JP5952646B2 - Oral dissolution type film preparation - Google Patents
Oral dissolution type film preparation Download PDFInfo
- Publication number
- JP5952646B2 JP5952646B2 JP2012129676A JP2012129676A JP5952646B2 JP 5952646 B2 JP5952646 B2 JP 5952646B2 JP 2012129676 A JP2012129676 A JP 2012129676A JP 2012129676 A JP2012129676 A JP 2012129676A JP 5952646 B2 JP5952646 B2 JP 5952646B2
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- drug
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- mass
- coating layer
- preparation
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- 238000002360 preparation method Methods 0.000 title claims description 75
- 238000004090 dissolution Methods 0.000 title claims description 15
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- 229940079593 drug Drugs 0.000 claims description 130
- 239000010410 layer Substances 0.000 claims description 107
- 239000011247 coating layer Substances 0.000 claims description 58
- 239000002245 particle Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 11
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- 239000000843 powder Substances 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 5
- 229960003088 loratadine Drugs 0.000 claims description 5
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 4
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 claims description 2
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- 229960001475 zolpidem Drugs 0.000 claims description 2
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 claims description 2
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Description
本発明は、崩壊剤を添加しなくても口腔内での崩壊性に優れ、かつ薬物の味がマスキングされた口腔内溶解型フィルム製剤に関する。 The present invention relates to an intraoral-dissolving film preparation that is excellent in disintegration in the oral cavity without adding a disintegrant and masks the taste of the drug.
経口投与用製剤のうち、フィルム状製剤、特に口腔内溶解型フィルム製剤は、水なしで服用可能、高齢者等の嚥下能力の低下したヒトでも服用可能、携帯性に優れる等の利点があることから、近年、研究開発され、広く使用されるに至っている（特許文献１〜３等）。 Among preparations for oral administration, film-form preparations, particularly oral-dissolving film preparations, have the advantages that they can be taken without water, can be taken even by elderly people with reduced swallowing ability, and have excellent portability. In recent years, it has been researched and developed and has been widely used (Patent Documents 1 to 3, etc.).
口腔内溶解型フィルム製剤は、製剤が薄く、質量が軽いという特徴がある。このため、製剤設計において添加することができる基剤成分の量に制限が生じる傾向にある。従って、錠剤の場合と異なり、製剤の崩壊性を高めたり、制御するための崩壊剤の添加や、薬物の苦味を抑えるための矯味剤や甘味剤の添加においてもその配合量に自ずと制限が生じてしまうという問題がある。すなわち、薬物が苦味等を有する場合には、その味をマスキングするために矯味剤や甘味剤を多量に添加すると、崩壊性が低下したり、フィルム製剤の形状とならなくなってしまうという問題があった。
従って、本発明の課題は、崩壊性が良好で、かつ薬物の味がマスキングされた口腔内溶解型フィルム製剤を提供することにある。
The intraoral dissolution type film preparation is characterized in that the preparation is thin and the mass is light. This tends to limit the amount of base component that can be added in the formulation design. Therefore, unlike tablets, there is a limit to the amount of compounding even when adding disintegrants to increase or control the disintegration of the drug, and adding flavoring and sweeteners to suppress the bitterness of drugs. There is a problem of end. In other words, when a drug has a bitter taste or the like, if a large amount of a corrigent or sweetener is added to mask the taste, there is a problem that the disintegration is lowered or the shape of the film preparation is lost. It was.
Accordingly, an object of the present invention is to provide an intraoral dissolution type film preparation having good disintegration and masking the taste of a drug.
そこで本発明者は、フィルム製剤全体の量や厚さを大きく変化させることなく、崩壊性と薬物の味のマスキングの両立を図るべく種々検討したところ、意外にも、薬物を粉体の状態で薬物層中に分散させ、かつ製剤の厚さと薬物の粒子径とをコントロールすることによって崩壊速度がコントロールでき、かつ薬物の味をマスキングできることを見出し、本発明を完成した。 Therefore, the present inventor made various studies to achieve both disintegration and masking of the taste of the drug without greatly changing the amount and thickness of the entire film preparation. It was found that the disintegration rate can be controlled and the taste of the drug can be masked by dispersing in the drug layer and controlling the thickness of the preparation and the particle size of the drug, thereby completing the present invention.
すなわち、本発明は、以下の〔１〕〜〔４〕を提供するものである。
〔１〕薬物が、水溶性高分子を含有する薬物層中に粉体分散しており、製剤の厚さが５０〜２４０μｍ、薬物の粒子径が５〜１００μｍである、口腔内溶解型フィルム製剤。
〔２〕製剤の厚さと薬物の粒子径の比が４５：１〜１．３：１である〔１〕記載の口腔内溶解型フィルム製剤。
〔３〕製剤中の薬物の含有量が１〜５０質量％である〔１〕又は〔２〕記載の口腔内溶解型フィルム製剤。
〔４〕製剤の最外層にコーティング層を有する〔１〕〜〔３〕のいずれかに記載の口腔内溶解型フィルム製剤。
That is, the present invention provides the following [1] to [4].
[1] An oral-dissolving film preparation in which a drug is powder-dispersed in a drug layer containing a water-soluble polymer, the thickness of the preparation is 50 to 240 μm, and the particle size of the drug is 5 to 100 μm .
[2] The oral dissolution film preparation according to [1], wherein the ratio of the thickness of the preparation to the particle size of the drug is 45: 1 to 1.3: 1.
[3] The oral-dissolving film preparation according to [1] or [2], wherein the drug content in the preparation is 1 to 50% by mass.
[4] The intraoral dissolution type film preparation according to any one of [1] to [3], which has a coating layer on the outermost layer of the preparation.
本発明の口腔内溶解型フィルム製剤においては、薬物が水溶性高分子含有層中に粉体分散していることにより、薬物自体が崩壊剤としての機能を有している。
薬物自体に崩壊剤としての機能を持たせたこと、及び薬物の粒子径を一定の大きさ以上にすることによって、崩壊剤、嬌味剤及び甘味料等の添加量を無くすか、少なくすることができたので、製剤中に添加できる薬物の割合を高くすることができた。また、本発明は製造時に特別な前処理工程を必要としないので、特別な装置を必要とせず、製造管理上も簡便である。
In the oral-dissolving film preparation of the present invention, the drug itself has a function as a disintegrant because the drug is powder-dispersed in the water-soluble polymer-containing layer.
Eliminate or reduce the amount of disintegrants, flavoring agents, sweeteners, etc. by making the drug itself function as a disintegrant and making the particle size of the drug more than a certain size. As a result, the ratio of the drug that can be added to the preparation could be increased. Further, since the present invention does not require a special pretreatment process at the time of production, a special apparatus is not required and the production management is simple.
本発明の口腔内溶解型フィルム製剤は、薬物が水溶性高分子を含有する薬物層中に粉体分散しており、製剤の厚さが５０〜２４０μｍ、薬物の粒子径が５〜１００μｍである。 In the intraoral dissolution type film preparation of the present invention, the drug is powder-dispersed in a drug layer containing a water-soluble polymer, the thickness of the preparation is 50 to 240 μm, and the particle diameter of the drug is 5 to 100 μm. .
本発明に使用される薬物としては、下記のような薬物が挙げられる。解熱鎮痛消炎剤としてアセトアミノフェン、イソプロピルアンチピリン、イブプロフェン、エトドラク、エピリゾール、ケトプロフェン、ジクロフェナックナトリウム、ピロキシカム、フルフェナム酸等が挙げられ；ステロイド系抗炎症剤としてプレドニゾロン等が挙げられ；抗潰瘍剤としてエカベトナトリウム、シメチジン、ニザチジン、ラニチジン塩酸塩、ラフチジン、レバミピド、ロキサチジンアセタート塩酸塩等が挙げられ；冠血管拡張剤としてジピリダモール、ジルチアゼム塩酸塩等が挙げられ；末梢血管拡張剤としてヒドララジン塩酸塩、ニセリトロール等が挙げられる。また抗生物質としてアジスロマイシン、エリスロマイシン、クラリスロマイシン、クロラムフェニコール、バカンピシリン塩酸塩等が挙げられ；合成抗菌剤としてエノキサシン等が挙げられ；抗ウイルス剤としてアシクロビル等が挙げられる。
また、鎮けい剤として臭化プロパンテリン、スコポラミン臭化水素酸、メチル硫酸Ｎ−メチルスコポラミン等が挙げられ；鎮咳剤としてジメモルファンリン酸塩、臭化水素酸デキストロメトルファン、メチルエフェドリン塩酸塩等が挙げられ；去たん剤としてエチルシステイン塩酸塩、ブロムヘキシン塩酸塩等が挙げられ；気管支拡張剤としてアミノフィリン、ジプロフィリン、テオフィリン等が挙げられる。
また強心剤としてカフェイン、ドカルパミン等が挙げられ；利尿剤としてアセタゾラミド、アゾセミド、イソソルビド、ヒドロクロロチアジド等が挙げられる。
また筋弛緩剤としてプリジノールメシル酸塩、メトカルバモール等が挙げられ；脳代謝改善剤としてホパンテン酸カルシウム、メクロフェノキセート塩酸塩等が挙げられる。マイナートランキライザーとしてクロルジアゼポキシド、ジアゼパム等が挙げられ；メジャートランキライザーとしてクロルプロマジン等が挙げられる。
また、β−ブロッカーとしてアルプレノロール塩酸塩、プロプラノロール塩酸塩等が挙げられる。抗不整脈剤としてキニジン硫酸塩等が挙げられる。痛風治療剤としてブコローム、プロベネシド等が挙げられる。
Examples of the drug used in the present invention include the following drugs. Antipyretic analgesic and anti-inflammatory agents include acetaminophen, isopropylantipyrine, ibuprofen, etodolac, epilysole, ketoprofen, diclofenac sodium, piroxicam, flufenamic acid, etc .; steroidal anti-inflammatory agents such as prednisolone; ecabet Sodium, cimetidine, nizatidine, ranitidine hydrochloride, lafutidine, rebamipide, roxatidine acetate hydrochloride and the like; dipyridamole, diltiazem hydrochloride and the like as coronary vasodilators; hydralazine hydrochloride as a peripheral vasodilator, Niseritrol and the like. Antibiotics include azithromycin, erythromycin, clarithromycin, chloramphenicol, bacampicillin hydrochloride and the like; synthetic antibacterial agents include enoxacin and the like; antiviral agents include acyclovir and the like.
Examples of the antitussive include bromide propantheline, scopolamine hydrobromic acid, methyl sulfate N-methyl scopolamine, and the like; As an expectorant, ethyl cysteine hydrochloride, bromohexine hydrochloride, etc. are mentioned; As a bronchodilator, aminophylline, diprofylline, theophylline, etc. are mentioned.
Further, as a cardiotonic agent, caffeine, docarpamine and the like can be mentioned; as a diuretic, acetazolamide, azosemide, isosorbide, hydrochlorothiazide and the like can be mentioned.
Examples of muscle relaxants include pridinol mesylate and methocarbamol; examples of brain metabolism improving agents include calcium hopantenate and meclofenoxate hydrochloride. Minor tranquilizers include chlordiazepoxide, diazepam and the like; major tranquilizers include chlorpromazine and the like.
Examples of the β-blocker include alprenolol hydrochloride and propranolol hydrochloride. Examples of antiarrhythmic agents include quinidine sulfate. Examples of gout treatment agents include bucolome and probenecid.
また、血液凝固阻止剤としてチクロピジン塩酸塩等が挙げられる。偏頭痛剤としてエルゴタミン酒石酸塩、無水カフェイン等が挙げられ；抗てんかん剤としてカルバマゼピン、トピラマート、バルプロ酸ナトリウム、ラモトリギン等が挙げられる。抗アレルギー剤としてエピナスチン塩酸塩、オロパタジン塩酸塩、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、ジフェンヒドラミン、セチリジン塩酸塩、ベポタスチンベシル酸塩、メキタジン、ロラタジン等が挙げられる。鎮吐剤としてトリメブチンマレイン酸、ベタヒスチンメシル酸、モサプリドクエン酸塩等が挙げられる。降圧剤としてアテノロール、アムロジピンベシル酸塩、アラセプリル、インダパミド等が挙げられる。高脂血症用剤としてシンバスタチン、プラバスタチンナトリウム等が挙げられる。
交感神経興奮剤としてエチレフリン塩酸塩等が挙げられる。アルツハイマー痴呆治療剤としてドネペジル塩酸塩等が挙げられる。抗腫瘍剤としてカペシタビン、テガフール等が挙げられる。アルカロイド系麻薬としてコデイン等が挙げられる。ビタミン剤としてアスコルビン酸カルシウム、チアミン硝酸塩、ニコチン酸アミド、ピリドキシン塩酸塩、フルスルチアミン塩酸塩、リボフラビン等が挙げられる。頻尿治療剤としてソリフェナシンコハク酸塩、フラボキサート塩酸塩、プロピベリン塩酸塩等が挙げられる。アンジオテンシン変換酵素阻害剤としてアラセプリル等が挙げられる。勃起不全治療剤としてアバナフィル、シルデナフィルクエン酸塩、タダラフィル、バルデナフィル塩酸塩等が挙げられる。維持透析下の二次性副甲状腺機能亢進症治療剤としてシナカルセト塩酸塩等が挙げられる。不眠症治療薬としてゾルピデム酒石酸塩等が挙げられる。抗プラスミン剤としてトラネキサム酸等が挙げられる。切迫流・早産治療薬としてリトドリン塩酸塩等が挙げられる。利胆剤としてウルソデオキシコール酸等が挙げられる。抗うつ剤としてパロキセチン塩酸塩等が挙げられる。糖尿病治療剤としてピオグリタゾン塩酸塩、ミチグリニドカルシウム等が挙げられる。統合失調症治療薬としてリスペリドン等が挙げられる。
このうち、ドネペジル及びその塩、ゾルピデム及びその塩、オロパタジン及びその塩、ロラタジン、ケトチフェン及びその塩がより好ましく、ドネペジル塩酸塩、ゾルピデム酒石酸塩、オロパタジン塩酸塩、ロラタジン、ケトチフェンフマル酸塩がさらに好ましい。
Moreover, ticlopidine hydrochloride etc. are mentioned as a blood coagulation inhibitor. Migraine agents include ergotamine tartrate, anhydrous caffeine and the like; antiepileptic agents include carbamazepine, topiramate, sodium valproate, lamotrigine and the like. Antiallergic agents include epinastine hydrochloride, olopatadine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, diphenhydramine, cetirizine hydrochloride, bepotastine besylate, mequitazine, loratadine and the like. Examples of the antiemetic include trimebutine maleic acid, betahistine mesylic acid, mosapride citrate and the like. Examples of the antihypertensive agent include atenolol, amlodipine besylate, alacepril, indapamide and the like. Examples of hyperlipidemic agents include simvastatin and pravastatin sodium.
Examples of sympathomimetic agents include ethylephrine hydrochloride. Donepezil hydrochloride etc. are mentioned as a therapeutic agent for Alzheimer's dementia. Examples of antitumor agents include capecitabine and tegafur. An example of an alkaloid narcotic is codeine. Examples of vitamin agents include calcium ascorbate, thiamine nitrate, nicotinamide, pyridoxine hydrochloride, fursultiamine hydrochloride, and riboflavin. Examples of frequent urine treatment agents include solifenacin succinate, flavoxate hydrochloride, propiverine hydrochloride and the like. Examples of the angiotensin converting enzyme inhibitor include alacepril. Examples of therapeutic agents for erectile dysfunction include avanafil, sildenafil citrate, tadalafil, vardenafil hydrochloride and the like. Cinacalcet hydrochloride and the like are mentioned as a therapeutic agent for secondary hyperparathyroidism under maintenance dialysis. Zolpidem tartrate etc. are mentioned as a therapeutic agent for insomnia. Examples of antiplasmin agents include tranexamic acid. Ritodrine hydrochloride and the like can be mentioned as a treatment for threatening and premature birth. Ursodeoxycholic acid etc. are mentioned as a bile agent. Paroxetine hydrochloride etc. are mentioned as an antidepressant. Examples of the therapeutic agent for diabetes include pioglitazone hydrochloride, mitiglinide calcium and the like. Risperidone etc. are mentioned as a therapeutic drug for schizophrenia.
Among these, donepezil and its salt, zolpidem and its salt, olopatadine and its salt, loratadine, ketotifen and its salt are more preferable, and donepezil hydrochloride, zolpidem tartrate, olopatadine hydrochloride, loratadine and ketotifen fumarate are more preferable.
これらの薬物の製剤中の含有量は、当該薬物の一回投与量として認められた量の範囲内であればよく、通常一回投与量として０．００１mg〜５０mg程度が好ましい。
また、これらの薬物の薬物層中の含有量は、崩壊性、味のマスキング効果、製剤の取り扱い性、服用感等の点から、１〜６０質量％が好ましく、５〜５０質量％がより好ましく、１０〜５０質量％がさらに好ましい。
さらに、これらの薬物の製剤中の含有量は、崩壊性、味のマスキング効果、製剤の取り扱い性、服用感の点から、１〜５０質量％が好ましく、５〜４０質量％がより好ましく、６〜３０質量％がさらに好ましい。
The content of these drugs in the preparation may be in the range of the amount recognized as a single dose of the drug, and is usually preferably about 0.001 mg to 50 mg as a single dose.
In addition, the content of these drugs in the drug layer is preferably 1 to 60% by mass, more preferably 5 to 50% by mass, from the viewpoints of disintegration, taste masking effect, formulation handleability, and feeling of administration. 10 to 50% by mass is more preferable.
Furthermore, the content of these drugs in the preparation is preferably 1 to 50% by mass, more preferably 5 to 40% by mass from the viewpoints of disintegration, taste masking effect, formulation handleability, and ingestion feeling. More preferably, it is -30 mass%.
本発明のフィルム製剤においては、これらの薬物は水溶性高分子を含有する薬物層中に粉体の状態で分散しており、当該薬物の粒子径は５〜１００μｍである。本発明においては、薬物が薬物層中にこの粒子径の粉体状態で分散していることにより、優れた崩壊性が得られる。薬物の粒子径が１００μｍを超えると薬物層分散液の展延時に、薬物の粉体が塗工コーターに引っかかり、いわゆる線引きが発生し、均一で綺麗な薬物層を得ることができない。また、薬物の粒子径が１００μｍを超えると、薬物層に１０μｍ以上の凹凸ができ、薬物層同士を上手く貼り合わせることができないことがある。また、薬物層上にコーティング層溶液を展延して乾燥し、コーティング層を形成するときに、綺麗に形成できなくなる恐れがある。一方、薬物の粒子径が５μｍより小さいと薬物粉体の口腔内での溶解が速くなり、薬物の不快味を感じる。また、製剤を服用したときに、口腔内で唾液が製剤に染み込みにくくなり崩壊性が低下する。
好ましい薬物の粒子径は１０〜１００μｍであり、より好ましくは１０〜８０μｍであり、さらに好ましくは１０〜６０μｍである。
ここで、薬物の粒子径は、例えば回折式の粒度分布測定装置（例えば、（株）島津製作所製ＳＡＬＤシリーズ、日機装(株)製マイクロトラックシリーズ）により測定することができる。測定条件（分散方式、分散溶媒等）は薬物の物理化学的特性を考慮した適正な方法であれば、特に問わない。
本発明における薬物粒子径は、薬物粒子の小さいほうから積算して９０％に当たる粒子径（Ｄ９０）を用いる。
In the film preparation of the present invention, these drugs are dispersed in a powder state in a drug layer containing a water-soluble polymer, and the particle diameter of the drug is 5 to 100 μm. In the present invention, excellent disintegration is obtained by dispersing the drug in the drug layer in a powder state of this particle size. When the particle size of the drug exceeds 100 μm, the drug powder is caught by the coating coater during spreading of the drug layer dispersion, so-called drawing occurs, and a uniform and beautiful drug layer cannot be obtained. In addition, if the particle size of the drug exceeds 100 μm, the drug layer may have irregularities of 10 μm or more, and the drug layers may not be well bonded. In addition, when the coating layer solution is spread on the drug layer and dried to form a coating layer, it may not be formed beautifully. On the other hand, when the particle size of the drug is smaller than 5 μm, dissolution of the drug powder in the oral cavity is accelerated and the unpleasant taste of the drug is felt. In addition, when the preparation is taken, saliva hardly penetrates into the preparation in the oral cavity and the disintegration property decreases.
The particle diameter of a preferable drug is 10 to 100 μm, more preferably 10 to 80 μm, and still more preferably 10 to 60 μm.
Here, the particle diameter of the drug can be measured by, for example, a diffraction type particle size distribution measuring apparatus (for example, SALD series manufactured by Shimadzu Corporation, Microtrack series manufactured by Nikkiso Co., Ltd.). The measurement conditions (dispersion method, dispersion solvent, etc.) are not particularly limited as long as they are appropriate methods considering the physicochemical properties of the drug.
As the drug particle diameter in the present invention, a particle diameter (D90) corresponding to 90% is used from the smaller drug particle.
本発明の口腔内溶解型フィルム製剤は、前記薬物層のみからなる単層製剤であっても良いが、通常薬物層の両側（最外層）にコーティング層を有する３層のフィルム製剤であるのが好ましい。尚、薬物層とコーティング層の間に、製剤に他の機能を付与するための層が挿入されていても良い。 The oral-dissolving film preparation of the present invention may be a single-layer preparation consisting only of the drug layer, but is usually a three-layer film preparation having coating layers on both sides (outermost layer) of the drug layer. preferable. A layer for imparting other functions to the preparation may be inserted between the drug layer and the coating layer.
本発明のフィルム製剤においては、製剤の厚さが５０〜２４０μｍであることが、崩壊性と味のマスキング効果を得るうえで重要である。製剤の厚さが２４０μｍを超えると、口腔内での溶解又は崩壊が遅くなったり、製剤が崩壊した後も口腔内にいわゆる粘つき感が残る等服用感を悪くする。一方、厚さが５０μｍ未満だと、取り扱い性が悪くなったり、必要量の薬物を含有させることが困難となる。好ましい製剤の厚さは５０〜２００μｍであり、さらに好ましくは５０〜１８０μｍである。 In the film preparation of the present invention, the thickness of the preparation is 50 to 240 μm, which is important for obtaining disintegration and taste masking effect. When the thickness of the preparation exceeds 240 μm, the dissolution or disintegration in the oral cavity is delayed, or the so-called sticky feeling remains in the oral cavity even after the preparation disintegrates, and the feeling of dosing is worsened. On the other hand, when the thickness is less than 50 μm, the handleability is deteriorated and it becomes difficult to contain a necessary amount of drug. The thickness of a preferable formulation is 50-200 micrometers, More preferably, it is 50-180 micrometers.
本発明のフィルム製剤は、前記のように、薬物層の片面及び／又は両面には必要に応じて最外部にコーティング層を設けたり、薬物層とコーティング層の間に他の機能を有する層を設けることができる。これらの層は、薬物が潮解性や吸湿性を有する場合、薬物が酸素や水分と触れたときに安定性が悪くなる場合等に有効である。
従って、本発明における製剤の厚さは、薬物層及びコーティング層等を含む合計の厚さである。また、薬物層とコーティング層の間に他の機能を有する層を設けた場合は、これら層の厚みも含める。なお、コーティング層の両面合計の厚さは１０〜４０μｍが好ましい。また薬物層の厚さは４０〜２３０μｍが好ましく、４０〜１９０μｍがより好ましく、４０〜１７０μｍがさらに好ましい。
In the film preparation of the present invention, as described above, a coating layer is provided on the outermost surface of one and / or both sides of the drug layer as necessary, or a layer having other functions is provided between the drug layer and the coating layer. Can be provided. These layers are effective when the drug has deliquescence and hygroscopicity, or when the drug becomes unstable when it comes into contact with oxygen or moisture.
Therefore, the thickness of the preparation in the present invention is the total thickness including the drug layer, the coating layer, and the like. In addition, when layers having other functions are provided between the drug layer and the coating layer, the thicknesses of these layers are also included. The total thickness of both sides of the coating layer is preferably 10 to 40 μm. The thickness of the drug layer is preferably 40 to 230 μm, more preferably 40 to 190 μm, and still more preferably 40 to 170 μm.
本発明のフィルム製剤においては、製剤の厚さと薬物の粒子径の比は崩壊性と味のマスキング効果の点から、４５：１〜１．３：１が好ましく、３０：１〜１．４：１がより好ましく、３０：１〜１．５：１がさらに好ましく、３０：１〜１．８：１がさらに好ましく、２０：１〜１．８：１がさらに好ましい。 In the film preparation of the present invention, the ratio between the thickness of the preparation and the particle diameter of the drug is preferably 45: 1 to 1.3: 1 from the viewpoint of disintegration and taste masking effect, and 30: 1 to 1.4: 1 is more preferable, 30: 1 to 1.5: 1 is further preferable, 30: 1 to 1.8: 1 is further preferable, and 20: 1 to 1.8: 1 is further preferable.
本発明の薬物層に用いられる水溶性高分子としては、可食性の水溶性高分子であればよく、例えばヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ、別名：ヒプロメロース）、ヒドロキシエチルセルロース（ＨＥＣ）、カルボキシメチルセルロース・ナトリウム（ＣＭＣ−Ｎａ、別名：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（ＣＭＣ−Ｃａ、別名：カルメロース・カルシウム）、カルボキシメチルセルロース・カリウム（ＣＭＣ−Ｋ、別名：カルメロース・カリウム）、カルボキシメチルセルロース（ＣＭＣ、別名：カルメロース）、メチルセルロース、ポリビニルピロリドン（ＰＶＰ、別名：ポビドン）、アルギン酸ナトリウム、ポリビニルアルコール（ＰＶＡ）、プルラン、α化デンプン、キサンタンガム等が挙げられる。これらは、単独で又は組み合わせて使用することができる。中でも、口腔内におけるフィルム製剤の崩壊性の観点から、特にＨＰＣ、ＨＰＭＣが好適である。なお、ＨＰＣ及びＨＰＭＣの粘度は特に限定されるものではないが、例えば、ＨＰＣの場合、２０℃における２％水溶液の動粘度が２．０〜１０ｍＰａ・ｓ、特に３．０〜１０ｍＰａ・ｓであるものが好ましく、ＨＰＭＣの場合、２０℃における２％水溶液の動粘度が３．０〜１０ｍＰａ・ｓ、特に３．０〜６ｍＰａ・ｓであるものが好ましい。かかる動粘度は、第１６改正日本薬局方に記載の試験方法に基づく値である。 The water-soluble polymer used in the drug layer of the present invention may be any edible water-soluble polymer, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, also known as hypromellose), hydroxyethylcellulose (HEC). ), Carboxymethylcellulose sodium (CMC-Na, also known as carmellose sodium), carboxymethylcellulose calcium (CMC-Ca, also known as carmellose calcium), carboxymethylcellulose potassium (CMC-K, also known as carmellose potassium), Carboxymethylcellulose (CMC, also known as carmellose), methylcellulose, polyvinylpyrrolidone (PVP, also known as povidone), sodium alginate, polyvinyl alcohol (PV ), Pullulan, alpha-starch, xanthan gum, and the like. These can be used alone or in combination. Among these, HPC and HPMC are particularly preferable from the viewpoint of the disintegration property of the film preparation in the oral cavity. The viscosity of HPC and HPMC is not particularly limited. For example, in the case of HPC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 2.0 to 10 mPa · s, particularly 3.0 to 10 mPa · s. Some are preferable, and in the case of HPMC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 3.0 to 10 mPa · s, particularly 3.0 to 6 mPa · s. Such kinematic viscosity is a value based on the test method described in the 16th revised Japanese Pharmacopoeia.
薬物層中の水溶性高分子の含有量は、崩壊性の点から、１０〜９８質量％が好ましく、２０〜８０質量％がより好ましく、３０〜８０質量％がさらに好ましい。 The content of the water-soluble polymer in the drug layer is preferably 10 to 98% by mass, more preferably 20 to 80% by mass, and still more preferably 30 to 80% by mass from the viewpoint of disintegration.
本発明フィルム製剤の薬物層には、前記成分以外に糖類、可塑剤、甘味料、矯味剤、着色剤、pH調整剤、界面活性剤、安定化剤、香料の他、水、エタノール等の溶媒が含まれていてもよい。糖類としては、マルトース、還元麦芽糖水アメ、マルチトール、エリスリトール、キシリトール、ショ糖、ソルビトール、マンニトール、トレハロース等が挙げられる。可塑剤としては、ポリエチレングリコール（別名：マクロゴール）、グリセリン、ソルビトール、クエン酸トリエチル等が挙げられる。甘味料としては、サッカリンナトリウム、アスパルテーム、アセスムファムカリウム、スクラロース、グリチルリチン酸二カリウム等が挙げられる。矯味剤としては、ｌ−メントール等が挙げられる。着色剤としては、酸化チタン、三二酸化鉄、黄色三二酸化鉄、食用色素等が挙げられる。その他、pH調整剤としては、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム等が挙げられる。界面活性剤としては、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、グリセリン脂肪酸エステル、ポリオキシエチレンアルキルエーテル等が挙げられる。安定化剤としては、塩化カルシウム等が挙げられる。 In addition to the above components, the drug layer of the film preparation of the present invention includes sugars, plasticizers, sweeteners, corrigents, colorants, pH adjusters, surfactants, stabilizers, fragrances, and solvents such as water and ethanol. May be included. Examples of the saccharide include maltose, reduced maltose water candy, maltitol, erythritol, xylitol, sucrose, sorbitol, mannitol, trehalose and the like. Examples of the plasticizer include polyethylene glycol (also known as macrogol), glycerin, sorbitol, triethyl citrate, and the like. Examples of the sweetener include saccharin sodium, aspartame, acesulfame potassium, sucralose, dipotassium glycyrrhizinate and the like. Examples of the corrigent include l-menthol. Examples of the colorant include titanium oxide, iron sesquioxide, yellow iron sesquioxide, and food coloring. In addition, examples of the pH adjuster include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate and the like. Examples of the surfactant include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene alkyl ether, and the like. Examples of the stabilizer include calcium chloride.
コーティング層は、通常のフィルム製剤のコーティング層であればよく、水溶性高分子、糖類、可塑剤、甘味料、矯味剤、着色剤、香料の他、水、エタノール等の溶媒が含まれていてもよい。ここで用いられる水溶性高分子、糖類、可塑剤、甘味料、矯味剤及び着色剤としては、前記薬物層の成分として列挙したものが挙げられる。コーティング層の２０〜９８質量％、さらに３０〜９０質量％、特に４０〜９０質量％は水溶性高分子であるのが好ましい。 The coating layer may be a coating layer of a normal film preparation, and includes a solvent such as water and ethanol in addition to a water-soluble polymer, a saccharide, a plasticizer, a sweetener, a corrigent, a coloring agent, and a fragrance. Also good. Examples of the water-soluble polymer, saccharide, plasticizer, sweetener, corrigent and colorant used here include those listed as components of the drug layer. It is preferable that 20 to 98% by mass, further 30 to 90% by mass, particularly 40 to 90% by mass of the coating layer is a water-soluble polymer.
本発明のフィルム製剤の大きさは、服用しやすいものであれば特に限定されるものではないが、例えば、１〜７ｃｍ2程度の大きさにすることが好ましい。また、その形状も服用しやすいものであれば特に限定されるものではないが、例えば、円形、楕円形、方形等を適宜選択することが可能である。 Although the magnitude | size of the film formulation of this invention will not be specifically limited if it is easy to take, For example, it is preferable to make it a magnitude | size of about 1-7 cm < 2 >. Further, the shape is not particularly limited as long as it is easy to take, but for example, a circle, an ellipse, a square, or the like can be appropriately selected.
本発明のフィルム製剤は、迅速に溶解又は崩壊することが可能であり、かつ水への溶解性に優れるものである。例えば、口腔内における溶解又は崩壊時間は１分以内、特に３０秒以内であることが好ましく、また水に対する溶解時間は３分以内、特に１分以内であることが好ましい。 The film preparation of the present invention can be rapidly dissolved or disintegrated and has excellent solubility in water. For example, the dissolution or disintegration time in the oral cavity is preferably within 1 minute, particularly within 30 seconds, and the dissolution time in water is preferably within 3 minutes, particularly within 1 minute.
また、本発明のフィルム製剤は、複数個の製剤が行列状に配置され、該製剤の形状を画定する切断線が設けられたシート状の形態とすることも可能であり、その一方面には樹脂フィルムが設けられていてもよい。このような製剤は、患者が１つの製剤を切断線に沿って分離しながら樹脂フィルムから剥離し服用することが可能である。かかる樹脂フィルムとしては、ポリエチレンテレフタレート（ＰＥＴ）、ポリエチレンナフタレート、共重合ポリエステル、ポリイミド、ポリプロピレン、セルローストリアセテート、酢酸ビニル樹脂、エチレン−酢酸ビニル共重合体、ポリエチレン、ポリ塩化ビニル、ポリカーボネート、ポリプロピレン、トリアセテート、フッ素樹脂（ＥＴＦＥ、ＰＦＡ、ＦＥＰ）等の樹脂からなるフィルムから適宜選択して使用することができる。中でも、特にＰＥＴが好ましい。 In addition, the film preparation of the present invention can be in the form of a sheet in which a plurality of preparations are arranged in a matrix and provided with cutting lines that define the shape of the preparation. A resin film may be provided. Such a preparation can be taken by a patient while separating one preparation along a cutting line from the resin film. Such resin films include polyethylene terephthalate (PET), polyethylene naphthalate, copolymer polyester, polyimide, polypropylene, cellulose triacetate, vinyl acetate resin, ethylene-vinyl acetate copolymer, polyethylene, polyvinyl chloride, polycarbonate, polypropylene, triacetate. , A film made of a resin such as fluororesin (ETFE, PFA, FEP) can be appropriately selected for use. Among these, PET is particularly preferable.
本発明の口腔内溶解型フィルム製剤の単層製剤は、薬物層分散液を剥離フィルム上に展延して乾燥し得られた薬物層を所定の大きさに切断することができる。また、薬物層の両側にコーティング層を有するフィルム製剤は、コーティング層を形成し、その上に薬物層を形成させ、次いでこの２層を、薬物層を内側にして貼り合わせて積層することにより製造することができる。即ち、コーティング層の形成は、コーティング層溶液を調製し、剥離フィルム上に展延して乾燥すればよい。次に、薬物層の形成は、薬物層分散液をコーティング層上に展延して乾燥すればよい。得られた薬物層とコーティング層の積層体は、薬物層同士が対向するようにラミネート機で熱圧着させれば、薬物層の両側にコーティング層を有するフィルム製剤が製造できる。この製造方法により得られたフィルム製剤の同一組成の薬物層同士を貼り合わせて積層した薬物層は、１層とする。
また、前述の薬物層とコーティング層の積層体の薬物層上に、コーティング層溶液を展延して乾燥しコーティング層を形成する方法でも、製造できる。尚、本発明のフィルム製剤の製造方法は、これら製造方法に限定されるものではない。
The monolayer preparation of the intraoral dissolution type film preparation of the present invention can cut a drug layer obtained by spreading a drug layer dispersion on a release film and drying it to a predetermined size. In addition, a film preparation having a coating layer on both sides of a drug layer is produced by forming a coating layer, forming a drug layer thereon, and then laminating the two layers with the drug layer inside. can do. That is, the coating layer may be formed by preparing a coating layer solution, spreading it on the release film, and drying it. Next, the drug layer may be formed by spreading the drug layer dispersion on the coating layer and drying it. The obtained drug layer and coating layer laminate can be manufactured by a thermocompression bonding with a laminating machine so that the drug layers face each other, whereby a film preparation having coating layers on both sides of the drug layer can be produced. The drug layer obtained by laminating and laminating drug layers having the same composition of the film preparation obtained by this production method is one layer.
Further, it can also be produced by a method in which the coating layer solution is spread on the drug layer of the laminate of the drug layer and the coating layer and dried to form the coating layer. In addition, the manufacturing method of the film formulation of this invention is not limited to these manufacturing methods.
薬物層分散液は、前記薬物層に必要な成分を水及び／又はエタノールを含有する溶媒に分散することにより得ることができる。コーティング層溶液も、薬物層分散液と同様に調製でき、コーティング層の形成手段も薬物層と同様である。溶媒は水、エタノール及び水−エタノール溶液等を用いることができる。尚、溶媒量は、薬物及び使用する添加物により適宜増減できる。 The drug layer dispersion can be obtained by dispersing components necessary for the drug layer in a solvent containing water and / or ethanol. The coating layer solution can be prepared in the same manner as the drug layer dispersion, and the means for forming the coating layer is the same as that of the drug layer. As the solvent, water, ethanol, a water-ethanol solution, or the like can be used. The amount of solvent can be appropriately increased or decreased depending on the drug and the additive used.
次に実施例を挙げて本発明を詳細に説明する。 EXAMPLES Next, an Example is given and this invention is demonstrated in detail.
試験例１
[実施例１]
エタノール２５質量部に、ドネペジル塩酸塩５質量部、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＳＬ、日本曹達（株））９．３質量部、スクラロース１質量部、ｌ−メントール０．１６質量部、マクロゴール４００ １．５０質量部を加えて攪拌混合し、薬物層分散液を得た。
また、精製水／エタノール（１５質量部／１５質量部）混合溶媒に、ヒプロメロース（信越化学工業（株））６質量部、スクラロース０．１質量部、酸化チタン２質量部を加えて攪拌混合し、コーティング層溶液を得た。
先ず、ポリエステル製剥離フィルム上にコーティング層溶液を展延し乾燥してコーティング層を形成した後、該コーティング層上に薬物層分散液を展延し乾燥して薬物層を積層させ、２層構造体を得た。
この２層構造体を２式作製し、２つの２層構造体の薬物層同士が対向するようにラミネート機で熱圧着させ、コーティング層／薬物層／コーティング層の３層構造体を得た。この３層構造体を１４ｍｍ×２０ｍｍに切断し、フィルム製剤を得た。なお、薬物は薬物層中に粉体で分散していることは、肉眼で確認できる。
Test example 1
[Example 1]
25 parts by mass of ethanol, 5 parts by mass of donepezil hydrochloride, 9.3 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.), 1 part by mass of sucralose, 0.16 parts by mass of l-menthol, Macrogol 400 1.50 parts by mass was added and mixed by stirring to obtain a drug layer dispersion.
Further, 6 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd.), 0.1 part by mass of sucralose and 2 parts by mass of titanium oxide are added to a mixed solvent of purified water / ethanol (15 parts by mass / 15 parts by mass), and the mixture is stirred and mixed. A coating layer solution was obtained.
First, a coating layer solution is spread on a polyester release film and dried to form a coating layer, and then a drug layer dispersion is spread on the coating layer and dried to laminate the drug layer. Got the body.
Two sets of this two-layer structure were produced, and thermocompression bonded with a laminating machine so that the drug layers of the two two-layer structures were opposed to each other to obtain a three-layer structure of coating layer / drug layer / coating layer. This three-layer structure was cut into 14 mm × 20 mm to obtain a film preparation. It can be confirmed with the naked eye that the drug is dispersed in powder form in the drug layer.
［実施例２〜３及び比較例１〜２］
表２記載の成分を用いて実施例１と同様にして、フィルム製剤を得た。
[Examples 2-3 and Comparative Examples 1-2]
A film preparation was obtained in the same manner as in Example 1 using the components shown in Table 2.
[実施例４]
エタノール２５質量部に、ゾルピデム酒石酸塩５質量部、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＳＬ、日本曹達（株））８質量部、ポビドン１質量部、水酸化ナトリウム０．５１５質量部、ｌ−メントール０．０５質量部、マクロゴール４００ ０．７５質量部を加えて攪拌混合し、薬物層分散液を得た。
また、精製水／エタノール（１５質量部／１５質量部）混合溶媒に、ヒプロメロース（信越化学工業（株））８．５質量部、トレハロース１質量部、スクラロース０．５質量部、サッカリンナトリウム０．２５質量部、酸化チタン１質量部を加えて攪拌混合し、コーティング層溶液を得た。
先ず、ポリエステル製剥離フィルム上にコーティング層溶液を展延し乾燥してコーティング層を形成した後、該コーティング層上に薬物層分散液を展延し乾燥して薬物層を積層させ、２層構造体を得た。
この２層構造体を２式作製し、２つの２層構造体の薬物層同士が対向するようにラミネート機で熱圧着させ、コーティング層／薬物層／コーティング層の３層構造体を得た。この３層構造体を１４ｍｍ×２０ｍｍに切断し、フィルム製剤を得た。なお、薬物は薬物層中に粉体で分散していることは、肉眼で確認できる。
[Example 4]
25 parts by mass of ethanol, 5 parts by mass of zolpidem tartrate, 8 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.), 1 part by mass of povidone, 0.515 parts by mass of sodium hydroxide, 0. 05 parts by mass and 0.75 part by mass of Macrogol 400 were added and mixed by stirring to obtain a drug layer dispersion.
Further, in a purified water / ethanol (15 parts by mass / 15 parts by mass) mixed solvent, 8.5 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd.), 1 part by mass of trehalose, 0.5 parts by mass of sucralose, 0.25 saccharin sodium Part by mass and 1 part by mass of titanium oxide were added and mixed with stirring to obtain a coating layer solution.
First, a coating layer solution is spread on a polyester release film and dried to form a coating layer, and then a drug layer dispersion is spread on the coating layer and dried to laminate the drug layer. Got the body.
Two sets of this two-layer structure were produced, and thermocompression bonded with a laminating machine so that the drug layers of the two two-layer structures were opposed to each other to obtain a three-layer structure of coating layer / drug layer / coating layer. This three-layer structure was cut into 14 mm × 20 mm to obtain a film preparation. It can be confirmed with the naked eye that the drug is dispersed in powder form in the drug layer.
［比較例３］
表３記載の成分を用いて実施例４と同様にして、フィルム製剤を得た。
[Comparative Example 3]
A film preparation was obtained in the same manner as in Example 4 using the components shown in Table 3.
[実施例５]
エタノール２５質量部に、オロパタジン塩酸塩２．５質量部、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＳＬ、日本曹達（株））１５質量部、スクラロース１質量部、ｌ−メントール０．３質量部、マクロゴール４００ １．５質量部、塩化カルシウム１質量部を加えて攪拌混合し、薬物層分散液を得た。
また、精製水／エタノール（５．４質量部／１２．６質量部）混合溶媒に、ヒプロメロース（信越化学工業（株））３．３質量部、マクロゴール４００ ０．５質量部、色素０．００５質量部を加えて攪拌混合し、コーティング層溶液を得た。
先ず、ポリエステル製剥離フィルム上にコーティング層溶液を展延し乾燥してコーティング層を形成した後、該コーティング層上に薬物層分散液を展延し乾燥して薬物層を積層させ、２層構造体を得た。
この２層構造体を２式作製し、２つの２層構造体の薬物層同士が対向するようにラミネート機で熱圧着させ、コーティング層／薬物層／コーティング層の３層構造体を得た。この３層構造体を１４ｍｍ×２０ｍｍに切断し、フィルム製剤を得た。なお、薬物は薬物層中に粉体で分散していることは、肉眼で確認できる。
[Example 5]
25 parts by mass of ethanol, 2.5 parts by mass of olopatadine hydrochloride, 15 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.), 1 part by mass of sucralose, 0.3 parts by mass of l-menthol, Macrogol 400 1.5 parts by mass and 1 part by mass of calcium chloride were added and mixed with stirring to obtain a drug layer dispersion.
Further, in a purified water / ethanol (5.4 parts by mass / 12.6 parts by mass) mixed solvent, hypromellose (Shin-Etsu Chemical Co., Ltd.) 3.3 parts by mass, Macrogol 400 0.5 parts by mass, dye 0. 005 parts by mass was added and mixed by stirring to obtain a coating layer solution.
First, a coating layer solution is spread on a polyester release film and dried to form a coating layer, and then a drug layer dispersion is spread on the coating layer and dried to laminate the drug layer. Got the body.
Two sets of this two-layer structure were produced, and thermocompression bonded with a laminating machine so that the drug layers of the two two-layer structures were opposed to each other to obtain a three-layer structure of coating layer / drug layer / coating layer. This three-layer structure was cut into 14 mm × 20 mm to obtain a film preparation. It can be confirmed with the naked eye that the drug is dispersed in powder form in the drug layer.
［実施例６及び比較例４〜５］
表４記載の成分を用いて実施例５と同様にして、フィルム製剤を得た。
[Example 6 and Comparative Examples 4 to 5]
A film preparation was obtained in the same manner as in Example 5 using the components shown in Table 4.
[実施例７]
精製水３０質量部に、ロラタジン１０質量部、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＳＬ、日本曹達（株））１０質量部、ポビドン１質量部、粉末還元麦芽糖水アメ１．４質量部、ポリソルベート８０ ０．２質量部、グリセリン脂肪酸エステル０．００２質量部、マクロゴール４００ ２質量部を加えて攪拌混合し、薬物層分散液を得た。
また、精製水／エタノール（１５質量部／１５質量部）混合溶媒に、ヒプロメロース（信越化学工業（株））８．５質量部、酸化チタン１質量部、サッカリンナトリウム０．５質量部を加えて攪拌混合し、コーティング層溶液を得た。
先ず、ポリエステル製剥離フィルム上にコーティング層溶液を展延し乾燥してコーティング層を形成した後、該コーティング層上に薬物層分散液を展延し乾燥して薬物層を積層させ、２層構造体を得た。
この２層構造体を２式作製し、２つの２層構造体の薬物層同士が対向するようにラミネート機で熱圧着させ、コーティング層／薬物層／コーティング層の３層構造体を得た。この３層構造体を１４ｍｍ×２０ｍｍに切断し、フィルム製剤を得た。なお、薬物は薬物層中に粉体で分散していることは、肉眼で確認できる。
[Example 7]
30 parts by mass of purified water, 10 parts by mass of loratadine, 10 parts by mass of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.), 1 part by mass of povidone, 1.4 parts by mass of powdered reduced maltose water candy, polysorbate 80 2 parts by mass, 0.002 parts by mass of glycerin fatty acid ester and 2 parts by mass of Macrogol 400 were added and mixed by stirring to obtain a drug layer dispersion.
In addition, 8.5 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd.), 1 part by mass of titanium oxide, and 0.5 parts by mass of sodium saccharin are added to purified water / ethanol (15 parts by mass / 15 parts by mass) and stirred. Mixing was performed to obtain a coating layer solution.
First, a coating layer solution is spread on a polyester release film and dried to form a coating layer, and then a drug layer dispersion is spread on the coating layer and dried to laminate the drug layer. Got the body.
Two sets of this two-layer structure were produced, and thermocompression bonded with a laminating machine so that the drug layers of the two two-layer structures were opposed to each other to obtain a three-layer structure of coating layer / drug layer / coating layer. This three-layer structure was cut into 14 mm × 20 mm to obtain a film preparation. It can be confirmed with the naked eye that the drug is dispersed in powder form in the drug layer.
［実施例８及び比較例６〜７］
表５記載の成分を用いて実施例７と同様にして、フィルム製剤を得た。
[Example 8 and Comparative Examples 6-7]
A film preparation was obtained in the same manner as in Example 7 using the components shown in Table 5.
[実施例９]
精製水３０質量部に、ケトチフェンフマル酸塩１．３８質量部、ヒドロキシプロピルセルロース（ＨＰＣ−ＳＬ、日本曹達（株））７．６２質量部、クエン酸トリエチル １質量部を加えて攪拌混合し、薬物層分散液を得た。
また、精製水／エタノール（１２質量部／１２質量部）混合溶媒に、ヒプロメロース（信越化学工業（株））５．２９質量部、酸化チタン１質量部、スクラロース１．５質量部、トレハロース１質量部、グリチルリチン酸二カリウム０．６質量部、ｌ−メントール０．１２質量部、クエン酸トリエチル１．７１質量部を加えて攪拌混合し、コーティング層溶液を得た。
先ず、ポリエステル製剥離フィルム上にコーティング層溶液を展延し乾燥してコーティング層を形成した後、該コーティング層上に薬物層分散液を展延し乾燥して薬物層を積層させ、２層構造体を得た。
この２層構造体を２式作製し、２つの２層構造体の薬物層同士が対向するようにラミネート機で熱圧着させ、コーティング層／薬物層／コーティング層の３層構造体を得た。この３層構造体を１４ｍｍ×２０ｍｍに切断し、フィルム製剤を得た。なお、薬物は薬物層中に粉体で分散していることは、肉眼で確認できる。
[Example 9]
To 30 parts by mass of purified water, 1.38 parts by mass of ketotifen fumarate, 7.62 parts by mass of hydroxypropylcellulose (HPC-SL, Nippon Soda Co., Ltd.), 1 part by mass of triethyl citrate are added and stirred. A drug layer dispersion was obtained.
In addition, 5.29 parts by mass of hypromellose (Shin-Etsu Chemical Co., Ltd.), 1 part by mass of titanium oxide, 1.5 parts by mass of sucralose, 1 part by mass of trehalose in a mixed solvent of purified water / ethanol (12 parts by mass / 12 parts by mass) Part, 0.6 parts by weight of dipotassium glycyrrhizinate, 0.12 parts by weight of 1-menthol and 1.71 parts by weight of triethyl citrate were added and mixed by stirring to obtain a coating layer solution.
First, a coating layer solution is spread on a polyester release film and dried to form a coating layer, and then a drug layer dispersion is spread on the coating layer and dried to laminate the drug layer. Got the body.
Two sets of this two-layer structure were produced, and thermocompression bonded with a laminating machine so that the drug layers of the two two-layer structures were opposed to each other to obtain a three-layer structure of coating layer / drug layer / coating layer. This three-layer structure was cut into 14 mm × 20 mm to obtain a film preparation. It can be confirmed with the naked eye that the drug is dispersed in powder form in the drug layer.
［実施例１０及び比較例８］
表６記載の成分を用いて実施例９と同様にして、フィルム製剤を得た。
[Example 10 and Comparative Example 8]
A film preparation was obtained in the same manner as in Example 9 using the components shown in Table 6.
得られた実施例１〜１０及び比較例１〜８のフィルム製剤を、パネラー３名によりハンドリング（取り扱いやすさ）、溶解時間、服用感（残渣感）及び味を評価した。溶解性は、各フィルム製剤を口中で溶解して表１の基準により評価した。
評価基準を表１に示す。また評価結果（スコアの平均）を表２〜表６に示す。
The film formulations of Examples 1 to 10 and Comparative Examples 1 to 8 obtained were evaluated for handling (ease of handling), dissolution time, feeling of taking (residue feeling) and taste by three panelists. The solubility was evaluated according to the criteria shown in Table 1 after dissolving each film preparation in the mouth.
The evaluation criteria are shown in Table 1. The evaluation results (score average) are shown in Tables 2-6.
表２〜表６より、粒子径（Ｄ９０）が５〜１００μｍの薬物が薬物層中に分散しており、かつ製剤の厚さが５０〜２４０μｍのフィルム製剤は、崩壊性が良好であり、味もマスキングされており、さらにハンドリング及び服用感も良好であった。 From Tables 2 to 6, a film preparation having a drug particle size (D90) of 5 to 100 μm dispersed in the drug layer and a preparation thickness of 50 to 240 μm has good disintegration, taste Were also masked, and the handling and feeling of taking were also good.
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