JP6453712B2 - Method for producing film preparation for oral administration - Google Patents
Method for producing film preparation for oral administration Download PDFInfo
- Publication number
- JP6453712B2 JP6453712B2 JP2015113775A JP2015113775A JP6453712B2 JP 6453712 B2 JP6453712 B2 JP 6453712B2 JP 2015113775 A JP2015113775 A JP 2015113775A JP 2015113775 A JP2015113775 A JP 2015113775A JP 6453712 B2 JP6453712 B2 JP 6453712B2
- Authority
- JP
- Japan
- Prior art keywords
- drug
- oral administration
- layer
- preparation
- film preparation
- 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、スクリーン印刷技術を用いる経口投与用フィルム製剤の製造方法及び経口投与用フィルム製剤に関する。 The present invention relates to a method for producing a film preparation for oral administration using a screen printing technique and a film preparation for oral administration.
近年、錠剤、顆粒剤、カプセル剤等の製剤に加えて、口腔粘膜から薬物を経粘膜投与したり、水無しで薬物を経口投与できる経口投与用製剤としてフィルム製剤が研究され、上市されている(例えば、特許文献1〜3)。 In recent years, film preparations have been studied and marketed as preparations for oral administration in which drugs can be transmucosally administered from the oral mucosa, or orally without water, in addition to preparations such as tablets, granules and capsules. (For example, Patent Documents 1 to 3).
これらのフィルム製剤の製造技術としては、塗工乾燥を繰り返し積層する方法(特許文献4)や塗工乾燥したものを貼り合わせる方法(特許文献5)によって得られたシートを、打ち抜き/裁断する方法が知られている。いずれの方法でも、塗工にはコーター方式が用いられている。また、コーター方式による塗工手段以外の方法として、予め形成された水溶性フィルムの表面にインクジェット印刷技術によりニコチンを塗布する方法が報告されている(特許文献6)。 As a manufacturing technique of these film preparations, a method of punching / cutting a sheet obtained by a method of repeatedly laminating coating and drying (Patent Document 4) or a method of pasting coated and dried materials (Patent Document 5) It has been known. In any method, the coater method is used for coating. Further, as a method other than the coating method by the coater method, a method of applying nicotine to the surface of a previously formed water-soluble film by an ink jet printing technique has been reported (Patent Document 6).
しかしながら、コーター方式による塗工を行う方法では、塗工乾燥後積層又は貼り合わせて得られたシートを打ち抜き/裁断する工程が必要であり、打ち抜き/裁断した後の残り、いわゆるスクラップが生じてしまうため、薬物の損失が多くなるという問題を有している。この問題は、薬物が高価な場合、また薬物が麻薬指定のような取り扱いや廃棄に規制がある場合は深刻である。また、インクジェット印刷技術による塗布では、固形分率の高い、高粘度の調製液を塗布することができない。また、調製液の粘度を低くすると溶媒の使用量が多くなり、更に繰り返し塗布を行う必要があり非効率である。更に、薬物や賦形剤が粉体で分散された調製液を塗布する場合目詰まりの問題を有している。 However, in the method of coating by the coater method, a step of punching / cutting a sheet obtained by laminating or bonding after coating drying is necessary, and the remainder after punching / cutting, so-called scrap is generated. Therefore, there is a problem that drug loss increases. This problem is serious when the drug is expensive and when the drug is restricted in handling and disposal as specified by the drug. In addition, a high-viscosity preparation liquid with a high solid content cannot be applied by application using an inkjet printing technique. Moreover, if the viscosity of a preparation liquid is made low, the usage-amount of a solvent will increase and it will be necessary to apply | coat repeatedly and is inefficient. Furthermore, there is a problem of clogging when a preparation liquid in which a drug or excipient is dispersed in powder is applied.
また、医薬品には、高い含量均一性が求められており、例えば日本薬局方(16局)製剤均一性試験に適合するには、塗工精度は、塗工量の相対標準偏差として4.7%以下であることが必要である。 In addition, pharmaceuticals are required to have high content uniformity. For example, in order to meet the Japanese Pharmacopoeia (16) formulation uniformity test, the coating accuracy is 4.7 as a relative standard deviation of the coating amount. % Or less.
従って、本発明の課題は、スクラップが生じず、かつ塗工精度の良好な経口投与用フィルム製剤及びその製造方法を提供することにある。 Accordingly, an object of the present invention is to provide a film preparation for oral administration having no coating scrap and good coating accuracy, and a method for producing the same.
そこで本発明者は、スクリーン印刷技術に着目して検討したところ、当該技術により薬物層を塗布すれば、コーター方式による塗工のようなスクラップの発生は防止できることが分かった。しかし、スクリーン印刷で薬物含有液を形成した場合、塗布量のバラツキが大きく、日本薬局方の製剤均一性試験に適合させることが困難であることが判明した。そこでさらに検討した結果、スクリーン印刷により塗布する薬物含有液のチキソトロピー性により塗工精度が変化し、チキソトロピー指数を一定の範囲とすることにより、日本薬局方の製剤均一性試験に適合するために必要な塗工量の相対標準偏差を4.7%以下に制御できることを見出し、本発明を完成した。 Therefore, the present inventor studied paying attention to the screen printing technique, and found that the application of the drug layer by the technique can prevent the generation of scrap like coating by the coater method. However, when the drug-containing liquid was formed by screen printing, it was found that the variation in the coating amount was large and it was difficult to adapt it to the formulation uniformity test of the Japanese Pharmacopoeia. Therefore, as a result of further investigation, it is necessary to meet the Japanese Pharmacopoeia formulation uniformity test by changing the coating accuracy depending on the thixotropy of the drug-containing liquid applied by screen printing and keeping the thixotropy index within a certain range. And found that the relative standard deviation of the coating amount can be controlled to 4.7% or less, and completed the present invention.
すなわち、本発明は、次の〔1〕〜〔6〕を提供するものである。 That is, the present invention provides the following [1] to [6].
〔1〕薬物含有層を、チキソトロピー指数0.1以上0.7以下の薬物含有液のスクリーン印刷により形成することを特徴とする経口投与用フィルム製剤の製造方法。
〔2〕薬物含有液のチキソトロピー指数が、0.15以上0.6以下である〔1〕記載の経口投与用フィルム製剤の製造方法。
〔3〕薬物含有層の両面又は片面に機能層を有する〔1〕又は〔2〕記載の経口投与用フィルム製剤の製造方法。
〔4〕機能層が、水溶性高分子を含有する層である〔3〕記載の経口投与用フィルム製剤の製造方法。
〔5〕薬物含有液が、水溶性高分子、薬物及びチキソトロピー性付与物質を含有する液である〔1〕〜〔4〕のいずれかに記載の経口投与用フィルム製剤の製造方法。
〔6〕〔1〕〜〔5〕のいずれかに記載の製造方法により得られた経口投与用フィルム製剤。
[1] A method for producing a film preparation for oral administration, wherein the drug-containing layer is formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 to 0.7.
[2] The method for producing a film preparation for oral administration according to [1], wherein the thixotropic index of the drug-containing liquid is 0.15 or more and 0.6 or less.
[3] The method for producing a film preparation for oral administration according to [1] or [2], wherein the drug-containing layer has functional layers on both sides or one side.
[4] The method for producing a film preparation for oral administration according to [3], wherein the functional layer is a layer containing a water-soluble polymer.
[5] The method for producing a film preparation for oral administration according to any one of [1] to [4], wherein the drug-containing liquid is a liquid containing a water-soluble polymer, a drug, and a thixotropic substance.
[6] A film preparation for oral administration obtained by the production method according to any one of [1] to [5].
本発明の製造方法によれば、打ち抜き/裁断工程によるスクラップがほとんど生じず、かつ医薬品として求められる塗工量の重量バラツキの小さい経口投与用フィルム製剤が工業的に有利に得られる。 According to the production method of the present invention, a film preparation for oral administration that produces almost no scrap due to the punching / cutting process and has a small weight variation in coating amount required as a pharmaceutical product is industrially advantageously obtained.
本発明の経口投与用フィルム製剤の製造方法は、薬物含有層を、チキソトロピー指数0.1以上0.7以下の薬物含有液のスクリーン印刷により形成することを特徴とする。 The method for producing a film preparation for oral administration of the present invention is characterized in that the drug-containing layer is formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 or more and 0.7 or less.
本発明において、スクリーン印刷に用いる薬物含有液は、塗工精度を日本薬局方の製剤均一性試験に適合できるように相対標準偏差を4.7%以下に保つため、チキソトロピー指数0.1以上0.7以下であることが重要である。チキソトロピー指数が0.1未満では、塗布が不可能であるか、又は相対標準偏差が4.7%を超えてしまう。一方、チキソトロピー指数が0.7を超えると、チキソトロピー性を付与するための添加物が、乾燥工程で凝集してしまい均一な製剤を得られない。好ましいチキソトロピー指数は0.15以上であり、より好ましくは0.17以上である。また、好ましいチキソトロピー指数は0.65以下であり、より好ましくは0.6以下である。好ましいチキソトロピー指数の範囲は0.15〜0.65であり、より好ましくは0.17〜0.6である。 In the present invention, the drug-containing liquid used for screen printing maintains a relative standard deviation of 4.7% or less so that the coating accuracy can be adapted to the formulation uniformity test of the Japanese Pharmacopoeia. .7 or less is important. If the thixotropy index is less than 0.1, application is not possible or the relative standard deviation exceeds 4.7%. On the other hand, if the thixotropy index exceeds 0.7, the additive for imparting thixotropy aggregates in the drying step, and a uniform preparation cannot be obtained. A preferable thixotropy index is 0.15 or more, more preferably 0.17 or more. Moreover, a preferable thixotropy index is 0.65 or less, more preferably 0.6 or less. The range of a preferable thixotropy index is 0.15-0.65, More preferably, it is 0.17-0.6.
ここでチキソトロピー指数(TI)とは、液の5rpm及び50rpmの粘度から次式(1)を用いて計算される値であり、チキソトロピー性能を示す値である。 Here, the thixotropy index (TI) is a value calculated from the viscosity of the liquid at 5 rpm and 50 rpm using the following equation (1), and is a value indicating thixotropy performance.
TI=Log(η5/η50)/Log(50/5)・・・(1)
η5 :5rpmにおける粘度
η50:50rpmにおける粘度
TI = Log (η 5 / η 50 ) / Log (50/5) (1)
η 5 : Viscosity at 5 rpm η 50 : Viscosity at 50 rpm
薬物含有液の粘度は5rpmにおける粘度が20000mPa・s以上であるのが好ましく、さらに20000〜40000mPa・sであるのがより好ましい。また、50rpmにおける粘度は、10000〜30000mPa・sが好ましく、12000〜20000mPa・sがより好ましい。100rpmにおける粘度は、8000〜20000mPa・sが好ましく、10000〜15000mPa・sがより好ましい。 The viscosity of the drug-containing liquid is preferably 20000 mPa · s or more at 5 rpm, more preferably 20000 to 40000 mPa · s. The viscosity at 50 rpm is preferably 10,000 to 30,000 mPa · s, more preferably 12,000 to 20,000 mPa · s. The viscosity at 100 rpm is preferably 8000 to 20000 mPa · s, and more preferably 10,000 to 15000 mPa · s.
チキソトロピー指数が0.1以上0.7以下の薬物含有液のスクリーン印刷により形成される薬物含有層は、例えば水溶性高分子、薬物及びチキソトロピー性付与物質を含有する層である。ここで、水溶性高分子としては、フィルム形成性を有し、可食性であれば特に限定されないが、例えばヒプロメロース(ヒドロキシプロピルメチルセルロース)、ヒドロキシプロピルセルロース、プルラン、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースカリウム、カルボキシメチルセルロース、ポリビニルピロリドン及びアルギン酸ナトリウム等が挙げられる。これらの水溶性高分子は1種又は2種以上を混合して用いることができる。 The drug-containing layer formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 or more and 0.7 or less is a layer containing, for example, a water-soluble polymer, a drug, and a thixotropy-imparting substance. Here, the water-soluble polymer is not particularly limited as long as it has film-forming properties and is edible. For example, hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, pullulan, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Examples include calcium, carboxymethylcellulose potassium, carboxymethylcellulose, polyvinylpyrrolidone, and sodium alginate. These water-soluble polymers can be used alone or in combination of two or more.
薬物としては、経口投与可能な薬物であれば、特に限定されず、医薬品、機能性食品、特定保健用食品等の有効成分が挙げられる。医薬品としては、中枢神経系用薬(催眠鎮静剤、抗不安剤、抗てんかん剤、解熱鎮痛消炎剤、興奮剤、覚せい剤、抗パーキンソン剤、精神神経用剤、総合感冒剤等)、末梢神経系用薬(局所麻酔剤、骨格筋弛緩剤、自律神経剤、鎮けい剤等)、感覚器官用薬(眼科用剤、鎮暈剤等)、循環器官用薬(強心剤、不整脈用剤、利尿剤、血圧降下剤、血管収縮剤、血管拡張剤、高脂血症用剤等)、呼吸器官用薬(呼吸促進剤、鎮咳剤、去たん剤、気管支拡張剤、含漱剤等)、消化器官用薬(止しゃ剤、整腸剤、消化性潰瘍用剤、下剤、浣腸剤等)、ホルモン剤(唾液腺ホルモン剤、甲状腺・副甲状腺ホルモン剤、タンパク同化ステロイド剤、副腎ホルモン剤、卵胞ホルモンおよび黄体ホルモン剤、混合ホルモン剤等)、泌尿生殖器および肛門用薬(子宮収縮剤、避妊剤、痔疾用剤等)、歯科口腔用薬(歯科用抗生物質製剤等)、ビタミン剤、滋養強壮薬(無機質製剤等)、血液・体液用薬(血液凝固阻止剤等)、肝臓疾患用剤、解毒剤、痛風治療剤、糖尿病用剤、細胞賦活用薬、腫瘍用薬(アルキル化剤、代謝拮抗剤等)、アレルギー用薬(抗ヒスタミン剤等)、生薬、漢方製剤、抗生物質製剤、抗ウイルス剤、駆虫剤、アルカロイド系麻薬(アヘンアルカロイド系製剤、コカアルカロイド系製剤等)、非アルカロイド系麻薬(クエン酸フェンタニルなどの合成麻薬)等が挙げられる。 The drug is not particularly limited as long as it is an orally administrable drug, and includes active ingredients such as pharmaceuticals, functional foods, foods for specified health use. Drugs include central nervous system drugs (hypnotic sedatives, anxiolytics, antiepileptics, antipyretic analgesics, antistimulants, stimulants, antiparkinsonian agents, psychiatric agents, general cold agents, etc.), peripheral nerves Systemic drugs (local anesthetics, skeletal muscle relaxants, autonomic nerve agents, antispasmodics, etc.), sensory organ drugs (ophthalmic drugs, antipruritics, etc.), cardiovascular drugs (cardiotonic drugs, arrhythmic drugs, diuretics) , Antihypertensive, vasoconstrictor, vasodilator, hyperlipidemia, etc.), respiratory organs (respiratory, antitussive, expectorant, bronchodilator, gargle etc.), digestive organ Drugs (depressants, intestinal preparations, peptic ulcers, laxatives, enemas, etc.), hormones (salivary gland hormones, thyroid / parathyroid hormones, anabolic steroids, adrenal hormones, follicular hormones and luteinizing hormones, Mixed hormones), genitourinary and anal drugs ( Miya Shrink Agents, Contraceptives, Vaginal Agents, Dental Oral Drugs (Dental Antibiotics, etc.), Vitamins, Nutrition Tonics (Inorganic Preparations, etc.), Blood and Body Fluids (Blood Coagulation Inhibitors, etc.) , Liver disease agent, antidote, gout treatment agent, diabetes agent, cell stimulant, tumor agent (alkylating agent, antimetabolite, etc.), allergy agent (antihistamine, etc.), herbal medicine, Chinese medicine, antibiotics Examples include substance preparations, antiviral agents, anthelmintics, alkaloid narcotics (opium alkaloids, coca alkaloids, etc.), non-alkaloid narcotics (synthetic narcotics such as fentanyl citrate), and the like.
チキソトロピー性付与物質としては、軽質無水ケイ酸、カオリン、デンプン(スターチ)、架橋ポリビニルピロリドン(Kollidon CL)、低置換ヒドロキシプロピルセルロース等が挙げられる。
これらのチキソトロピー性を付与する物質は、添加量のほか、粒子径を調整することでチキソトロピー性を調整することができる。
更に、チキソトロピー性はカルボキシメチルセルロースナトリウムやカルボキシビニルポリマー等、溶解すると流動性の低いゲルを形成する高分子化合物を添加することによっても、付与することができる。
Examples of the thixotropic substance include light anhydrous silicic acid, kaolin, starch (starch), cross-linked polyvinyl pyrrolidone (Kollidon CL), low-substituted hydroxypropyl cellulose, and the like.
These substances imparting thixotropy can be adjusted for thixotropy by adjusting the particle size in addition to the addition amount.
Furthermore, thixotropic property can be imparted by adding a polymer compound that forms a gel having low fluidity when dissolved, such as sodium carboxymethylcellulose or carboxyvinyl polymer.
また、薬物含有層には、前記成分以外に、可塑剤、糖類、安定剤、甘味料、pH調整剤、着色剤、着香料等を配合することができる。
可塑剤としては、例えばプロピレングリコール、グリセリン、ポリエチレングリコール(マクロゴール)、ゴマ油、ヒマシ油、クエン酸トリエチル、ショ糖脂肪酸エステル等を用いることができる。
糖類としては、ショ糖、果糖、ブドウ糖、麦芽糖(マルトース)、白糖、糖アルコール(マルチトール、還元麦芽糖水飴、ソルビトール、エリスリトール、キシリトール等)、トレハロース等を用いることができる。
安定化剤としては、アスコルビン酸、亜硫酸水素ナトリウム、亜硫酸ナトリウム、エデト酸ナトリウム、エリソルビン酸、酢酸トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール等を用いることができる。
甘味料としては、アスパルテーム、ステビア、スクラロース、グリチルリチン酸、ソーマチン、アセスルファムカリウム、サッカリン等を用いることができる。pH調整剤としては、酒石酸、クエン酸、リン酸等及びこれ等の薬学的に許容できる塩を用いることができる。着色剤としては、三二酸化鉄、黄色三二酸化鉄、銅クロロフィリンナトリウム、食用色素等を用いることができる。着香剤としては、メントール及びバニラ、オレンジ、ストロベリーグレープフルーツ等のフレーバー類を用いることができる。
In addition to the above-described components, the drug-containing layer can contain plasticizers, sugars, stabilizers, sweeteners, pH adjusters, colorants, flavoring agents, and the like.
As the plasticizer, for example, propylene glycol, glycerin, polyethylene glycol (macrogol), sesame oil, castor oil, triethyl citrate, sucrose fatty acid ester and the like can be used.
Examples of saccharides that can be used include sucrose, fructose, glucose, maltose (maltose), sucrose, sugar alcohol (such as maltitol, reduced maltose starch syrup, sorbitol, erythritol, xylitol), trehalose, and the like.
As the stabilizer, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, butylhydroxyanisole and the like can be used.
As the sweetener, aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin and the like can be used. As the pH adjuster, tartaric acid, citric acid, phosphoric acid and the like and pharmaceutically acceptable salts thereof can be used. As the colorant, iron sesquioxide, yellow iron sesquioxide, copper chlorophyllin sodium, food coloring, and the like can be used. Flavors such as menthol and vanilla, orange, strawberry grapefruit can be used as a flavoring agent.
薬物含有液の溶媒は、経口投与用であることから、水、エタノール又はこれらの混合溶媒が好ましい。 Since the solvent of the drug-containing liquid is for oral administration, water, ethanol or a mixed solvent thereof is preferable.
薬物含有層の形成に用いられるスクリーン印刷装置及び条件は、特に制限されず、所望の形状に薬物含有層を形成させることができればよい。 The screen printing apparatus and conditions used for forming the drug-containing layer are not particularly limited as long as the drug-containing layer can be formed in a desired shape.
印刷(塗布)用スクリーンの材質としては、絹、綿などの天然系繊維系スクリーン、ポリエステル、ナイロンなどの合成樹脂系スクリーンやステンレス、タングステンなどの金属系スクリーン等を使用することができる。中でも印刷位置精度や薬物含有液塗布量の確保の点から金属系スクリーン、特にステンレススクリーンが好適である。 As a material for the printing (coating) screen, natural fiber screens such as silk and cotton, synthetic resin screens such as polyester and nylon, and metal screens such as stainless and tungsten can be used. Of these, metal screens, particularly stainless steel screens are preferred from the standpoint of ensuring printing position accuracy and the amount of drug-containing liquid applied.
スクリーンメッシュの線径及びメッシュ数は、目的とする塗布量及び薬物含有液の流体特性により適宜選択組合せができる。薬物含有液塗布を目的とした時、太い線径の低メッシュを使用すると、高塗布量が得られるものの塗布表面の均一性・平滑性が悪くなる可能性がある。一方、細い線径の高メッシュを使用すると、塗布量が少なくなるとともに薬物含有液中の薬物が粉体分散している場合は目詰まりなどの原因となり得る。これ等のことから、スクリーンメッシュの線経として0.010〜0.160mm、メッシュ数は40〜730が好ましい。 The wire diameter and the number of meshes of the screen mesh can be appropriately selected and combined depending on the target coating amount and the fluid characteristics of the drug-containing liquid. When a drug-containing liquid is intended for application, if a low mesh having a large wire diameter is used, a high application amount can be obtained, but the uniformity and smoothness of the application surface may be deteriorated. On the other hand, when a high mesh with a thin wire diameter is used, the amount of application decreases, and when the drug in the drug-containing liquid is dispersed in powder, it may cause clogging. For these reasons, it is preferable that the screen mesh has a line diameter of 0.010 to 0.160 mm and the number of meshes is 40 to 730.
スクリーンの織り方としては、平織、綾織、平畳織、綾畳織等があるが、何れでも良い。但し、印刷性や洗浄性等から平織もしくは綾織が好ましい。 Examples of screen weaving methods include plain weave, twill weave, plain tatami weave, and twill woven weave. However, plain weave or twill weave is preferred from the standpoint of printability and cleanability.
印刷(塗布)条件のうち、スキージ速度は、10mm/秒〜300mm/秒がよく、薬物含有液の粘度及びチキソトロピー性に応じて適宜調整するのが良い。中でも薬物含有液転写性、生産性などの点から50mm/秒以上が好適である。
スキージ圧は、スキージが0.5mm〜3.0mm程度押し込まれる様なスキージ圧がよく、目標とする塗布量、薬物含有液の粘度及びチキソトロピー性に応じて適宜調整するのが良い。中でも印刷位置精度の点からスキージが0.5mm〜1.0mm程度押し込まれるスキージ圧が好適である。
Of the printing (coating) conditions, the squeegee speed is preferably 10 mm / second to 300 mm / second, and is suitably adjusted according to the viscosity and thixotropy of the drug-containing liquid. Among these, 50 mm / sec or more is preferable from the viewpoint of transferability of drug-containing liquid and productivity.
The squeegee pressure is such that the squeegee is pushed in by about 0.5 mm to 3.0 mm, and is suitably adjusted according to the target application amount, the viscosity of the drug-containing liquid and the thixotropy. Of these, a squeegee pressure at which the squeegee is pushed by about 0.5 mm to 1.0 mm is preferable from the viewpoint of printing position accuracy.
スクリーン印刷後の乾燥は、温風の吹き付け、遠赤外線、マイクロウエーブによる加温乾燥や減圧乾燥が好ましく、温風吹き付け方式がより好ましい。温風の温度は100℃以下が好ましく、40〜70℃がより好ましい。 Drying after screen printing is preferably warm air spraying, far-infrared rays, heating drying with a microwave or vacuum drying, and a hot air spraying method is more preferable. The temperature of the warm air is preferably 100 ° C. or less, and more preferably 40 to 70 ° C.
本発明の経口投与用フィルム製剤は、前記薬物含有層単独でもよいが、薬物含有層の両面又は片面に機能層を設けてもよい。機能層は製剤を取り扱い易くしたり、薬物の苦味をマスキングしたり、薬物層を水分、酸素、光等から護り薬物層中の薬物の安定化を図る等、種々の機能を持たせることができる。機能層には、前記薬物含有層に含まれる成分から、薬物を除いた全ての成分を含有させることができる。また、機能層をスクリーン印刷で形成する場合には、チキソトロピー性付与物質を含有させてもよく、機能層をロールコーターで塗工する場合はチキソトロピー性付与物質を配合する必要がない。また、機能層をスクリーン印刷で形成する場合には、機能層調製液のチキソトロピー指数及び粘度は、薬物含有液と同様であるのが好ましい。 The film preparation for oral administration of the present invention may be the drug-containing layer alone, but may be provided with functional layers on both sides or one side of the drug-containing layer. The functional layer can have various functions such as making the formulation easy to handle, masking the bitter taste of the drug, protecting the drug layer from moisture, oxygen, light, etc., and stabilizing the drug in the drug layer. . The functional layer can contain all components excluding the drug from the components contained in the drug-containing layer. Further, when the functional layer is formed by screen printing, a thixotropic property-imparting substance may be contained, and when the functional layer is applied by a roll coater, it is not necessary to add a thixotropic property-imparting substance. When the functional layer is formed by screen printing, the thixotropy index and viscosity of the functional layer preparation liquid are preferably the same as those of the drug-containing liquid.
例えば、(機能層)/(薬物含有層)/(機能層)の3層の構造からなるフィルム剤の製造は、以下の方法により行うことができる。
(1)ポリエステルフィルム上にスクリーン印刷技術を用いて機能層調製液を塗布乾燥し機能層を形成した後、その上に同様に薬物含有層、機能層の順でスクリーン印刷技術を用いて塗布乾燥を繰り返し製造することができる。
(2)ポリエステルフィルム上にロールコーターを用いて機能層調製液を塗工乾燥し機能層を製した後、この上にスクリーン印刷技術を用いて薬物含有液を塗布乾燥し薬物含有層を製した後、更にこの上から、ロールコーターを用いて機能層調製液を塗工乾燥する。更に、薬物含有層が形成されている部分を打ち抜き製造することができる。
(3)ポリエステルフィルム上にロールコーターを用いて機能層調製液を塗工乾燥し機能層を製した後、この上にスクリーン印刷技術を用いて薬物含有液を塗布し薬物含有層を製する。次に、薬物含有層同士が接するように貼り合わせた後、薬物含有層部分を打ち抜き製造することができる。
薬物含有層の各々の面に設けられる機能層は同一の組成でも、異なる組成でも良い。また、(1)〜(3)の方法を組み合わせて製造することもできる。
For example, production of a film agent having a three-layer structure of (functional layer) / (drug-containing layer) / (functional layer) can be performed by the following method.
(1) A functional layer preparation solution is applied and dried on a polyester film using a screen printing technique to form a functional layer, and then a drug-containing layer and a functional layer are similarly applied and dried using a screen printing technique in that order. Can be produced repeatedly.
(2) A functional layer preparation solution was applied and dried on a polyester film using a roll coater to produce a functional layer, and then a drug-containing solution was applied and dried thereon using a screen printing technique to produce a drug-containing layer. Thereafter, the functional layer preparation liquid is further applied and dried from above using a roll coater. Furthermore, it is possible to punch and manufacture the part where the drug-containing layer is formed.
(3) A functional layer preparation liquid is applied and dried on a polyester film using a roll coater to produce a functional layer, and then a drug-containing liquid is applied thereon using a screen printing technique to produce a drug-containing layer. Next, after bonding so that the drug-containing layers are in contact with each other, the drug-containing layer portion can be punched and manufactured.
The functional layers provided on each surface of the drug-containing layer may have the same composition or different compositions. Moreover, it can also manufacture combining the method of (1)-(3).
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.
(1)機能層調製液の調製
精製水(適量)に還元麦芽糖水飴(10質量部)、ポリエチレングリコール400(PEG−400)(8質量部)及び食用黄色色素(0.125質量部)を溶解した。この液に、エタノール(適量)に酸化チタン(10質量部)を分散したものを添加し、分散した後、ヒドロキシプロピルメチルセルロース(HPMC)(72質量部)を添加後、撹拌溶解し機能層調製液とした。
(1) Preparation of functional layer preparation solution Reduced maltose starch syrup (10 parts by mass), polyethylene glycol 400 (PEG-400) (8 parts by mass) and edible yellow pigment (0.125 parts by mass) in purified water (appropriate amount) did. To this solution, a solution in which titanium oxide (10 parts by mass) is dispersed in ethanol (appropriate amount) is added, and after dispersion, hydroxypropylmethylcellulose (HPMC) (72 parts by mass) is added and stirred to dissolve to prepare a functional layer preparation solution It was.
(2)薬物含有液の調製
精製水に還元麦芽糖水飴(マルチトール)、スクラロース及びポリエチレングリコール400(PEG−400)を加え撹拌溶解した。この液にフルルビプロフェンを加えて撹拌分散したものに、ヒドロキシプロピルセルロース(HPC)及び軽質無水ケイ酸を撹拌投入し、均一になるまで撹拌した。
各調製液の組成は下表の通りである。
(2) Preparation of drug-containing solution Reduced maltose starch syrup (maltitol), sucralose and polyethylene glycol 400 (PEG-400) were added to purified water and dissolved by stirring. Hydroxypropyl cellulose (HPC) and light anhydrous silicic acid were stirred into a solution in which flurbiprofen was added and dispersed in this solution, and stirred until uniform.
The composition of each preparation solution is as shown in the table below.
(3)調製液粘度の測定
ブルックフィールド型粘度計を用いて、日本薬局方粘度測定法に準じて、5rpm及び50rpmにおける粘度を測定した。
(4)チキソトロピー指数(TI)の計算
調製液の5rpm及び50rpmの粘度から、前記式(1)を用いて計算した。
(3) Measurement of viscosity of prepared solution Using a Brookfield viscometer, the viscosity at 5 rpm and 50 rpm was measured according to the Japanese Pharmacopoeia viscosity measurement method.
(4) Calculation of thixotropy index (TI) It calculated from the viscosity of 5 rpm and 50 rpm of a preparation liquid using said Formula (1).
(5)スクリーン印刷版
320mm×320mmの枠に、スクリーンメッシュを装着し、12mm×18mm、r=1.8mmの大きさの塗布が、行列状に30箇所(6×5)塗布することが出来るスクリーン印刷版を用いた(図1)。
スクリーン印刷版の主な仕様は下表の通りである。
(5) Screen printing plate A screen mesh is mounted on a 320 mm x 320 mm frame, and a coating of 12 mm x 18 mm and r = 1.8 mm can be applied in 30 places (6 x 5) in a matrix. A screen printing plate was used (FIG. 1).
The main specifications of the screen printing version are as shown in the table below.
(6)フィルム剤の作成
機能層調製液の塗工乾燥
厚さ75μmのポリエステルフィルムに機能層調製液をロールコーターを用いて、乾燥後の塗工量が18.4g/m2となるように塗工乾燥した。
ポリエステルフィルム上に機能層を塗工乾燥したものを被塗工物とした。
薬物含有液の塗工乾燥
スクリーン印刷機に、被塗布物を、機能層の上に薬物含有層が塗布出来るようにセットした。更に、スクリーン印刷版と被塗布物のクリアランスが1.8mmとなるように調整した。スクリーン印刷版上に適量の調製液を適用し、平型スキージを移動させて塗布を行った。
調製液を塗布したものは、乾燥器に入れ乾燥を行った。次に、塗布乾燥したもの薬物含有層塗布部分を1箇所ずつ打ち抜き、ポリエステルフィルムを剥がし、(機能層)/(薬物含有層)からなる2層型フィルム剤を得た。
塗布乾燥条件は下記のとおりである。
(6) Preparation of film agent Application drying of functional layer preparation liquid Using a roll coater, the functional layer preparation liquid is applied to a polyester film having a thickness of 75 μm so that the coating amount after drying is 18.4 g / m 2. The coating was dried.
What coated and dried the functional layer on the polyester film was made into the coating object.
Coating / Drying of Drug-Containing Liquid In a screen printer, an article to be coated was set so that the drug-containing layer could be coated on the functional layer. Further, the clearance between the screen printing plate and the coated object was adjusted to 1.8 mm. An appropriate amount of the preparation liquid was applied onto the screen printing plate, and the flat squeegee was moved to perform application.
What applied the preparation liquid was put into the drier and dried. Next, the coated and dried product-coated layer-coated portions were punched one by one, and the polyester film was peeled off to obtain a two-layer film agent composed of (functional layer) / (drug-containing layer).
The coating and drying conditions are as follows.
(7)塗布量バラツキの測定
フィルム剤中のフルルビプロフェンの量を指標に塗布量バラツキを求めた。
即ち、フィルム剤中のフルルビプロフェンを1枚ずつ高速液体クロマトグラフィー法により定量した。1回の塗布乾燥で得られたフィルム剤30枚のフルルビプロフェン含量から、相対標準偏差を計算し、塗布量バラツキとした。
(7) Measurement of coating amount variation The coating amount variation was determined using the amount of flurbiprofen in the film agent as an index.
That is, flurbiprofen in the film agent was quantified one by one by high performance liquid chromatography. The relative standard deviation was calculated from the flurbiprofen content of 30 film agents obtained by one coating and drying, and the variation in coating amount was obtained.
(8)結果
結果を表6に示す。
(8) Results Table 6 shows the results.
表6には実施例及び比較例の調製液のチキソトロピー指数(TI)及びフィルム剤中のフルルビプロフェンの含量を指標とした、塗布量のバラツキを示した。
表6から分かるように、チキソトロピー指数を0.1以上にすることで、塗布量バラツキの相対標準偏差を4.7%以下とすることができた。
また、参考例1で示したように、チキソトロピー指数が0.01の調製液では、全く塗布を行うことが出来なかった。
Table 6 shows the variation in coating amount using the thixotropy index (TI) of the preparation solutions of Examples and Comparative Examples and the content of flurbiprofen in the film preparation as indices.
As can be seen from Table 6, by setting the thixotropy index to 0.1 or more, the relative standard deviation of the coating amount variation could be 4.7% or less.
Moreover, as shown in Reference Example 1, the preparation solution having a thixotropy index of 0.01 could not be applied at all.
1.印刷版
2.経口投与用フィルム剤の塗布部分
1. Print version 2. Application part of film for oral administration
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