that does not cause cracking or chipping when the tablet is taken out of the PTP. Specifically, an orally disintegrating tablet having a hardness of 25 N or more, preferably 30 N or more, more preferably 35 N or more, and most preferably 40 N or more in a 7 mm diameter tablet is exemplified. More preferably, the orally disintegrating tablet has a hardness of 25 N or more, preferably 30 N or more, more preferably 35 N or more, and most preferably 40 N or more after storage under the conditions of 25 ° C. and 75% relative humidity for 1 week. Is mentioned.
口腔内崩壊錠を製造する方法については特に限定することなく任意のものであってよい。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、及び非晶質糖類を打錠後加湿乾燥)、特開平08-291051号(薬物、水溶性結合剤及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、これらの文献に記載されている薬物に代えてアムロジピン含有粒子を本発明の比率で用いることで製造することができる。 The method for producing the orally disintegrating tablet is not particularly limited and may be any method. 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 (humidified and dried after tableting of drug, saccharide and amorphous saccharide), 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) Hydroxypropylcellulose, crystalline cellulose as excipient, and tableting with this and lubricants) include the disclosed production methods, and amlodipine-containing particles instead of the drugs described in these documents It can manufacture by using in the ratio of this invention.
また、使用する添加剤としては、医薬的に許容されるものであればよく、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、甘味剤、矯味剤、香料、流動化剤、着色剤、安定化剤などが挙げられる。賦形剤では、例えば、乳糖、白糖、ショ糖、果糖、フラクトオリゴ糖、ブドウ糖、マルトース、還元麦芽糖、粉糖、粉末飴、還元乳糖などの糖類、D−マンニトール、エリスリトール、D−ソルビトール、マルチトール、キシリトールなどの糖アルコール類、コーンスターチ、バレイショデンプン、コメデンプン、部分アルファ化デンプンなどのデンプン類などが挙げられる。崩壊剤としては、例えば、コーンスターチ、バレイショデンプン、コメデンプン、部分アルファ化デンプンなどのデンプン類、カルメロースカルシウム、クロスカルメロースナトリウム、カルメロース、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、クロスポビドン、低置換度ヒドロキシプロピルセルロースなどが挙げられる。結合剤としては、例えば、デンプン類、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ゼラチン、プルランなどが挙げられる。甘味剤では、例えば、アスパルテーム、スクラロース、サッカリンナトリウム、グリチルリチン酸二カリウム、ステビア、アセスルファムK、マルチトール等が挙げられる。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、ステアリン酸、タルク、ポリエチレングリコール、ショ糖脂肪酸エステルなどが挙げられる。流動化剤では、例えば軽質無水ケイ酸、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルクなどが挙げられる。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。 The additive used may be any pharmaceutically acceptable, for example, excipients, disintegrants, binders, lubricants, sweeteners, corrigents, fragrances, fluidizing agents, coloring. Agents, stabilizers and the like. Examples of the excipient include sugars such as lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered koji, reduced lactose, D-mannitol, erythritol, D-sorbitol, maltitol And sugar alcohols such as xylitol, starches such as corn starch, potato starch, rice starch, and partially pregelatinized starch. Examples of the disintegrant include starches such as corn starch, potato starch, rice starch, and partially pregelatinized starch, carmellose calcium, croscarmellose sodium, carmellose, carmellose sodium, carboxymethyl starch sodium, crospovidone, low substitution degree Examples thereof include hydroxypropylcellulose. Examples of the binder include starches, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pullulan and the like. Examples of the sweetener include aspartame, sucralose, sodium saccharin, dipotassium glycyrrhizinate, stevia, acesulfame K, maltitol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, sucrose fatty acid ester and the like. Examples of the fluidizing agent include light anhydrous silicic acid, stearic acid, magnesium stearate, calcium stearate, talc and the like. These additives are appropriately added in an appropriate amount by one or a combination of two or more.
好ましくは、例えばWO00/047233に記載の方法に準じて、即ち次の(1)−(5)いずれかの方法で得ることができる。 Preferably, it can be obtained, for example, according to the method described in WO00 / 047233, that is, by any of the following methods (1) to (5).
(1)アムロジピン含有粒子、水溶性賦形剤、および結合剤を含有する組成物を打錠する。
(2)アムロジピン含有粒子、水溶性賦形剤、およびデンプンを含有する組成物を打錠する。
(3)アムロジピン含有粒子、水溶性賦形剤、およびデンプンを含有する混合物を結合剤で造粒し、得られる造粒物を含有する組成物を打錠する。
(4)アムロジピン含有粒子、水溶性賦形剤、およびデンプンを含有する混合物をアルファ化デンプン溶液を結合剤として造粒し、得られる造粒物を含有する組成物を打錠する。
(5)水溶性賦形剤およびデンプンを含有する混合物をアルファ化デンプン溶液を結合剤として造粒して得られる造粒物、およびアムロジピン含有粒子を含む組成物を打錠する。
(1) Tablet a composition containing amlodipine-containing particles, a water-soluble excipient, and a binder.
(2) Tablet a composition containing amlodipine-containing particles, a water-soluble excipient, and starch.
(3) A mixture containing amlodipine-containing particles, a water-soluble excipient, and starch is granulated with a binder, and the resulting composition containing the granulated product is tableted.
(4) The mixture containing amlodipine-containing particles, water-soluble excipients and starch is granulated using the pregelatinized starch solution as a binder, and the resulting composition containing the granulated product is tableted.
(5) A granulated product obtained by granulating a mixture containing a water-soluble excipient and starch using a pregelatinized starch solution as a binder, and a composition containing amlodipine-containing particles are tableted.
ここで、『水溶性賦形剤』は、好ましくは溶解度が30mg/mL以上で、単独で不快な味を有さない、医薬的に許容されるものであればよく、例えば、糖類や糖アルコール類、甘味を有するアミノ酸等が挙げられる。好ましくは糖類では乳糖、ショ糖、フラクトオリゴ糖、ブドウ糖、パラチノース、マルトース、還元麦芽糖、粉糖、粉末飴、果糖、異性化乳糖、蜂蜜糖などが挙げられ、糖アルコールでは、D−ソルビトール、D−マンニトール、マルチトール、エリスリトール、キシリトールなどが挙げられ、甘味を有するアミノ酸ではグリシン、アラニン、スレオニンなどが挙げられる。その中でも乳糖、エリスリトール、及びD−マンニトールが好ましく、特にD−マンニトールが好ましい。 Here, the “water-soluble excipient” is preferably a pharmaceutically acceptable one having a solubility of 30 mg / mL or more and having no unpleasant taste alone. And amino acids having a sweet taste. Preferred sugars include lactose, sucrose, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powder koji, fructose, isomerized lactose, honey sugar and the like, and sugar alcohols include D-sorbitol, D- Mannitol, maltitol, erythritol, xylitol and the like can be mentioned. Examples of sweet amino acids include glycine, alanine and threonine. Among these, lactose, erythritol, and D-mannitol are preferable, and D-mannitol is particularly preferable.
『デンプン』としては、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプンなどの天然物またはそれらから得られるもの、あるいはそれらを水と共に常圧下もしくは加圧下で加温し部分的にアルファ化して乾燥した部分アルファ化デンプンなどが好ましい。 As "starch", natural products such as corn starch, potato starch, rice starch, wheat starch or the like, or those obtained from them, or warmed with water under normal pressure or under pressure, partially alphalated and dried Partially pregelatinized starch and the like are preferred.
ここで本発明における『結合剤』とは、医薬的に許容される溶媒に溶解した溶液が溶媒のみよりも粘着性を有し、溶媒を蒸発させたときに他の固体間に架橋を形成させることのできる物質で、粒子を複合化したり粒子に他の粒子を付着させたりすることのできる、医薬的に許容されるものであればよい。該『結合剤』としては例えば、デンプン、ポリビニルアルコール、ポリビニルピロリドン、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、メチルセルロース、結晶セルロース、ゼラチン、プルラン、アラビアゴム末、低置換度ヒドロキシプロピルセルロースなどが挙げられ、その中でも特にデンプンが好ましい。結合剤として用いられる『デンプン』は上記に挙げた、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプンなどの天然物またはそれらから得られるもの、あるいはそれらを水と共に常圧下もしくは加圧下で加温し部分的にアルファ化した部分アルファ化デンプンなどが挙げられる。結合剤として『デンプン』を用いる場合、結合液中のデンプンの一部あるいは全部をアルファ化したアルファ化デンプン溶液が好ましく、該アルファ化デンプン溶液は、上記『デンプン』を常温状態で水に分散させた後、温度管理下のもと攪拌しながら昇温させ、デンプンの一部もしくは全部をアルファ化することで調液される。このとき、結合液のデンプン濃度は0.05〜20%が好ましく、0.05%〜15%がより好ましく、0.1%〜15%がさらに好ましく、0.1〜10%が最も好ましい。また、結合液中のデンプンのアルファ化度については20%〜100%、好ましくは40〜100%さらに好ましくは50〜100%であるものを用いるのが良い。アルファ化デンプンはそのまま放置するともとのデンプンに戻ってしまうので、結合液は用時調製するのが好ましい。 Here, the “binder” in the present invention means that a solution dissolved in a pharmaceutically acceptable solvent is more sticky than the solvent alone, and forms a crosslink between other solids when the solvent is evaporated. Any pharmaceutically acceptable substance can be used as long as it is capable of complexing the particles and attaching other particles to the particles. Examples of the “binder” include starch, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, crystalline cellulose, gelatin, pullulan, gum arabic powder, low-substituted hydroxypropyl cellulose, and the like. Of these, starch is particularly preferable. “Starch” used as a binder is a natural product such as corn starch, potato starch, rice starch, wheat starch or the like obtained above, or those obtained from them, or warmed with water under normal pressure or pressure. Partially pregelatinized starch and the like may be mentioned. When “starch” is used as a binder, a pregelatinized starch solution in which part or all of the starch in the binding solution is pregelatinized is preferable, and the pregelatinized starch solution is obtained by dispersing the above “starch” in water at room temperature. After that, the mixture is heated by stirring under temperature control, and part or all of the starch is pregelatinized to prepare a liquid. At this time, the starch concentration of the binding solution is preferably 0.05 to 20%, more preferably 0.05% to 15%, further preferably 0.1% to 15%, and most preferably 0.1 to 10%. Moreover, it is good to use what is 20 to 100% about the pregelatinization degree of a starch in a binding liquid, Preferably it is 40 to 100%, More preferably, it is 50 to 100%. Since the pregelatinized starch returns to the original starch when left as it is, it is preferable to prepare the binding solution at the time of use.
本発明において、『連続層形成担体』とは、加熱溶融後冷却したり、溶媒などに溶解/分散後加温乾燥し、必要に応じて成膜工程を介する事により、その物質単独でフィルム状の連続層の形成が可能な固体である。例えば、水溶性高分子、水不溶性高分子、胃溶性高分子、腸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。また、フィルム状の連続層形成を容易 にし、連続層の柔軟性を得るために、適宜可塑剤を添加することができる。
連続層形成坦体を含有する組成物とは、上記連続層を形成する組成物であり、連続層形成坦体と添加物(例えば崩壊剤、可塑剤、賦形剤等が挙げられる)からなる。
In the present invention, the “continuous layer forming carrier” is a film formed of the substance alone by cooling after heating and melting, or by heating / drying after dissolving / dispersing in a solvent and the like, and through a film forming step as necessary. It is a solid capable of forming a continuous layer. Examples thereof include water-soluble polymers, water-insoluble polymers, gastric polymers, enteric polymers, and thermoplastic substances (wax-like substances). In addition, a plasticizer can be appropriately added in order to facilitate the formation of a film-like continuous layer and to obtain flexibility of the continuous layer.
The composition containing a continuous layer-forming carrier is a composition that forms the above-mentioned continuous layer, and consists of a continuous layer-forming carrier and additives (for example, disintegrating agents, plasticizers, excipients, etc.). .
『水溶性高分子』としては、特に限定されないが例として、アラビアゴム末、ゼラチン、プルラン、デキストリン、カルボキシメチルスターチナトリウム、アルギン酸ナトリウムなどの天然高分子類や多糖類とそれらの誘導体、カルメロース、カルメロースナトリウム、カルメロースカルシウム、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、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、メチルセルロース、カルボキシメチルセルロースなどのセルロース誘導体、ポリビニルピロリドン、ポリビニルアルコールなどの水溶性ビニル誘導体などが挙げられる。 Examples of the “water-soluble polymer” include, but are not limited to, natural polymers such as gum arabic powder, gelatin, pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, polysaccharides and their derivatives, carmellose, carme Examples thereof include cellulose derivatives such as sodium sodium, carmellose calcium, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and carboxymethylcellulose, and water-soluble vinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol.
『水不溶性高分子』としては、特に限定されないがエチルセルロース(例えばその分散液、商品名:アクアコート、FMC社製)、エチルメチルセルロース、エチルプロピルセルロース、イソプロピルセルロース、ブチルセルロース、ベンジルセルロース、シアノエチルセルロース等の水不溶性セルロースエーテル類、アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチル共重合体(例えば、商品名:オイドラギットRS、オイドラギットRS30D、オイドラギットRL、オイドラギットRL30D、レーム社製)、アクリル酸エチル・メタアクリル酸メチルコポリマー分散液(商品名:オイドラギットNE30D、レーム社製)等の水不溶性アクリル酸系共重合体などが挙げられる。 The “water-insoluble polymer” is not particularly limited, but ethyl cellulose (for example, a dispersion thereof, trade name: Aqua Coat, manufactured by FMC), ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose, benzyl cellulose, cyanoethyl cellulose, etc. Water-insoluble cellulose ethers, ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (for example, trade names: Eudragit RS, Eudragit RS30D, Eudragit RL, Eudragit RL30D, manufactured by Laem), acrylic And water-insoluble acrylic copolymers such as ethyl methacrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D, manufactured by Laem Co.).
『胃溶性高分子』としては、特に限定されないがポリビニルアセタール・ジエチルアミノアセテート(例えば、商品名:AEA「三共」、三共ライフテック社製)等のアミノアセタール類化合物、アミノアルキルメタクリレートコポリマーE(例えば、商品名:オイドラギットE、レーム社製)、それらの混合物等が挙げられる。 The “gastric polymer” is not particularly limited, but aminoacetal compounds such as polyvinyl acetal diethylaminoacetate (for example, trade name: AEA “Sankyo”, Sankyo Lifetech Co., Ltd.), aminoalkyl methacrylate copolymer E (for example, Product name: Eudragit E, manufactured by Rohm Co., Ltd.), and mixtures thereof.
『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エステル類、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、レーム社製、商品名:ポリキッドPA30、三洋化成社製、商品名:コリコートMAE30DP、武田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、レーム社製)、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、レーム社製)などの腸溶性アクリル酸系共重合体等が挙げられる。 “Enteric polymer” is not particularly limited, but enteric cellulose esters such as cellulose acetate propionate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, etc. Methacrylic acid copolymer LD (for example, trade name: Eudragit L30D-55, manufactured by Laem Co., Ltd., trade name: Polykid PA30, manufactured by Sanyo Kasei Co., Ltd., trade name: Kollicoat MAE30DP, manufactured by Takeda BASF) Methacrylic acid copolymer L (for example, product Name: Eudragit L, manufactured by Laem Co.), methacrylic acid copolymer S (for example, trade names: Eudragit S, Eudragit S100, Eudragit F) 30D, Rohm Co.) enteric acrylic acid copolymer, etc., and the like.
『熱可塑性物質』としてはワックス状物質が挙げられ、具体的には例えば、硬化ヒマシ油、硬化やし油、硬化ナタネ油、牛脂等の硬化油・固形油脂類、パラフィン、カルナウバロウ、ミツロウ、さらしミツロウ、パラフィン等のロウ状物質類、ステアリン酸、ラウリン酸、ミリスチン酸、パルミチン酸等の高級脂肪酸類、アセチルグリセリン脂肪酸エステル、グリセリン酸脂肪酸エステル、プロピレングリコール脂肪酸エステル、モノステアリン酸グリセリン等の脂肪酸エステル類、セチルアルコール、ステアリルアルコール等の高級アルコール類が挙げられる。
なかでも、被覆する場合においては、水不溶性高分子、胃溶性高分子、腸溶性高分子、熱可塑性物質などのすべてのpHで溶解しないかもしくはある特定のpH範囲以外では溶解しないような高分子が好ましい。その中でも、水不溶性高分子、胃溶性高分子および腸溶性高分子が好ましく、さらに好ましくは水不溶性高分子および腸溶性高分子が挙げられ、最も好ましくは腸溶性高分子が挙げられる。また、アムロジピン含有粒子の粒子制御を容易にするため、被覆に使用する液は粘度が上がらない水分散系で被覆操作を行うことのできる高分子が好ましい。好ましい水不溶性高分子としてはエチルセルロース(特にエチルセルロース水分散液(アクアコート(商品名)、固形分量:エチルセルロース26.1%、セタノール2.7%、ラウリル硫酸ナトリウム1.2%、FMC社))、酢酸ビニルポリマー(例えば、商品名:コリコートSR30D,BASFジャパン社製)が挙げられる。また、好ましい胃溶性高分子としてはアミノアルキルメタクリレートコポリマーE(例えば、商品名:オイドラギットE、レーム社製)が挙げられる。さらに、好ましい腸溶性高分子としては、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、レーム社製、商品名:ポリキッドPA30、ポリキッドPA30S、三洋化成社製、商品名:コリコートMAE30DP、武田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、レーム社製)が挙げられる。
また、腸溶性高分子を用いる場合には、溶出改善のために崩壊剤を入れることが好ましい。崩壊剤としては、医薬的に許容される添加剤でよく、好ましくは前記の崩壊剤が挙げられ、その中でもコーンスターチ、カルメロースナトリウム、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等が選ばれる。また、微粒子原薬にコーティングすることから、上記崩壊剤を微粉砕したものを用いる等ができる。
この場合、溶出が改善され尚且つ苦味隠蔽効果を十分に保つ崩壊剤の含有量は、連続層形成担体に対し重量/重量で10%〜50%、好ましくは15%〜45%、より好ましくは15〜40%、最も好ましくは20〜35%である。
Examples of the “thermoplastic material” include wax-like substances, such as hardened castor oil, hardened coconut oil, hardened rapeseed oil, beef fat and other hardened oils / solid fats, paraffin, carnauba wax, beeswax, bleached Waxy substances such as beeswax and paraffin, higher fatty acids such as stearic acid, lauric acid, myristic acid and palmitic acid, fatty acid esters such as acetyl glycerin fatty acid ester, glyceric acid fatty acid ester, propylene glycol fatty acid ester and glyceryl monostearate Higher alcohols such as cetyl alcohol and stearyl alcohol.
Among them, when coated, a polymer that does not dissolve at all pH, such as water-insoluble polymer, gastric polymer, enteric polymer, and thermoplastic substance, or does not dissolve outside a specific pH range. Is preferred. Among these, water-insoluble polymers, gastric polymers and enteric polymers are preferable, water-insoluble polymers and enteric polymers are more preferable, and enteric polymers are most preferable. In order to facilitate particle control of the amlodipine-containing particles, the liquid used for coating is preferably a polymer that can be coated in an aqueous dispersion that does not increase in viscosity. Preferred water-insoluble polymers include ethyl cellulose (particularly ethyl cellulose aqueous dispersion (Aquacoat (trade name), solid content: ethyl cellulose 26.1%, cetanol 2.7%, sodium lauryl sulfate 1.2%, FMC)), vinyl acetate polymer (for example, Product name: Kollicoat SR30D, manufactured by BASF Japan Ltd.). Further, as a preferable gastric soluble polymer, aminoalkyl methacrylate copolymer E (for example, trade name: Eudragit E, manufactured by Rohm Co., Ltd.) can be mentioned. Further, as a preferable enteric polymer, methacrylic acid copolymer LD (for example, trade name: Eudragit L30D-55, manufactured by Laem Co., Ltd., trade name: Polykid PA30, Polykid PA30S, manufactured by Sanyo Kasei Co., Ltd., trade name: Kollicoat MAE30DP, Takeda) BASF) and methacrylic acid copolymer L (for example, trade name: Eudragit L, manufactured by Laem Co.).
Moreover, when using enteric polymer | macromolecule, it is preferable to add a disintegrating agent for the elution improvement. The disintegrant may be a pharmaceutically acceptable additive, and preferably includes the disintegrants described above, among which corn starch, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium and the like are selected. In addition, since the fine particle drug substance is coated, a finely pulverized product of the disintegrant can be used.
In this case, the content of the disintegrant in which elution is improved and the bitter taste masking effect is sufficiently maintained is 10% to 50%, preferably 15% to 45%, more preferably 10% to 50% by weight / weight with respect to the continuous layer forming carrier. 15-40%, most preferably 20-35%.
本発明に用いられる水不溶性高分子、胃溶性高分子、腸溶性高分子には、適宜可塑剤の添加が好ましく、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等の日本薬局方及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。
噴霧乾燥する場合においても、これらの連続層形成担体を用いることができ、なかでも水不溶性高分子、胃溶性高分子、腸溶性高分子が好ましく、脱有機溶媒系で製造できることから、これらのラテックス水分散液がさらに好ましい。また、ラテックス水分散液の中では、アムロジピンを添加した場合にラテックスの凝集が起こりにくいことから、アクリル酸エチル・メタアクリル酸メチルコポリマー分散液(商品名:オイドラギットNE30D、レーム社製)、アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチル共重合体(例えば、商品名:オイドラギットRS、オイドラギットRS30D、レーム社製)が好ましい。
The water-insoluble polymer, gastric polymer, and enteric polymer used in the present invention are preferably appropriately added with a plasticizer. Examples of the plasticizer include triacetin, triethyl citrate, dibutyl sebacate, acetylated monoglyceride, Examples include those described in Japanese pharmacopoeia such as propylene glycol and polysorbate 80, and official standards such as pharmaceutical additive standards.
Even in the case of spray drying, these continuous layer-forming carriers can be used, and among them, water-insoluble polymers, gastric polymers and enteric polymers are preferable, and these latexes can be produced in a deorganic solvent system. An aqueous dispersion is more preferred. Also, in latex aqueous dispersions, when amlodipine is added, latex agglomeration is unlikely to occur. Therefore, ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D, manufactured by Rohm), acrylic acid Ethyl / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer (for example, trade name: Eudragit RS, Eudragit RS30D, manufactured by Laem Co.) is preferable.
また、溶出制御を好適に行う目的で、これらの連続層形成担体を1種類単独、もしくは数種類を混合などして用いてもよい。例えば水不溶性高分子および腸溶性高分子の混合、水不溶性高分子同士、腸溶性高分子同士の混合などが好ましいものとして挙げられる。水不溶性高分子、腸溶性高分子、またはそれらの混合物の連続層形成担体に占める割合としては、重量/重量で50%以上、好ましくは60%以上、より好ましくは70%以上、さらに好ましくは80%以上、最も好ましくは90%以上が挙げられる。 Further, for the purpose of suitably controlling the elution, these continuous layer forming carriers may be used alone or in combination of several kinds. For example, preferable examples include a mixture of a water-insoluble polymer and an enteric polymer, a mixture of water-insoluble polymers, and an enteric polymer. The proportion of the water-insoluble polymer, enteric polymer, or mixture thereof in the continuous layer forming carrier is 50% or more by weight / weight, preferably 60% or more, more preferably 70% or more, and still more preferably 80%. % Or more, and most preferably 90% or more.
本明細書において『平均粒子径』とは、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 this specification, “average particle diameter” means a cumulative 50% average particle diameter D50 (volume-based average particle diameter) in volume-based measurement of powder particles. 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.
本発明において、被覆開始時におけるアムロジピン原薬の平均粒子径の上限としては、平均粒子径150μm以下、好ましくは100μm以下、さらに好ましくは50μm以下、最も好ましくは30μm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。一方、アムロジピン原薬が0.3μmより小さい粒子が多いと苦味抑制のために必要な連続層形成担体の量が増加し、それに伴ってバイオアベイラビリティーが低下する。従って粒子径0.3μm以下の粒子が10%以下、好ましくは粒子径0.3μm以下の粒子が5%以下であることが好ましい。噴霧乾燥においては、連続層形成担体とアムロジピンとの溶解/分散液中でアムロジピンが分散状態で存在する場合、アムロジピン原薬の平均粒子径は120μm以下、好ましくは90μm以下さらに好ましくは40μm以下、さらに好ましくは30μm以下であることが好ましい。 In the present invention, the upper limit of the average particle size of the amlodipine drug substance at the start of coating is an average particle size of 150 μm or less, preferably 100 μm or less, more preferably 50 μm or less, and most preferably 30 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. On the other hand, if the amlodipine drug substance has many particles smaller than 0.3 μm, the amount of the continuous layer forming carrier necessary for bitterness suppression increases, and the bioavailability decreases accordingly. Accordingly, it is preferable that particles having a particle size of 0.3 μm or less are 10% or less, preferably particles having a particle size of 0.3 μm or less are 5% or less. In spray drying, when amlodipine is present in a dispersed state in a solution / dispersion of a continuous layer-forming carrier and amlodipine, the average particle size of the amlodipine drug substance is 120 μm or less, preferably 90 μm or less, more preferably 40 μm or less, The thickness is preferably 30 μm or less.
本発明のアムロジピン含有粒子は、アムロジピン原薬単独またはアムロジピン原薬と添加剤とを含有するアムロジピン含有組成物を連続層形成担体により被覆またはアムロジピン原薬単独またはアムロジピン原薬と添加剤を含有する連続層形成担体の溶液または分散液を噴霧乾燥して得ることができる。かかる添加剤としては、医薬的に許容されるものであればよく、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、流動化剤、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。特に被覆する場合には、流動化剤を含有することが好ましい。流動化剤としてはステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、ステアリン酸、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が挙げられる。これら流動化剤は、被覆する場合において過剰造粒防止や流動性改善といった粒子制御のために添加され、アムロジピン原薬に対し0.01%以上、好ましくは0.05%以上、さらに好ましくは0.1%以上適宜配合される。その中でも特に軽質無水ケイ酸、含水二酸化ケイ素が好ましく、その場合アムロジピン原薬に対し0.1%以上好ましくは0.15%以上、さらに好ましくは0.2%以上適宜配合される。また、これらの流動化剤は一種または二種以上を組み合わせて配合してもよい。アムロジピン含有組成物は公知の製剤工程によって得られるが、被覆する場合には、アムロジピン含有組成物を得る工程から被覆までを連続して実施できることから、混合、造粒などの工程によって得ることが好ましい。特に造粒する場合には、被覆に使用する液を使って造粒することが好ましい。 The amlodipine-containing particles of the present invention are coated with an amlodipine drug substance alone or an amlodipine drug substance and an additive by a continuous layer forming carrier, or amlodipine drug substance alone or an amlodipine drug substance and an additive continuously. It can be obtained by spray drying a solution or dispersion of the layer forming carrier. Such additives may be any pharmaceutically acceptable, for example, excipients, disintegrants, binders, lubricants, fluidizers, sweeteners, fragrances, stabilizers, plasticizers, Examples include coloring agent flavoring agents. These additives are appropriately added in an appropriate amount by one or a combination of two or more. In particular, when coating, it is preferable to contain a fluidizing agent. Examples of the fluidizing agent include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, sucrose fatty acid ester, light anhydrous silicic acid, hydrous silicon dioxide and the like. These fluidizing agents are added for particle control, such as prevention of excessive granulation and fluidity improvement, when coating, 0.01% or more, preferably 0.05% or more, more preferably 0.1% or more with respect to the amlodipine drug substance. Is done. Of these, light anhydrous silicic acid and hydrous silicon dioxide are particularly preferred. In that case, 0.1% or more, preferably 0.15% or more, and more preferably 0.2% or more is appropriately blended with the amlodipine drug substance. These fluidizing agents may be used alone or in combination of two or more. The amlodipine-containing composition can be obtained by a known formulation process. However, in the case of coating, it can be carried out continuously from the process of obtaining the amlodipine-containing composition to the coating. . In particular, when granulating, it is preferable to granulate using a liquid used for coating.
本発明における『界面活性剤』とは、水と親和し難い物質の界面に作用し、水中での均一状態を補助したり、水中への溶け込みを補助するもので、乳化剤や分散剤等も含み、例えばラウリル硫酸ナトリウム、カルボキシビニルポリマー、グリセリン、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ジオクチルソジウムスルホサクシネート、セタノール、セスキオレイン酸ソルビタン、ソルビタン脂肪酸エステル、中鎖脂肪酸トリグリセリド、トリオレイン酸ソルビタン、ヒドロキシプロピルセルロース、プロピレングリコール、プロピレングリコール酸エステル、ポリオキシエチレンノニルフェニルエーテル、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート80、マクロゴール300、マクロゴール400、モノオレイン酸ソルビタン、モノステアリン酸グリセリン、モノラウリン酸ソルビタン、経口投与が許容されるポリオキシエチレンポリオキシプロピレングリコール(例えば、ポリオキシエチレン(105)ポリオキシプロピレン(5)グリコール、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールなど)などが挙げられる。
The “surfactant” in the present invention acts on the interface of a substance that does not have a strong affinity for water, assists the uniform state in water, and assists in dissolution in water, and includes emulsifiers and dispersants. For example, sodium lauryl sulfate, carboxyvinyl polymer, glycerin, glycerin fatty acid ester, sucrose fatty acid ester, dioctyl sodium sulfosuccinate, cetanol, sorbitan sesquioleate, sorbitan fatty acid ester, medium chain fatty acid triglyceride, sorbitan trioleate, hydroxy Propyl cellulose, propylene glycol, propylene glycolate, polyoxyethylene nonylphenyl ether,
本発明において『被覆』とは、原薬または原薬含有組成物の表面に連続層形成担体または連続層形成担体及び界面活性剤を含有する溶液または分散液あるいは溶融液を付着させ、表面の全部または一部を覆うことである。被覆層が単層であるとは、異なった種類の組成を有する被覆層が複数積層して被覆されているのではなく、実質的に同種の組成を有する被覆層1層のみで覆われていることを意味する。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 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SFP-01 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。噴霧乾燥するための装置としては、一般的なスプレードライヤー(大川原製作所製、大川原化工機製、ヤマト社製、ニロ社製など)を用いることができる。 In the present invention, the term “coating” means that a continuous layer-forming carrier or a solution or dispersion containing a continuous layer-forming carrier and a surfactant or a melt containing the surfactant is attached to the surface of the drug substance or the drug substance-containing composition. Or cover part. That the coating layer is a single layer means that a plurality of coating layers having different kinds of compositions are not laminated and covered but only one coating layer having substantially the same kind of composition. Means that. 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 (for example, SPC manufactured by POWREC Co., Ltd.) with 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, ramp A composite fluidized bed granulator with a breaker or the like (for example, a fine particle coating / granulating apparatus SFP-01 manufactured by Paulek) or a rotating fluidized bed granulator (for example, Omnitex manufactured by Nara Machinery Co., Ltd.) is preferable. As an apparatus for spray drying, a general spray dryer (Okawara Seisakusho, Okawara Kakoki, Yamato, Niro, etc.) can be used.
本発明のアムロジピン含有粒子は、平均粒子径が200μm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200μm以下であることが好ましく、より好ましくは175μm以下、さらに好ましくは150μm以下が挙げられ、最も好ましくは120μm以下が挙げられる。一方、粒子径の小さな粒子が多いとアムロジピン含有粒子の比表面積が大きいため、苦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50μm以上であることが好ましい。粒度分布で表現すれば、レーザー回折式粒度分布測定装置(島津製作所製、SALD3000)で測定した際の粒度の分布が275μm以上が20%以下好ましくは15%以下さらに好ましくは10%以下で、275μm〜50μmが50%〜100%好ましくは65%〜100%さらに好ましくは80%〜100%、50μm以下の粒子が60%以下好ましくは55%以下、さらに好ましくは50%以下であるものがよい。 When the average particle diameter of the amlodipine-containing particles of the present invention exceeds 200 μm, the addition amount or the spray solid content can be suppressed to a small level, but there may be a feeling of roughness in the oral cavity or a feeling of foreign matter. Therefore, the average particle diameter is preferably 200 μm or less, more preferably 175 μm or less, still more preferably 150 μm or less, and most preferably 120 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 amlodipine-containing particles is large, and thus bitterness may not be sufficiently suppressed. For this reason, it is preferable that an average particle diameter is 50 micrometers or more. Expressed in terms of particle size distribution, the particle size distribution measured with a laser diffraction particle size distribution analyzer (SALD3000, manufactured by Shimadzu Corporation) is 275 μm or more, 20% or less, preferably 15% or less, more preferably 10% or less, and more preferably 275 μm. -50 μm is 50% to 100%, preferably 65% to 100%, more preferably 80% to 100%, and particles of 50 μm or less are 60% or less, preferably 55% or less, more preferably 50% or less.
本発明に用いる連続層形成担体の添加量・噴霧量は、本発明のアムロジピン含有粒子を口腔内崩壊錠とした際、具体的には上記平均粒子径を有する粒子を作製するに際し、被覆する場合にはコーティング液を噴霧する前の粉末組成物(アムロジピンまたはその薬学上許容される塩および添加物(賦形剤、滑沢剤等)等からなる)に対し重量/重量で10%〜300%、好ましくは10%〜150%、より好ましくは10%〜100%、さらに好ましくは30〜100%、20%〜80%もしくは、30%〜70%、もしくは35%〜110%がよく、最も好ましくは、40%〜90%もしくは、50%〜90%がよい。
噴霧乾燥で製する場合はアムロジピンまたはその薬学上許容される塩含有量に対し10%〜300%、好ましくは10%〜200%、より好ましくは20%〜150%、最も好ましくは30%〜100%もしくは、50%〜100%がよい。
また、特に水不溶性高分子では30〜120%、好ましくは35〜110%、より好ましくは37.5〜100%がよく、さらに好ましくは40〜100%がよく、最も好ましくは40〜90%が好ましい。さらに、特に腸溶性高分子を用いた場合では、30〜120%、好ましくは35〜110%、より好ましくは37.5〜100%、さらに好ましくは40〜100%がよく、最も好ましくは40〜90%がよい。胃溶性高分子を用いた場合では30〜120%、好ましくは35〜110%、より好ましくは40〜110%、さらに好ましくは40〜100%がよく、最も好ましくは50〜90%がよい。
The amount of the continuous layer-forming carrier used in the present invention and the amount of spray are such that when the amlodipine-containing particles of the present invention are used as orally disintegrating tablets, specifically, when the particles having the above average particle diameter are prepared, 10% to 300% by weight / weight with respect to the powder composition before spraying the coating liquid (comprising amlodipine or a pharmaceutically acceptable salt thereof and additives (excipients, lubricants, etc.)) 10% to 150%, more preferably 10% to 100%, more preferably 30 to 100%, 20% to 80%, or 30% to 70%, or 35% to 110%, most preferably Is preferably 40% to 90% or 50% to 90%.
When produced by spray drying, the content of amlodipine or a pharmaceutically acceptable salt thereof is 10% to 300%, preferably 10% to 200%, more preferably 20% to 150%, most preferably 30% to 100%. % Or 50% to 100% is preferable.
In particular, for water-insoluble polymers, 30 to 120%, preferably 35 to 110%, more preferably 37.5 to 100%, more preferably 40 to 100%, and most preferably 40 to 90% are preferable. Further, particularly when an enteric polymer is used, it is 30 to 120%, preferably 35 to 110%, more preferably 37.5 to 100%, further preferably 40 to 100%, most preferably 40 to 90%. Is good. In the case of using a gastric polymer, it is 30 to 120%, preferably 35 to 110%, more preferably 40 to 110%, still more preferably 40 to 100%, and most preferably 50 to 90%.
また、本発明に用いる連続層形成担体の量は、アムロジピンまたはその薬学上許容される塩に対する量で表せば、重量/重量で10〜300%、好ましくは、30〜120%、さらに好ましくは32〜110%、最も好ましくは34〜100%が挙げられる。 The amount of the continuous layer forming carrier used in the present invention is 10 to 300% by weight / weight, preferably 30 to 120%, more preferably 32 when expressed in terms of the amount to amlodipine or a pharmaceutically acceptable salt thereof. -110%, most preferably 34-100%.
さらに、当該発明の連続層形成担体の量をアムロジピン含有粒子全量に対する量で表せば、連続層形成担体が重量/重量で20〜50%、好ましくは22〜45%、さらに好ましくは23〜40%、最も好ましくは25〜35%が挙げられる。 Further, when the amount of the continuous layer-forming carrier of the present invention is expressed as an amount relative to the total amount of amlodipine-containing particles, the continuous layer-forming carrier is 20 to 50% by weight / weight, preferably 22 to 45%, more preferably 23 to 40%. Most preferably, 25-35% is mentioned.
口腔内崩壊錠がバイオアベイラビリティを損なわない製剤としては、例えばアムロジピン5mg相当量分の製剤の溶出試験を、日局パドル法で水900ml、回転数75rpmの条件下で行った場合、30分で70%以上好ましくは75%以上、より好ましくは80%以上の溶出率を示すものが挙げられる。 As a preparation in which the orally disintegrating tablet does not impair bioavailability, for example, when a dissolution test of a preparation corresponding to 5 mg of amlodipine is performed under the conditions of 900 ml of water and 75 rpm in the JP paddle method, 70 minutes in 70 minutes. % Or more, preferably 75% or more, more preferably 80% or more.
口腔内崩壊錠における、当該発明によるアムロジピン含有粒子の含有量は、重量/重量で2%〜35%、好ましくは2〜25%、好ましくは3%〜20%、より好ましくは4%〜18%がよく、さらに好ましくは、5〜18%、最も好ましくは5〜15%がよい。特に、腸溶性高分子を用いる場合には、2%〜35%、好ましくは3%〜20%、より好ましくは4%〜18%がよく、さらに好ましくは5〜18%、最も好ましくは5〜15%がよい。また、胃溶性高分子を用いる場合は2%〜25%、好ましくは2%〜20%、より好ましくは4%〜18%がよく、さらに好ましくは、5〜18%、最も好ましくは5〜15%がよい。アムロジピン含有粒子の含有量が多くなりすぎると、口腔内崩壊錠としての物性、特に口腔内崩壊時間に影響を与え、また、打錠時にアムロジピン含有粒子の皮膜層が破損すること等により苦味の抑制が不十分となる。 The content of the amlodipine-containing particles according to the present invention in the orally disintegrating tablet is 2% to 35%, preferably 2 to 25%, preferably 3% to 20%, more preferably 4% to 18% by weight / weight. More preferably, it is 5 to 18%, and most preferably 5 to 15%. In particular, when using an enteric polymer, 2% to 35%, preferably 3% to 20%, more preferably 4% to 18%, even more preferably 5 to 18%, most preferably 5 to 5%. 15% is good. In the case of using a gastric polymer, 2% to 25%, preferably 2% to 20%, more preferably 4% to 18%, more preferably 5 to 18%, most preferably 5 to 15%. % Is good. If the content of amlodipine-containing particles is too large, the physical properties of the orally disintegrating tablet, particularly the disintegration time in the oral cavity, will be affected, and the bitterness will be suppressed by damaging the coating layer of the amlodipine-containing particles during tableting. Is insufficient.
また、連続層形成担体の含有量を口腔内崩壊錠全体に対する量で表せば、重量/重量で1%〜20%、好ましくは2〜15%、さらに好ましくは2〜10%、最も好ましくは2〜8%が挙げられる。 Further, when the content of the continuous layer-forming carrier is expressed as an amount with respect to the whole orally disintegrating tablet, the weight / weight is 1% to 20%, preferably 2 to 15%, more preferably 2 to 10%, most preferably 2. ~ 8%.
本発明における口腔内崩壊錠は、その口腔内における崩壊性と、製造過程・流通過程・医療現場などで取り扱う上で製剤としての形状を十分に保てる硬度とを具備しなければならない。空隙率が小さすぎると錠剤成型時にアムロジピン含有粒子の連続層形成担体が破損するなどして苦味を抑制できない可能性があり、一方空隙率が大きすぎると錠剤としての強度が十分に得られずに医薬品としての品質を保てない。そのため、錠剤の空隙率は5〜95%、好ましくは5〜80%、より好ましくは5〜70%、より好ましくは5〜60%、さらにより好ましくは5〜50%特に好ましくは5〜40%、最も好ましくは5〜20%が挙げられる。かかる錠剤の空隙率は、以下の式により計算にて求められる。
錠剤の空隙率(%)=(1−Wt/ρ×V)×100
ρ:錠剤の真密度(mg/mm3)、V:錠剤の体積(mm3)、Wt:錠剤重量(mg)
The orally disintegrating tablet in the present invention must have disintegration property in the oral cavity and hardness sufficient to maintain the shape as a preparation when handled in the manufacturing process, distribution process, medical field and the like. If the porosity is too small, there is a possibility that the bitumen cannot be suppressed by damaging the continuous layer forming carrier of amlodipine-containing particles during tablet molding, while if the porosity is too large, sufficient strength as a tablet cannot be obtained. Quality as a medicine cannot be maintained. Therefore, the porosity of the tablet is 5 to 95%, preferably 5 to 80%, more preferably 5 to 70%, more preferably 5 to 60%, still more preferably 5 to 50%, particularly preferably 5 to 40%. Most preferably, 5 to 20% is mentioned. The porosity of such a tablet can be calculated by the following formula.
Tablet porosity (%) = (1−Wt / ρ × V) × 100
ρ: True density of tablet (mg / mm 3 ), V: Tablet volume (mm 3 ), Wt: Tablet weight (mg)
本明細書における『注射筒正倒立法』とは、中村らの、口腔内を模倣した簡易的な溶出試験法(注射筒正倒立法)を用いるものである。この方法により、薬物の溶出量を測定することができ、それを薬物の苦味を感じる閾値と比較して苦味のマスキング評価をすることができる(参考文献:中村康彦 他 粒子設計と製剤技術、121-128 (1993))。本明細書の注射筒正倒立法は以下のようにして実施される。
(アムロジピン含有粒子についての試験)
先端に開孔径0.22μm〜0.45μmのサイズ33mmのフィルター(MILLEX(登録商標)GV)を装着し、液漏れ防止のためにフィルター先端の液出口をパラフィルム(PARAFILM(登録商標)M)で巻いて塞いだガラス製の10mL注射筒を用意する。このガラス10mL注射筒にベシル酸アムロジピン34.7mg相当量(被覆あるいは噴霧乾燥による増量分は適宜計算される)のアムロジピン含有粒子を注射筒先端の液出口に入らないように入れ、37±1℃に保った水あるいは日局崩壊試験第二液10mLを入れる。それと同時にピストンを装着し、3秒に一回の割合で30秒間、計10回注射筒を正倒立させてパラフィルムを外し、フィルターによりろ過、そのはじめのろ液を5mL捨てた後、残りのろ液を回収し、アムロジピン量を測定する。
In this specification, the “injection barrel inversion method” uses a simple dissolution test method (injection barrel inversion method) by Nakamura et al. By this method, the amount of drug elution can be measured, and the bitterness masking evaluation can be performed by comparing it with the threshold for feeling the bitterness of the drug (reference: Yasuhiko Nakamura et al. Particle Design and Formulation Technology, 121 -128 (1993). The syringe barrel upside-down method of this specification is implemented as follows.
(Test on amlodipine-containing particles)
Attach a filter (MILLEX (registered trademark) GV) with a pore size of 0.22 μm to 0.45 μm to the tip, and wind the liquid outlet at the filter tip with parafilm (PARAFILM (registered trademark) M) to prevent liquid leakage Prepare a sealed 10 mL glass syringe. Place amlodipine-containing particles of amlodipine besylate equivalent to 34.7 mg (the amount increased by coating or spray drying is calculated as appropriate) into this glass 10 mL syringe so that it does not enter the liquid outlet at the tip of the syringe and maintain at 37 ± 1 ° C. Add 10 ml of the retained water or the second solution of JP disintegration test. At the same time, the piston was attached, and the syringe was turned upside down 10 times for a total of 30 seconds at a rate of once every 3 seconds, removed the parafilm, filtered through a filter, discarded 5 mL of the first filtrate, and the rest Collect the filtrate and measure the amount of amlodipine.
アムロジピン量の測定は、例えば次のようにして行うことができる。
回収したろ液1mLを正確に量り取り、メタノール/水(4:1)混液を用いて正確に50mLとし試験溶液とする。別途、102℃ 2時間減圧乾燥させたべシル酸アムロジピン標準品を精密に約13.9mg量りとり、本試験の溶出に用いた水あるいは日局崩壊試験第二液8mLを加え、超音波照射して溶かし、更にメタノール/水(4:1)混液を加え正確に200mLにして標準溶液とする。この標準溶液および試験溶液を以下の条件でHPLC法により解析し、アムロジピンの累積面積As、Atを用いて以下に示す(1)式により簡易溶出試験(注射筒正倒立法)による溶出量を求める。
注射筒正倒立法による溶出量(μg/mL)=Ws×At/As×250・・・(1)
Ws:ベシル酸アムロジピン標準品の量(mg)
〜HPLC条件〜
検出器:紫外吸光光度計(測定波長:237 nm)
カラム:内径4.6 mm、長さ15 cmのステンレス管に5μmの液体クロマトグラフ用オクタデシルシリル化シリカゲルを充填する。
カラム温度:25℃付近の一定温度
移動相A:リン酸二水素カリウム4.1gを水1000mLに溶かした液に、リン酸水素二ナトリウム十二水和物5.4gを水500mLに溶かした液を加えてpH6.0に調整する。この液1000mLにメタノール1000mLを加える。
移動相B:リン酸二水素カリウム4.1gを水1000mLに溶かした液に、リン酸水素二ナトリウム十二水和物5.4gを水500mLに溶かした液を加えてpH6.0に調整する。この液50mLにメタノール950mLを加える。
移動相のグラディエント:移動相A:80%(注入後0〜10分)、80%→64%(注入後10〜15分)、移動相B:20%(注入後0〜10分)、20%→36%(注入後10〜15分)
流量:毎分1.0mL
The amount of amlodipine can be measured, for example, as follows.
Weigh accurately 1 mL of the collected filtrate and make exactly 50 mL using a methanol / water (4: 1) mixture to make the test solution. Separately, weighed approximately 13.9 mg of amlodipine besylate standard, which was dried at 102 ° C for 2 hours under reduced pressure, and added 8 mL of the water used for elution of this test or the 2nd solution of the JP disintegration test and dissolved by sonication. Add methanol / water (4: 1) mixture to make exactly 200 mL, and use this solution as the standard solution. This standard solution and test solution are analyzed by the HPLC method under the following conditions, and the elution amount by the simple elution test (injection cylinder upside-down method) is obtained by the following equation (1) using the accumulated area As and At of amlodipine. .
Elution amount (μg / mL) by syringe upside-down method = Ws × At / As × 250 (1)
Ws: Amlodipine besylate standard amount (mg)
~ HPLC conditions ~
Detector: UV absorptiometer (measurement wavelength: 237 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature mobile phase around 25 ° C A: To a solution of 4.1 g of potassium dihydrogen phosphate dissolved in 1000 mL of water, add a solution of 5.4 g of disodium hydrogen phosphate dodecahydrate in 500 mL of water Adjust to pH 6.0. Add 1000 mL of methanol to 1000 mL of this solution.
Mobile phase B: To a solution obtained by dissolving 4.1 g of potassium dihydrogen phosphate in 1000 mL of water, a solution prepared by dissolving 5.4 g of disodium hydrogen phosphate dodecahydrate in 500 mL of water is added to adjust to pH 6.0. Add 950 mL of methanol to 50 mL of this solution.
Mobile phase gradient: mobile phase A: 80% (0-10 minutes after injection), 80% → 64% (10-15 minutes after injection), mobile phase B: 20% (0-10 minutes after injection), 20 % → 36% (10-15 minutes after injection)
Flow rate: 1.0mL per minute
(口腔内崩壊錠についての試験)
先端に開孔径0.22μm〜0.45μmのサイズ33mmのフィルター(MILLEX(登録商標)GV)を装着し、液漏れ防止のためにフィルター先端の液出口をパラフィルム(PARAFILM(登録商標)M)で巻いて塞いだガラス製の10mL注射筒を用意する。このガラス10mL注射筒にアムロジピンの口腔内崩壊錠5錠を入れ、37±1℃に保った水あるいは日局崩壊試験第二液10mLを入れる。それと同時にピストンを装着し、3秒に一回の割合で30秒間計10回注射筒を正倒立させ、パラフィルムを外し、フィルターによりろ過、そのはじめのろ液を5mL捨てた後、残りのろ液を回収し、アムロジピン量を測定する。
アムロジピン量の測定は、例えば次のようにして行うことができる。
回収したろ液1mLを正確に量り取り、溶出に用いた水あるいは日局崩壊試験第二液を用いて正確に50mLとし試験溶液とする。別途、102℃ 2時間減圧乾燥させたべシル酸アムロジピン標準品を精密に約13.9mg量りとり、本試験の溶出に用いた水あるいは日局崩壊試験第二液8mLを加え、超音波照射して溶かし、更にメタノール/水(4:1)混液を加え正確に200mLにして標準溶液とする。この標準溶液および試験溶液を、アムロジピン含有粒子について行った試験と同様にHPLC法により解析し、アムロジピンの累積面積As、Atを用いて上記(1)式により簡易溶出試験(注射筒正倒立法)による溶出量を求める。
ここで1回の正倒立とは、液の入った部分の中心を通る水平軸を中心として180度ずつ交互に時計回りと反時計回りに回転させることをいい、これを1秒間に1往復行う。
(Test on orally disintegrating tablets)
Attach a filter (MILLEX (registered trademark) GV) with a pore size of 0.22 μm to 0.45 μm to the tip, and wind the liquid outlet at the filter tip with parafilm (PARAFILM (registered trademark) M) to prevent liquid leakage Prepare a sealed 10 mL glass syringe.
The amount of amlodipine can be measured, for example, as follows.
Weigh accurately 1 mL of the collected filtrate and make exactly 50 mL with the water used for elution or the second solution of JP disintegration test to make the test solution. Separately, weighed approximately 13.9 mg of amlodipine besylate standard, which was dried at 102 ° C for 2 hours under reduced pressure, and added 8 mL of the water used for elution of this test or the 2nd solution of the JP disintegration test and dissolved by sonication. Add methanol / water (4: 1) mixture to make exactly 200 mL, and use this solution as the standard solution. The standard solution and the test solution were analyzed by HPLC in the same manner as the test conducted on amlodipine-containing particles, and the simple dissolution test (injection cylinder upside-down method) using the accumulated area As and At of amlodipine according to the above formula (1) Determine the amount of elution by.
Here, the term “inverted once” refers to rotating clockwise and counterclockwise alternately 180 degrees around the horizontal axis passing through the center of the liquid-filled portion, and this is performed once a second. .
本発明のアムロジピン含有粒子、あるいは本発明のアムロジピン含有粒子を用いた口腔内崩壊錠は、上記『注射筒正倒立法』においてアムロジピンの溶出量が30秒で800μg/mL以下であることにより苦味が抑制される。一方これ以上の溶出量となる製剤では初期の薬物放出量が多いため、服用時における十分な苦味抑制は達成されないことがわかった。より好ましくは上記『注射筒正倒立法』による薬物溶出量が30秒で700μg/mL以下、より好ましくは650μg/mL以下、さらに好ましくは600μg/mL以下である製剤があげられる。 The amlodipine-containing particles of the present invention or the orally disintegrating tablets using the amlodipine-containing particles of the present invention have a bitter taste due to the elution amount of amlodipine being not more than 800 μg / mL in 30 seconds in the above “injection barrel inverted method”. It is suppressed. On the other hand, it was found that preparations with a higher elution amount have a higher initial drug release amount, so that sufficient bitterness suppression at the time of taking cannot be achieved. More preferable is a preparation having a drug elution amount of 700 μg / mL or less in 30 seconds, more preferably 650 μg / mL or less, and further preferably 600 μg / mL or less in 30 seconds.
以下、実施例及び比較例を挙げて、本発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。但し、実施例1、2、4は参考例である。 Hereinafter, although an example and a comparative example are given and the present invention is explained still more concretely, the present invention is not limited to these. However, Examples 1, 2, and 4 are reference examples.
[実施例1]
(1−1) 平均粒子径21.2μmの粒度を有する薬物原料ベシル酸アムロジピン600gを、複合型流動層造粒機(微粒子コーティング・造粒装置 SFP-01,(株)パウレック製)に入れ、表1の組成のエチルセルロース含有分散液を噴霧した。噴霧時は給気を約55℃、排気を約25〜35℃に保ち、接線スプレーで噴霧液流量3〜5g/min、風量0.6〜0.7m3/min、ローター回転速度1000rpmで製造を行った。噴霧したエチルセルロース含有分散液中のアクアコート固形分総量(トリアセチンを含まない)がベシル酸アムロジピンに対し10%では平均粒子径21.3μm、20%では平均粒子径53.8μm、30%では平均粒子径112.2μm、40%では平均粒子径132.3μmであった。噴霧時の様子は噴霧したベシル酸アムロジピンに対する固形分総量が30%前後から粒子が大きくなり、容器付着がなくなり比較的流動性の良いものとなった。その後、被膜の成熟のため、40℃30分乾燥の後、60℃1日棚乾燥を行った。
[Example 1]
(1-1) Put 600 g of drug raw amlodipine besylate having an average particle size of 21.2 μm in a combined fluidized bed granulator (Fine particle coating and granulator SFP-01, manufactured by POWREC Co., Ltd.) An ethylcellulose-containing dispersion of composition 1 was sprayed. During spraying, air supply was maintained at about 55 ° C, exhaust was maintained at about 25-35 ° C, and tangential spraying was performed at a spray liquid flow rate of 3-5 g / min, an air volume of 0.6-0.7 m 3 / min, and a rotor rotation speed of 1000 rpm. . The total amount of aquacoat solids (without triacetin) in the sprayed ethylcellulose-containing dispersion is 10% with an average particle size of 21.3 μm, 20% with an average particle size of 53.8 μm, and 30% with an average particle size of 112.2 with respect to amlodipine besylate. In μm and 40%, the average particle size was 132.3 μm. The state of spraying was such that the total solid content with respect to the sprayed amlodipine besylate was about 30%, the particles became larger, the container was not attached, and the fluidity was relatively good. Then, for maturation of the film, drying at 40 ° C. for 30 minutes was followed by shelf drying at 60 ° C. for 1 day.
(1−2) このようにして得られたアムロジピン含有粒子を口腔内崩壊錠として成形するために、アムロジピン含有粒子以外の組成物を以下の条件で造粒した。
D-マンニトール1080g、コーンスターチ113gの混合物を複合型流動層造粒機(マルチプレックスMP-01、(株)パウレック製)にて、予め一部もしくは完全にアルファー化した1%コーンスターチ水溶液を結合液とし、風量30m3/h、スプレーエアー圧1.2kg/cm2、スプレー速度10〜13g/min、排気温度28〜35℃に保ちながら液噴霧量800gで造粒を行った。その後、同装置内で給気温度60℃、風量30m3/hにて6分間乾燥を行い、D-マンニトール:コーンスターチ9:1造粒物を得た。
(1−3) 上記(1−1)で得られた噴霧固形分量40%のベシル酸アムロジピン含有粒子を表2の組成比となるよう、上記D-マンニトール:コーンスターチ9:1造粒物と混合し、打錠圧20kgf/cm2、錠剤直径7mm(平型)、120mg/錠で口腔内崩壊錠を得た。
[比較例1]
比較例として、ベシル酸アムロジピン原薬を表2の組成比となるよう上記(1−2)で得られたD-マンニトール:コーンスターチ9:1造粒物と混合し、上記(1−3)と同様の条件で打錠し、口腔内崩壊錠を得た。
(1-2) In order to shape the amlodipine-containing particles thus obtained as an orally disintegrating tablet, a composition other than the amlodipine-containing particles was granulated under the following conditions.
A mixture of 1080 g of D-mannitol and 113 g of corn starch was combined with a 1% corn starch aqueous solution that was partially or completely pre-alpharated in advance using a combined fluidized bed granulator (Multiplex MP-01, manufactured by POWREC Co., Ltd.). Granulation was carried out at a liquid spray amount of 800 g while maintaining an air volume of 30 m 3 / h, a spray air pressure of 1.2 kg / cm 2 , a spray speed of 10 to 13 g / min, and an exhaust temperature of 28 to 35 ° C. Thereafter, drying was performed in the same apparatus at a supply air temperature of 60 ° C. and an air volume of 30 m 3 / h for 6 minutes to obtain a D-mannitol: corn starch 9: 1 granulated product.
(1-3) The amlodipine besylate-containing particles having a spray solid content of 40% obtained in (1-1) above were mixed with the D-mannitol: corn starch 9: 1 granulated product so as to have the composition ratio shown in Table 2. Then, an orally disintegrating tablet was obtained at a tableting pressure of 20 kgf / cm 2 , a tablet diameter of 7 mm (flat type), and 120 mg / tablet.
[Comparative Example 1]
As a comparative example, amlodipine besylate drug substance was mixed with the D-mannitol: corn starch 9: 1 granulated product obtained in (1-2) so as to have the composition ratio in Table 2, and the above (1-3) Tableting was performed under the same conditions to obtain an orally disintegrating tablet.
[試験例1]
上記で得られた実施例1、比較例1の口腔内崩壊錠について被験者3名で味覚試験を行った。その結果を表3に示す。苦味の評価は口中に錠剤を含んでから苦味を感じ始めるまでの時間および各口腔内崩壊錠の口腔内における崩壊時間で行った。即ち、錠剤を含んでから苦味を感じ始めるまでの時間が錠剤の口腔内崩壊時間+5秒以上であれば口腔内崩壊錠において苦味を感じることなく服用可能であり、それ以下であれば服用時に苦味を感じないで服用できると考えられる。試験の結果、表3からわかるように本発明品である実施例1の口腔内崩壊錠は苦味を感じずに服用可能であり、アムロジピンの苦味を十分に低減させた口腔内崩壊錠であることが示された。
[Test Example 1]
A taste test was conducted with three subjects on the orally disintegrating tablets of Example 1 and Comparative Example 1 obtained above. The results are shown in Table 3. The bitterness was evaluated by the time from when the tablet was included in the mouth until the bitterness started to be felt and the disintegration time in the oral cavity of each orally disintegrating tablet. In other words, if the time from the inclusion of a tablet to the start of feeling bitterness is not less than the oral disintegration time of the tablet + 5 seconds or more, it can be taken without feeling bitterness in the orally disintegrating tablet. It is thought that it can be taken without feeling. As a result of the test, as can be seen from Table 3, the orally disintegrating tablet of Example 1, which is the product of the present invention, can be taken without feeling bitterness, and is an orally disintegrating tablet with sufficiently reduced bitterness of amlodipine It has been shown.
[比較例2]
平均粒子径21.2μmの粒度を有する薬物原料ベシル酸アムロジピン500gを、複合型流動層造粒機(微粒子コーティング・造粒装置 SFP-01,(株)パウレック製)に入れ、表1の組成のエチルセルロース含有分散液を噴霧した。噴霧時は給気を約60〜70℃、排気を約40℃に保ち、接線スプレーで噴霧液流量約3.5g/min、風量0.7m3/min、ローター回転速度1000rpmで製造を行った。噴霧したエチルセルロース含有分散液中のアクアコート固形分総量がベシル酸アムロジピンに対し10%では平均粒子径16.9μm、20%では平均粒子径26.6μm、30%では平均粒子径41.2μm、40%では平均粒子径47.3μmであった。その後、被膜の成熟のため、40℃30分乾燥の後、60℃1日棚乾燥を行った。
[Comparative Example 2]
500 g of drug raw amlodipine besylate having an average particle size of 21.2 μm is put into a combined fluidized bed granulator (fine particle coating / granulating apparatus SFP-01, manufactured by POWREC Co., Ltd.), and ethyl cellulose having the composition shown in Table 1 The containing dispersion was sprayed. At the time of spraying, air supply was maintained at about 60 to 70 ° C., exhaust was maintained at about 40 ° C., and tangential spraying was performed at a spray liquid flow rate of about 3.5 g / min, an air volume of 0.7 m 3 / min, and a rotor rotational speed of 1000 rpm. The total amount of aquacoat solids in the sprayed ethylcellulose-containing dispersion is 10% for amlodipine besylate with an average particle size of 16.9μm, 20% with an average particle size of 26.6μm, 30% with an average particle size of 41.2μm, and 40% with an average particle size of 40%. The particle size was 47.3 μm. Then, for maturation of the film, drying at 40 ° C. for 30 minutes was followed by shelf drying at 60 ° C. for 1 day.
[試験例2](簡易溶出試験)
上記で得られたベシル酸アムロジピンに対する噴霧固形分総量40%の実施例1、比較例2の各被覆ベシル酸アムロジピン含有粒子およびベシル酸アムロジピン原薬について、注射筒正倒立法を行って溶出量を比較した(表4)。
この結果、比較例2ではアムロジピン原薬に比べ苦味をマスクするものの、実施例1はその比較例2と比べても著しくその苦味マスク効果が高いことがわかった。このことは、実施例1と比較例2では噴霧した固形分総量が同じ40%であっても、比較例2では平均粒子径47.3μmであり、一方実施例1では平均粒子径が132.3μmであることによると考えられる。従って粒子径が小さくなる条件で被覆を行う場合、苦味を十分に抑制するには多量のコーティング量を要することが示唆される。
[Test Example 2] (Simple dissolution test)
For each of the coated amlodipine besylate-containing particles and the amlodipine besylate drug substance of Example 1 and Comparative Example 2 with a total amount of spray solid content of 40% of the amlodipine besylate obtained above, the amount of elution was determined by the syringe inversion method. Comparison was made (Table 4).
As a result, it was found that although Comparative Example 2 masked the bitter taste as compared to the amlodipine drug substance, Example 1 had a remarkably high bitter taste masking effect compared to Comparative Example 2. This means that in Example 1 and Comparative Example 2, the total amount of sprayed solids was the same 40%, but in Comparative Example 2, the average particle size was 47.3 μm, whereas in Example 1, the average particle size was 132.3 μm. It is thought that there is. Therefore, when coating is performed under conditions where the particle size is small, it is suggested that a large amount of coating is required to sufficiently suppress bitterness.
[試験例3](溶出試験)
実施例1および比較例1で得られた口腔内崩壊錠剤の溶出試験を行い、本発明の水不溶性物質での被覆による溶出挙動への影響を調べた。試験条件は、パドル法75rpmにより行い、試験液として37℃精製水、900mLを用いた。
試験の結果を表5に示す。精製水による溶出は0.5分においては比較例1での口腔内崩壊錠では16.9%であるのに対し、本発明を利用した実施例1の口腔内崩壊錠0.9%となった。このことから本発明を用いることで初期のアムロジピン溶出を抑ええられたことがわかる。一方、15分における溶出率は比較例1でも実施例1でも90%以上の溶出挙動を示し、本発明を利用することによるバイオアベイラビリティを低下させるような溶出遅延は認められなかった。
従って、本発明により製造されるアムロジピン含有粒子、およびその口腔内崩壊錠は、苦味を感じる初期溶出を十分に抑え、尚且つバイオアベイラビリティに影響しない溶出プロファイルを示すことが確認された。
[Test Example 3] (Dissolution test)
The dissolution test of the orally disintegrating tablets obtained in Example 1 and Comparative Example 1 was conducted, and the influence on the dissolution behavior due to the coating with the water-insoluble substance of the present invention was examined. The test conditions were a paddle method of 75 rpm, and 37 ° C. purified water and 900 mL were used as a test solution.
The test results are shown in Table 5. Elution with purified water was 16.9% for the orally disintegrating tablet of Comparative Example 1 at 0.5 minutes, whereas it was 0.9% for the orally disintegrating tablet of Example 1 using the present invention. From this, it can be seen that the initial amlodipine elution was suppressed by using the present invention. On the other hand, the elution rate at 15 minutes showed an elution behavior of 90% or more in both Comparative Example 1 and Example 1, and no elution delay that would reduce bioavailability by using the present invention was observed.
Therefore, it was confirmed that the amlodipine-containing particles produced according to the present invention and the orally disintegrating tablet exhibit an elution profile that sufficiently suppresses the initial elution that gives a bitter taste and does not affect bioavailability.
[実施例2]
精製水1831.6gにラウリル硫酸ナトリウム43.2gを十分に溶解させ、その溶液にアミノアルキルメタクリレートコポリマーE微粉砕物(Eudragit EPO(レーム社製))432.1gをエアーアジテーターで分散させたものに、ステアリン酸(植物性)を64.8g加えEudragitEPO分散液とした。別途精製水800gにタルク151.2gを分散させ、前述のEudragit EPO分散液にその全量を加えよく混合してEudragit Eコーティング液とした。
薬物原料ベシル酸アムロジピン400gと軽質無水ケイ酸(アエロジール200)1.6gをポリエチレン袋内で十分に混合し、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)パウレック製)に入れ、表6の組成のEudragit Eコーティング液を噴霧した。噴霧時は給気を約65〜75℃、排気を約28〜32℃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0.2MPa、給気風量0.45〜0.60m3/minで製造を行った。噴霧したEudragit EPO固形分量がベシル酸アムロジピンに対し60%(噴霧量約1800g)、70%(噴霧量約2100g)時、流動層内で乾燥/成膜工程を行いサンプリングを行った。アムロジピン含有粒子の平均粒子径はそれぞれ60%では61.9μm、70%では平均粒子径62.9μmであった。
[Example 2]
43.2 g of sodium lauryl sulfate is sufficiently dissolved in 1831.6 g of purified water, and 432.1 g of aminoalkyl methacrylate copolymer E finely pulverized product (Eudragit EPO (manufactured by Laem Co.)) is dispersed in the solution using an air agitator. 64.8 g of (vegetable) was added to obtain a Eudragit EPO dispersion. Separately, 151.2 g of talc was dispersed in 800 g of purified water, and the entire amount was added to the aforementioned Eudragit EPO dispersion and mixed well to obtain an Eudragit E coating solution.
A drug raw material amlodipine besylate 400g and light anhydrous silicic acid (Aeril 200) 1.6g are mixed thoroughly in a polyethylene bag, and a Wurster fluidized bed granulator with a forced circulation device (an improved Wurster fluidized bed granulator, MP- 01 SPC (manufactured by POWREC Co., Ltd.) and sprayed with Eudragit E coating solution having the composition shown in Table 6. When spraying, keep the supply air at about 65 to 75 ° C, exhaust at about 28 to 32 ° C, spray liquid flow rate at the bottom spray 10-12g / min, spray air flow rate 80L / min, spray air pressure 0.2MPa, supply air volume The production was performed at 0.45 to 0.60 m 3 / min. When the sprayed Eudragit EPO solid content was 60% with respect to amlodipine besylate (spray amount of about 1800 g) and 70% (spray amount of about 2100 g), sampling was performed by performing a drying / film formation process in the fluidized bed. The average particle size of the amlodipine-containing particles was 61.9 μm at 60% and 62.9 μm at 70%, respectively.
[実施例3]
精製水371.0gにクエン酸トリエチル(シトロフレックスNo.2 (SC-60))63.0gを十分に分散させ、その溶液にメタクリル酸コポリマーLD (固形分:メタクリル酸・アクリル酸エチルコポリマー 29.1%、ポリソルベート80 0.7%、ラウリル硫酸ナトリウム 0.2%; ポリキッドPA30S(商品名))1400.0gを混合しメタクリル酸コポリマーLDコーティング液とした。
薬物原料ベシル酸アムロジピン400gと軽質無水ケイ酸(アエロジール200)1.6gをポリエチレン袋内で十分に混合し、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)パウレック製)に入れ、表7の組成のメタクリル酸コポリマーLDコーティング液を噴霧した。噴霧時は給気を約75℃、排気を約28〜32℃に保ち、ボトムスプレーで噴霧液流量11〜12g/min、スプレーエア流量70〜80L/min、スプレーエアー圧力0.2MPa、給気風量0.55〜0.60m3/minで製造を行った。噴霧したメタクリル酸コポリマーLD固形分量がベシル酸アムロジピンに対し40%(噴霧量約700g)コーティングしたアムロジピン含有粒子を流動層内で乾燥/成膜工程経てサンプリングを行った。このアムロジピン含有粒子の平均粒子径は66.8μmであった。
[Example 3]
Thoroughly disperse 63.0 g of triethyl citrate (Citroflex No. 2 (SC-60)) in 371.0 g of purified water, and methacrylic acid copolymer LD (solid content: 29.1% methacrylic acid / ethyl acrylate copolymer, polysorbate) 80 0.7%, sodium lauryl sulfate 0.2%; 1400.0 g of Polykid PA30S (trade name)) were mixed to prepare a methacrylic acid copolymer LD coating solution.
A drug raw material amlodipine besylate 400g and light anhydrous silicic acid (Aeril 200) 1.6g are mixed thoroughly in a polyethylene bag, and a Wurster fluidized bed granulator with a forced circulation device (an improved Wurster fluidized bed granulator, MP- 01 SPC (manufactured by POWREC Co., Ltd.) and sprayed with a methacrylic acid copolymer LD coating solution having the composition shown in Table 7. When spraying, keep the supply air at about 75 ° C, exhaust at about 28-32 ° C, bottom spray with spray liquid flow rate 11-12g / min, spray air flow rate 70-80L / min, spray air pressure 0.2MPa, supply air volume The production was carried out at 0.55 to 0.60 m 3 / min. Amlodipine-containing particles coated with a sprayed methacrylic acid copolymer LD solid content of 40% based on amlodipine besylate (spray amount of about 700 g) were sampled in a fluidized bed through a drying / film formation step. The average particle size of these amlodipine-containing particles was 66.8 μm.
[実施例4]
精製水280.0gにトリアセチン67.2gを十分に分散させ、その溶液にエチルセルロース水分散液(アクアコート(商品名)、固形分量:エチルセルロース26.1%、セタノール2.7%、ラウリル硫酸ナトリウム1.2%、FMC社) 1120.0gを混合しエチルセルロースコーティング液とした。
薬物原料ベシル酸アムロジピン400gと軽質無水ケイ酸(アエロジール200)1.6gをポリエチレン袋内で十分に混合し、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)パウレック製)に入れ、表8の組成のエチルセルロースコーティング液を噴霧した。噴霧時は給気を約75℃、排気を約28〜35℃に保ち、ボトムスプレーで噴霧液流量13g/min、スプレーエア流量80L/min、スプレーエアー圧力0.2MPa、給気風量0.50〜0.60m3/minで製造を行った。噴霧したエチルセルロース固形分量がベシル酸アムロジピンに対し100%(噴霧量約1280g)コーティングしたアムロジピン含有粒子を流動層造粒機内で乾燥/成膜工程経てサンプリングを行った。このアムロジピン含有粒子の平均粒子径は86.6μmであった。
[Example 4]
67.2 g of triacetin is sufficiently dispersed in 280.0 g of purified water, and an aqueous dispersion of ethyl cellulose (Aquacoat (trade name), solid content: ethyl cellulose 26.1%, cetanol 2.7%, sodium lauryl sulfate 1.2%, FMC) 1120.0 g was mixed to obtain an ethylcellulose coating solution.
A drug raw material amlodipine besylate 400g and light anhydrous silicic acid (Aeril 200) 1.6g are mixed thoroughly in a polyethylene bag, and a Wurster fluidized bed granulator with a forced circulation device (an improved Wurster fluidized bed granulator, MP- 01 SPC (manufactured by POWREC Co., Ltd.) and sprayed with an ethylcellulose coating solution having the composition shown in Table 8. When spraying, keep the supply air at about 75 ° C, exhaust at about 28-35 ° C, bottom spray with spray liquid flow rate 13g / min, spray air flow rate 80L / min, spray air pressure 0.2MPa, supply air flow 0.50 ~ 0.60m Manufactured at 3 / min. Amlodipine-containing particles coated with 100% sprayed ethylcellulose solid content of amlodipine besylate (spray amount of about 1280 g) were sampled through a drying / film-forming process in a fluid bed granulator. The average particle size of the amlodipine-containing particles was 86.6 μm.
[実施例5]
精製水667.9gにポリソルベート80(日局ポリソルベート80(HX))37.8gを十分に分散させ、続いてタルク(タルカンハヤシ)88.2g、クロスカルメロースナトリウム(Ac-Di-Sol)63.0gを混合し、予めメタクリル酸コポリマーLD(固形分:メタクリル酸・アクリル酸エチルコポリマー 29.1%、ポリソルベート80 0.7%、ラウリル硫酸ナトリウム 0.2%; ポリキッドPA30S(商品名))840.0gに1N水酸化ナトリウム84.1gを加えて調製した混液を混和した。これを十分攪拌した後、250μm開口径のメッシュ網で篩過して表9に示した処方のコーティング液とした。
薬物原料ベシル酸アムロジピン400gと軽質無水ケイ酸(アエロジール200)1.6gをポリエチレン袋内で十分に混合し、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)パウレック製)に入れ、上記のコーティング液を噴霧した。噴霧時は給気を約75℃、排気を約30℃に保ち、ボトムスプレーで噴霧液流量12g/min、スプレーエア流量80L/min、スプレーエアー圧力0.2MPa、給気風量約0.50〜0.57 m3/minで製造を行った。噴霧したメタクリル酸コポリマーLD固形分量がベシル酸アムロジピンに対して50%(噴霧量約1410g)の時点で流動層内で乾燥/成膜工程を行い、サンプリングを行った。このアムロジピン含有粒子の平均粒子径は80.4μmであった。
[Example 5]
37.8 g of polysorbate 80 (JP polysorbate 80 (HX)) is sufficiently dispersed in 667.9 g of purified water, followed by mixing 88.2 g of talc (talcan palm) and 63.0 g of croscarmellose sodium (Ac-Di-Sol). , Methacrylic acid copolymer LD (solid content: methacrylic acid / ethyl acrylate copolymer 29.1%, polysorbate 80 0.7%, sodium lauryl sulfate 0.2%; Polyquid PA30S (trade name)) 840.0g, add 14.1% sodium hydroxide 84.1g The prepared mixed solution was mixed. After sufficiently stirring this, it was sieved with a mesh screen having an opening diameter of 250 μm to obtain a coating liquid having the formulation shown in Table 9.
A drug raw material amlodipine besylate 400g and light anhydrous silicic acid (Aeril 200) 1.6g are mixed thoroughly in a polyethylene bag, and a Wurster fluidized bed granulator with a forced circulation device (an improved Wurster fluidized bed granulator, MP- 01 SPC (manufactured by POWREC Co., Ltd.) and sprayed with the above coating solution. When spraying, keep the supply air at about 75 ° C, exhaust at about 30 ° C, bottom spray with spray liquid flow rate 12g / min, spray air flow rate 80L / min, spray air pressure 0.2MPa, supply air flow rate about 0.50 ~ 0.57 m 3 Manufactured at / min. When the sprayed methacrylic acid copolymer LD solid content was 50% with respect to amlodipine besylate (spraying amount: about 1410 g), the drying / film formation step was performed in the fluidized bed, and sampling was performed. The average particle size of the amlodipine-containing particles was 80.4 μm.
実施例2、3、4、5で得られた各アムロジピン含有粒子のアムロジピン含量を測定し、1錠あたりにベシル酸アムロジピン6.9mg相当量含有するように、実施例1(1−3)と同様の製法で各口腔内崩壊錠を得た。 The amlodipine content of each amlodipine-containing particle obtained in Examples 2, 3, 4, and 5 was measured, and the same amount as in Example 1 (1-3) was obtained so that each tablet contained 6.9 mg of amlodipine besylate. Each orally disintegrating tablet was obtained by the following production method.
このようにして実施例2、3、4、5で得られた各アムロジピン含有粒子から作製した口腔内崩壊錠について、試験例1((苦味を感じ始める時間)−(口腔内崩壊時間))、試験例2(簡易溶出試験)、試験例3(溶出試験)を行った。各試験結果およびアムロジピン含有粒子の平均粒子径を表10に示す。なお、試験例3については試験液にII液を用いたが、実施例5で得られたアムロジピン含有粒子から作製した口腔内崩壊錠についてはII液ではフィルター詰りにより濾過ができなかったため、試験液に水を用いたデータを示す。 Thus, for the orally disintegrating tablets prepared from the respective amlodipine-containing particles obtained in Examples 2, 3, 4, and 5, Test Example 1 ((starting to feel bitterness)-(orally disintegrating time)), Test example 2 (simple dissolution test) and test example 3 (elution test) were performed. Table 10 shows the test results and the average particle size of the amlodipine-containing particles. For Test Example 3, the solution II was used as the test solution, but for the orally disintegrating tablets prepared from the amlodipine-containing particles obtained in Example 5, the solution could not be filtered due to the clogging with the solution II. Shows data using water.
[試験例4](バイオアベイラビリティ試験)
製剤投与後の血中薬物濃度を、雄性ビーグル犬(体重:12〜15kg)6匹、絶食、2群×2群のクロスオーバーで評価を行った。標準製剤(下記参照)および試験製剤をアムロジピンとして5mg/head(1錠/1頭)で下記の投与および測定を行った。
標準製剤:
表11中(1)に示した割合でベシル酸アムロジピン、D-マンニトール、トウモロコシデンプン(コーンスターチ(XX16)W)、低置換度ヒドロキシプロピルセルロース(L-HPC(LH−21))、アスパルテーム、軽質無水ケイ酸(アエロジール200)を予備混合、及び流動層造粒機内で混合し、トウモロコシデンプンおよび精製水から調製したデンプン糊を(2)に示した割合で噴霧・造粒した。造粒物を500μm篩で篩過した後、(3)に示した割合で香料及びフマル酸ステアリルナトリウム(PRUV)を混合し、打錠用顆粒を製造した。
この打錠用顆粒を、120mg/1錠、7mm径(割線あり)で打錠し、標準製剤とした。
[Test Example 4] (Bioavailability test)
The blood drug concentration after administration of the preparation was evaluated by crossover of 6 male beagle dogs (body weight: 12 to 15 kg), fasting, and 2 groups × 2 groups. The following administration and measurement were performed at 5 mg / head (1 tablet / 1 head) using the standard preparation (see below) and the test preparation as amlodipine.
Standard formulation:
Amlodipine besylate, D-mannitol, corn starch (corn starch (XX16) W), low-substituted hydroxypropylcellulose (L-HPC (LH-21)), aspartame, light anhydrous in the proportions shown in Table 11 (1) Silicic acid (Aeriel 200) was premixed and mixed in a fluid bed granulator, and the starch paste prepared from corn starch and purified water was sprayed and granulated at the ratio shown in (2). The granulated product was sieved with a 500 μm sieve, and then the fragrance and sodium stearyl fumarate (PRUV) were mixed at the ratio shown in (3) to produce granules for tableting.
The granules for tableting were tableted at 120 mg / 1 tablet, 7 mm diameter (with a score line) to obtain a standard preparation.
(2) 投与18〜24時間前よりビーグル犬を絶食させ、1群目に1頭につき標準製剤1錠、2群目に1頭につき試験製剤1錠を経口投与させた。
(3) 製剤投与0.5、1、2、4、6、8、12、24、48、72時間後に前腕橈側皮静脈より4mLずつ採血を行った。
(4) 血液は30分以上室温にて放置後、遠心分離により血清を得た。
血清中の薬物濃度は、抽出処理を行ったのち未変化体についてHPLC(蛍光検出)により定量した。
(2) Beagle dogs were fasted from 18 to 24 hours before administration, and one tablet of the standard preparation was administered per group to the first group and one test preparation was administered to the second group.
(3) 0.5 mL, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after administration of the preparation, 4 mL of blood was collected from the forearm cephalic vein.
(4) After leaving the blood at room temperature for 30 minutes or more, serum was obtained by centrifugation.
The drug concentration in serum was quantified by HPLC (fluorescence detection) for the unchanged substance after extraction treatment.
実施例3の口腔内崩壊錠を試験製剤とし、標準製剤および試験製剤について上記試験を実施した。その結果を図1に示す。
また、各製剤の薬物動態パラメータの平均、および標準製剤との生物学的同等性判定について表12にまとめた。各パラメータの対数値の平均値の差の90%信頼区間をパラメータの信頼区間とし、これがlog(0.8)〜log(1.25)であれば生物学的に同等であると判定した。
Using the orally disintegrating tablet of Example 3 as a test preparation, the above test was performed on the standard preparation and the test preparation. The result is shown in FIG.
Table 12 summarizes the average pharmacokinetic parameters of each preparation and the bioequivalence determination with the standard preparation. The 90% confidence interval of the difference between the average values of the logarithmic values of each parameter was used as the parameter confidence interval, and if this was log (0.8) to log (1.25), it was determined that they were biologically equivalent.
以上より、本発明によって得られる口腔内崩壊錠は実用的な硬度を有し、口腔内崩壊時間が短く、ザラツキおよび苦味を感じず服用でき、バイオアベイラビリティを損なわない等の特徴を有するアムロジピン口腔内崩壊錠であることがわかった。
As described above, the orally disintegrating tablet obtained by the present invention has practical hardness, has a short oral disintegration time, can be taken without feeling the roughness and bitterness, and does not impair bioavailability. It turned out to be a disintegrating tablet.
[試験例5] アムロジピン含有粒子量の錠剤硬度および口腔内崩壊時間に与える影響
実施例2及び実施例3により製造されたアムロジピン含有粒子につき、1錠あたりのアムロジピン含有粒子の配合量を変化させ、打錠圧を0.5 tf、1.0tfで打錠する以外は、実施例1(1−3)の方法で口腔内崩壊錠を製造した。
得られた各サンプルについて、錠剤硬度(n=2)及び口腔内崩壊性(n=3)を評価した。その結果を表13に示す。
実施例2(Eudragit EPO固形分量60%(ベシル酸アムロジピンに対し))
実施例3(メタクリル酸コポリマーLD固形分量40%(ベシル酸アムロジピンに対し))
[Test Example 5] Effect of amlodipine-containing particle amount on tablet hardness and oral disintegration time For the amlodipine-containing particles produced according to Example 2 and Example 3, the amount of amlodipine-containing particles per tablet was changed, An orally disintegrating tablet was produced by the method of Example 1 (1-3), except that the tableting pressure was 0.5 tf and 1.0 tf.
About each obtained sample, tablet hardness (n = 2) and orally disintegrating property (n = 3) were evaluated. The results are shown in Table 13.
Example 2 (Eudragit EPO
Example 3 (methacrylic acid copolymer LD
n.d.は測定しなかったことを示す。
表13の結果から、口腔内崩壊錠中のアムロジピン含有粒子の配合量は、実施例2のアムロジピン含有粒子を用いた製剤では少なくとも25%以下、実施例3のアムロジピン含有粒子を用いた製剤では35%以下で30N以上の硬度および30秒以下の口腔内崩壊時間を有する口腔内崩壊錠を製造できることがわかった。
nd indicates that measurement was not performed.
From the results of Table 13, the blending amount of the amlodipine-containing particles in the orally disintegrating tablet is at least 25% or less for the preparation using the amlodipine-containing particles of Example 2, and 35 for the preparation using the amlodipine-containing particles of Example 3. It was found that an orally disintegrating tablet having a hardness of 30 N or less and an orally disintegrating time of 30 seconds or less can be produced.
本発明によって、口腔内で急速に崩壊し、実用的な硬度を有し、口腔内崩壊時間が短く、ザラつきと苦味を感じずに服用でき、バイオアベイラビリティを損なわない等の優れた特性を有するアムロジピン口腔内崩壊錠を提供することが可能となる。これによって、高齢者にとって易服用性となるだけでなく、多忙な現代社会人がどこへでも手軽に携帯し、水を摂取せず、苦痛を伴うことなくあらゆる場面で容易にアムロジピンを服用することが可能となる。 According to the present invention, it disintegrates rapidly in the oral cavity, has a practical hardness, has a short oral disintegration time, can be taken without feeling rough and bitter, and has excellent characteristics such as not impairing bioavailability. It becomes possible to provide an amlodipine orally disintegrating tablet. This not only makes it easy for the elderly to take, but also makes it easy for busy modern adults to carry it anywhere, not to drink water, and easily take amlodipine in any scene without suffering. Is possible.
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JP5080856B2 (en) * | 2007-05-14 | 2012-11-21 | 大正薬品工業株式会社 | Tablets for oral administration |
JP5072748B2 (en) * | 2007-07-10 | 2012-11-14 | 株式会社 メドレックス | Amlodipine stable solution and jelly |
ES2604307T3 (en) | 2009-05-20 | 2017-03-06 | Sumitomo Dainippon Pharma Co., Ltd. | Dry-coated oral disintegration tablet |
KR101907218B1 (en) | 2009-12-11 | 2018-10-11 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | Press-coated orally disintegrating tablets |
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JP6150564B2 (en) * | 2013-03-08 | 2017-06-21 | 杏林製薬株式会社 | Orally rapidly disintegrating tablets |
TWI659752B (en) | 2013-03-26 | 2019-05-21 | 日商橘生藥品工業股份有限公司 | Oral administration preparations masking the bitter taste of silodosin |
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