JP2019131511A - Method for producing medicine-containing particle - Google Patents
Method for producing medicine-containing particle Download PDFInfo
- Publication number
- JP2019131511A JP2019131511A JP2018015530A JP2018015530A JP2019131511A JP 2019131511 A JP2019131511 A JP 2019131511A JP 2018015530 A JP2018015530 A JP 2018015530A JP 2018015530 A JP2018015530 A JP 2018015530A JP 2019131511 A JP2019131511 A JP 2019131511A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- manufactured
- particles
- polymer
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
Description
本発明は、薬物含有粒子の製造方法に関する。 The present invention relates to a method for producing drug-containing particles.
従来、薬物を含有する微細粒子の製造方法の一つとして、ゼラチンや寒天等のゲル化能を有する高分子（ゲル化剤）を基剤として用いる方法がある。この方法では、ゲル化剤を溶解した溶液を調製するために、例えば４０〜９０℃に加温する必要があり、熱により分解が促進される薬物に適用できないという問題がある。また、この方法では、強酸・強塩基のようにゲル化を阻害する薬物が原料に含まれると製造が不可能になるため、適用可能な薬物の種類がさらに制限される問題もある。 Conventionally, as one of methods for producing fine particles containing a drug, there is a method using a polymer (gelling agent) having gelling ability such as gelatin or agar as a base. In this method, in order to prepare the solution which melt | dissolved the gelatinizer, it is necessary to heat, for example to 40-90 degreeC, and there exists a problem that it cannot apply to the drug by which decomposition | disassembly is accelerated | stimulated by a heat | fever. In addition, this method has a problem that the kind of applicable drug is further restricted because the production becomes impossible when the raw material contains a drug that inhibits gelation such as strong acid and strong base.
一方、基剤としてゲル化剤を使用せずに薬物を含有する微細粒子を製造可能な方法としては、噴霧凍結乾燥法が知られている。この方法は、薬物及び基剤として非ゲル化性の高分子を含有する混合液を液体窒素等に噴霧して急速に冷却・固化し、得られた粒子を、例えば−３５〜−２０℃といった低温下で凍結乾燥するというものである（特許文献１、非特許文献１参照）。 On the other hand, as a method capable of producing fine particles containing a drug without using a gelling agent as a base, a spray freeze-drying method is known. In this method, a liquid mixture containing a non-gelling polymer as a drug and a base is sprayed on liquid nitrogen or the like to rapidly cool and solidify, and the resulting particles are, for example, −35 to −20 ° C. It is freeze-dried at a low temperature (see Patent Document 1 and Non-Patent Document 1).
この噴霧凍結乾燥法は、比較的多種類の薬物に適用可能であるが、この方法により得られる粒子は比較的多孔質な構造を有し、低密度であるため、錠剤等の固形製剤を製造する際、機械圧力により破壊され易いという問題がある。 Although this spray freeze-drying method can be applied to a relatively wide variety of drugs, the particles obtained by this method have a relatively porous structure and low density, so that solid preparations such as tablets are produced. When doing so, there is a problem that it is easily destroyed by mechanical pressure.
本発明は、非ゲル化性高分子を基剤とする高密度な薬物含有粒子の製造方法を提供することを目的とする。 An object of the present invention is to provide a method for producing high-density drug-containing particles based on a non-gelling polymer.
本発明者らは、上記課題に対して鋭意検討を行った結果、薬物を含有する液状組成物を噴霧及び冷却固化した凍結粒子を従来方法に比べて比較的高い温度帯のみで乾燥することにより、高密度な薬物含有粒子が得られることを見出し、この知見に基づいて本発明をなすに至った。 As a result of intensive studies on the above problems, the present inventors have dried the frozen particles obtained by spraying and cooling and solidifying the liquid composition containing the drug only in a relatively high temperature range as compared with the conventional method. The present inventors have found that high-density drug-containing particles can be obtained, and have made the present invention based on this finding.
すなわち、本発明は、下記の（１）〜（３）からなっている。
（１）次の工程（Ａ）、（Ｂ）及び（Ｃ）：
（Ａ）非ゲル化性高分子及び薬物を水性成分に溶解及び／又は分散し、液状組成物を得る工程、
（Ｂ）前記液状組成物を噴霧及び冷却固化し、凍結粒子を得る工程、並びに
（Ｃ）前記凍結粒子を品温−５〜３０℃で乾燥する工程
を含む、薬物含有粒子の製造方法。
（２）工程（Ａ）における非ゲル化性高分子が水溶性高分子、水不溶性高分子、胃溶性高分子及び腸溶性高分子からなる群より選ばれる１種以上である前記（１）に記載の薬物含有粒子の製造方法。
（３）工程（Ａ）における液状組成物がゲル化能を有する高分子を実質的に含まない前記（１）又は（２）に記載の薬物含有粒子の製造方法。
That is, this invention consists of following (1)-(3).
(1) Next steps (A), (B) and (C):
(A) a step of dissolving and / or dispersing a non-gelling polymer and a drug in an aqueous component to obtain a liquid composition;
(B) A method for producing drug-containing particles, comprising the steps of spraying and cooling and solidifying the liquid composition to obtain frozen particles, and (C) drying the frozen particles at a product temperature of -5 to 30 ° C.
(2) In the above (1), the non-gelling polymer in step (A) is at least one selected from the group consisting of water-soluble polymers, water-insoluble polymers, gastric polymers and enteric polymers. A method for producing the described drug-containing particles.
(3) The method for producing drug-containing particles according to (1) or (2), wherein the liquid composition in the step (A) does not substantially contain a polymer having gelling ability.
本発明の製造方法により得られる薬物含有粒子は、比較的高密度であることから、錠剤等の固形製剤を製造する際、機械圧力により破壊され難く、打錠適性に優れている。 Since the drug-containing particles obtained by the production method of the present invention have a relatively high density, they are not easily broken by mechanical pressure when producing a solid preparation such as a tablet, and are excellent in tableting ability.
本発明の薬物含有粒子の製造方法は、（Ａ）非ゲル化性高分子及び薬物を水性成分に溶解及び／又は分散し、液状組成物を得る工程、（Ｂ）前記液状組成物を噴霧及び冷却固化し、凍結粒子を得る工程、並びに（Ｃ）前記凍結粒子を品温−５〜３０℃で乾燥する工程を含む。 The method for producing drug-containing particles of the present invention comprises (A) a step of dissolving and / or dispersing a non-gelling polymer and a drug in an aqueous component to obtain a liquid composition, (B) spraying the liquid composition and Cooling and solidifying to obtain frozen particles, and (C) drying the frozen particles at a product temperature of -5 to 30 ° C.
〔工程（Ａ）〕
工程（Ａ）は、非ゲル化性高分子及び薬物を水性成分に溶解及び／又は分散し、液状組成物を得る工程である。
[Process (A)]
Step (A) is a step in which a non-gelling polymer and a drug are dissolved and / or dispersed in an aqueous component to obtain a liquid composition.
工程（Ａ）で用いられる非ゲル化性高分子としては、例えば、水溶性高分子、水不溶性高分子、胃溶性高分子及び腸溶性高分子からなる群より選ばれる１種以上が挙げられる。本発明においては、薬物含有粒子に付与される徐放性や消化管内における溶解性等を考慮して非ゲル化性高分子を適宜選択することができる。 Examples of the non-gelling polymer used in the step (A) include one or more selected from the group consisting of a water-soluble polymer, a water-insoluble polymer, a gastric polymer, and an enteric polymer. In the present invention, a non-gelling polymer can be appropriately selected in consideration of sustained release imparted to the drug-containing particles, solubility in the digestive tract, and the like.
水溶性高分子としては、例えば、メチルセルロース、ヒプロメロース、ヒドロキシプロピルセルロース、ポリエチレングリコール、ポリビニルアルコール（部分けん化物）、ポリビニルピロリドン等が挙げられる。 Examples of the water-soluble polymer include methyl cellulose, hypromellose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol (partially saponified product), polyvinyl pyrrolidone, and the like.
水不溶性高分子としては、例えば、アクリル酸エチル・メタクリル酸メチル共重合体（例えば、アクリル酸エチル・メタクリル酸メチルコポリマー分散液）、アクリル酸エチル・メタクリル酸メチル・メタ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、アミノアルキルメタクリレートコポリマーＲＳ、アミノアルキルメタクリレートコポリマーＲＳ水分散液）等の水不溶性メタクリル酸系高分子化合物、エチルセルロース（例えば、エトセル、アクアコート）等の水不溶性セルロース系高分子化合物が挙げられる。 Examples of water-insoluble polymers include ethyl acrylate / methyl methacrylate copolymer (for example, ethyl acrylate / methyl methacrylate copolymer dispersion), ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer Water-insoluble methacrylic acid-based polymer compounds such as coalescence (for example, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS aqueous dispersion), and water-insoluble cellulose-based polymer compounds such as ethyl cellulose (for example, etosel, aquacoat). It is done.
胃溶性高分子としては、例えば、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、ＡＥＡ）等のポリビニルアセタール系高分子、メタクリル酸メチル・メタクリル酸ブチル・メタクリル酸ジメチルアミノエチル共重合体（例えば、アミノアルキルメタクリレートコポリマーＥ）、メタクリル酸メチル・メタクリル酸ジエチルアミノエチル共重合体等の胃溶性メタクリル酸系高分子化合物が挙げられる。 Examples of the gastric soluble polymer include polyvinyl acetal polymers such as polyvinyl acetal diethylaminoacetate (for example, AEA), methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (for example, aminoalkyl methacrylate copolymer E). ), Gastric soluble methacrylic acid polymer compounds such as methyl methacrylate / diethylaminoethyl methacrylate copolymer.
腸溶性高分子としては、例えば、メタクリル酸・アクリル酸エチル共重合体（例えば、メタクリル酸コポリマーＬＤ）、メタクリル酸・メタクリル酸メチル共重合体（例えば、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ）、アクリル酸メチル・メタクリル酸メチル・メタクリル酸コポリマー等の腸溶性メタクリル酸系高分子化合物、酢酸フタル酸セルロース、ヒプロメロースフタレート、ヒプロメロースアセテートサクシネート、ポリビニルアセテートフタレート、カルボキシメチルエチルセルロース等の腸溶性セルロース系高分子化合物が挙げられる。 Examples of the enteric polymer include methacrylic acid / ethyl acrylate copolymer (for example, methacrylic acid copolymer LD), methacrylic acid / methyl methacrylate copolymer (for example, methacrylic acid copolymer L, methacrylic acid copolymer S), Enteric properties of enteric methacrylic polymer such as methyl acrylate, methyl methacrylate, methacrylic acid copolymer, cellulose acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose Cellulosic polymer compounds are exemplified.
工程（Ａ）で用いられる薬物としては、治療学的又は予防学的に有効な活性成分であれば特に限定されず、例えば、イブプロフェン、ナプロキセン、ケトプロフェン、アセトアミノフェン、インドメタシン、ブフェキサマック、アスピリン、ジクロフェナック、アルクロフェナック、フェンクロフェナック、エトドラック、フルルビプロフェン、メフェナミック、メクロフェナミック、ピロキシカム等の非ステロイド抗炎症剤、ニトラゼパム、トリアゾラム、フェノバルビタ−ル、アミバルビタ−ル等の催眠・鎮静剤、フェニトイン、メタルビタ−ル、プリミドン、クロナゼパム、カルバマゼピン、バルプロ酸等の抗てんかん剤、塩酸メクリジン、ジメンヒドリナート等の鎮うん剤、イミプラニン、ノキシプチリン、フェネルジン等の抗うつ剤、ハロペリドール、メプロバメート、クロルジアゼポキシド、ジアゼバム、オキサゼバム、スルピリド等の精神神経用剤、パパベリン、アトロピン、エトミドリン等の鎮けい剤、ジゴキシン、ジギトキシン、メチルジゴキシン、ユビデカレノン等の強心剤、ピンドロール、アジマリン、ジソピラミド等の不整脈剤、ヒドロクロロチアジド、スピロノラクトン、トリアムテレン、フロセミド、ブメタニド等の利尿剤、レセルピン、メシル酸ジヒドロエルゴトキシン、塩酸プラゾシン、メトプロロール、プロプラノロール、アテノロール等の抗高血圧剤、ニトログリセリン、硝酸イソソルビド、ジルチアゼム、ニフェジピン、ジピリダモール等の冠血管拡張剤、ノスカピン、サルブタモール、プロカテロール、ツロプテロール、トラニラスト、ケトチフェン等の鎮咳剤、塩酸ブロムヘキシン、グアイフェネシン等の去痰剤、ニカルジピン、ピンポセチン等の脳循環改善剤、エリスロマイシン、ジョサマイシン、クロラムフェニコール、テトラサイクリン、リファンピシン、グリセオフルビン等の抗生物質、ジフェンヒドラミン、プロメタジン、メキタジン、フマル酸クレマスチン等の抗ヒスタミン剤、トリアムシノロン、デキサメタゾン、ベタメタゾン、プレドニソロン、ダナゾール、メチルテストステロン、酢酸クロルマジノン等のステロイド剤、ビタミンＡ類、ビタミンＤ類、ビタミンＥ類、ビタミンＫ類、葉酸（ビタミンＭ類）等のビタミン剤、ファモチジン、ジメチコン、シメチジン、ニザチジン、メトクロプラミド、オメプラゾール、スルピリド、トレピブトン、スクラルファート等の消化器系疾患治療剤、カフェイン、ジクマロール、シンナリジン、クロフィブラート、ゲファルナート、ブロベネシド、メルカプトプリン、メトトレキサート、ウルソデスオキシコール酸、メシル酸ジヒドロエルゴタミン等が挙げられる。 The drug used in the step (A) is not particularly limited as long as it is a therapeutically or prophylactically effective active ingredient. For example, ibuprofen, naproxen, ketoprofen, acetaminophen, indomethacin, bufexamac, aspirin , Diclofenac, alclofenac, fenclofenac, etodolac, flurbiprofen, non-steroidal anti-inflammatory drugs such as mefenamic, meclofenamic, and piroxicam, hypnotics and sedatives such as nitrazepam, triazolam, phenobarbital, and amibarbital , Phenytoin, metalbital, primidone, clonazepam, carbamazepine, valproic acid and other antiepileptics, meclizine hydrochloride, dimenhydrinate and other antidepressants, imiplanin, noxiptillin, phenelzine and other antidepressants , Haloperidol, meprobamate, chlordiazepoxide, diazebam, oxazebam, sulpiride and other neuropsychiatric agents, papaverine, atropine, etomirine, etc. Drugs, hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide and other diuretics, reserpine, dihydroergotoxin mesylate, prazosin hydrochloride, metoprolol, propranolol, atenolol and other antihypertensive agents, nitroglycerin, isosorbide nitrate, diltiazem, nifedipine Coronary vasodilators, noscapine, salbutamol, procaterol, turopterol, tranilast, Antitussives such as totifen, expectorants such as bromhexine hydrochloride and guaifenesin, cerebral circulation improving agents such as nicardipine and pinpocetine, antibiotics such as erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin, diphenhydramine, promethazine, mequitazine, fumar Antihistamines such as clemastine acid, steroids such as triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate, vitamins A, vitamin D, vitamin E, vitamin K, folic acid (vitamin M), etc. Vitamins, Famotidine, Dimethicone, Cimetidine, Nizatidine, Metoclopramide, Omeprazole, Sulpiride, Trepibutone, Sucralf Gastrointestinal disease therapeutic agents such as caffeine, caffeine, dicoumarol, cinnarizine, clofibrate, gefarnate, brobenesid, mercaptopurine, methotrexate, ursodeoxycholic acid, dihydroergotamine mesylate and the like.
工程（Ａ）で用いられる水性成分としては、例えば、「水」又は「水性溶媒、糖アルコール、多価アルコールから選ばれる１種以上を含有する水溶液」等が挙げられ、中でも、製造容易性及び入手容易性の観点から水が好ましく用いられる。水としては、例えば、蒸留水、イオン交換樹脂処理水、逆浸透膜処理水、限外ろ過膜処理水等の精製水、水道水等の飲料水が挙げられる。水性溶媒としては、水と相溶性があるものであれば特に制限はないが、例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒が挙げられる。糖アルコールとしては、例えば、ソルビトール、マンニトール、マルチトール、還元水飴等が挙げられる。多価アルコールとしては、例えば、プロピレングリコール、グリセリン、ポリグリセリン等が挙げられる。 Examples of the aqueous component used in the step (A) include “water” or “an aqueous solution containing one or more selected from an aqueous solvent, a sugar alcohol, and a polyhydric alcohol”. From the viewpoint of availability, water is preferably used. Examples of water include purified water such as distilled water, ion exchange resin treated water, reverse osmosis membrane treated water, ultrafiltration membrane treated water, and drinking water such as tap water. The aqueous solvent is not particularly limited as long as it is compatible with water, and examples thereof include alcohol solvents such as methanol, ethanol, and 2-propanol. Examples of the sugar alcohol include sorbitol, mannitol, maltitol, reduced starch syrup and the like. Examples of the polyhydric alcohol include propylene glycol, glycerin, polyglycerin and the like.
工程（Ａ）の液状組成物の形態としては、特に限定されず、例えば、非ゲル化性高分子及び薬物が水性成分に溶解及び／又は分散した溶液及び／又は分散液とすることができる。該液状組成物１００質量％中の非ゲル化性高分子、薬物及び水性成分の配合割合は、非ゲル化性高分子及び薬物の種類等により異なり一様ではないが、例えば、非ゲル化性高分子が通常５．０〜９５質量％、好ましくは１０〜８５質量％、薬物が通常０．１０〜９０質量％、好ましくは１．０〜８０質量％、残余が水性成分となるように調整することができる。 The form of the liquid composition in the step (A) is not particularly limited, and for example, it can be a solution and / or dispersion in which a non-gelling polymer and a drug are dissolved and / or dispersed in an aqueous component. The blending ratio of the non-gelling polymer, the drug and the aqueous component in 100% by mass of the liquid composition varies depending on the kind of the non-gelling polymer and the drug and is not uniform. The polymer is usually adjusted to 5.0 to 95% by mass, preferably 10 to 85% by mass, the drug is usually 0.10 to 90% by mass, preferably 1.0 to 80% by mass, and the remainder is an aqueous component. can do.
工程（Ａ）の液状組成物は、上記成分の他、必要に応じ、分散剤、ｐＨ調整剤、可塑剤等を適宜配合しても良い。分散剤としては、例えば、ヒドロキシプロピルセルロース等の多糖類、ラウリル硫酸ナトリウム等の界面活性剤、カオリン、タルク等の粘土物質、ラテックス、包接化合物、ステアリン酸等が挙げられる。ｐＨ調整剤としては、例えば、クエン酸、酢酸、乳酸、コハク酸、リンゴ酸、リン酸及びこれらの塩、水酸化ナトリウム、水酸化カリウム、酢酸ナトリウム等が挙げられる。可塑剤としては、例えば、クエン酸トリエチル、グリセリン、トリアセチン、プロピレングリコール、モノステアリン酸グリセリン、ポリエチレングリコール類等が挙げられる。 The liquid composition in the step (A) may contain a dispersant, a pH adjuster, a plasticizer, and the like as needed in addition to the above components. Examples of the dispersant include polysaccharides such as hydroxypropyl cellulose, surfactants such as sodium lauryl sulfate, clay substances such as kaolin and talc, latex, clathrate compounds, stearic acid and the like. Examples of the pH adjuster include citric acid, acetic acid, lactic acid, succinic acid, malic acid, phosphoric acid and salts thereof, sodium hydroxide, potassium hydroxide, sodium acetate and the like. Examples of the plasticizer include triethyl citrate, glycerin, triacetin, propylene glycol, glyceryl monostearate, polyethylene glycols, and the like.
ここで、本発明の製造方法は、ゲル化剤の使用が必須でないことから、工程（Ａ）の液状組成物は、ゲル化能を有する高分子を実質的に含まないことが好ましい。ゲル化能を有する高分子を実質的に含まないとは、ゲル化能を有する高分子を全く含有しないことのみならず、ゲル化能を有する高分子を含有するが、工程（Ａ）の液状組成物がゲル化しない程度にその含有量が十分に少ないことをも意味する。 Here, since the use of a gelling agent is not essential in the production method of the present invention, it is preferable that the liquid composition in step (A) does not substantially contain a polymer having gelling ability. “Containing substantially no polymer having gelling ability” not only does not contain any polymer having gelling ability but also contains a polymer having gelling ability. It also means that its content is sufficiently small to the extent that the composition does not gel.
尚、ゲル化能を有する高分子としては、例えば、ゼラチン、寒天、カラギーナン、ジェランガム等が挙げられる。 Examples of the polymer having gelling ability include gelatin, agar, carrageenan, gellan gum and the like.
工程（Ａ）の溶解及び／又は分散では、例えば、ＴＫホモミクサー（プライミクス社製）、クレアミックス（エム・テクニック社製）等の高速回転式分散・乳化機を用いて攪拌することが好ましい。攪拌条件としては、回転数を３０００〜１００００ｒｐｍ、攪拌時間を５〜６０分間とするのが好ましい。 In the dissolution and / or dispersion in the step (A), it is preferable to stir using, for example, a high-speed rotating dispersion / emulsifier such as TK homomixer (manufactured by PRIMIX Co., Ltd.) or CLEARMIX (manufactured by M Technique Co., Ltd.). As stirring conditions, it is preferable that a rotation speed is 3000-10000 rpm and stirring time is 5 to 60 minutes.
〔工程（Ｂ）〕
工程（Ｂ）は、工程（Ａ）で得た液状組成物を噴霧及び冷却固化し、凍結粒子を得る工程である。
[Process (B)]
Step (B) is a step of obtaining frozen particles by spraying and cooling and solidifying the liquid composition obtained in step (A).
工程（Ｂ）の噴霧及び冷却固化は、工程（Ａ）で得た液状組成物が凍結した状態の微細粒子が得られる方法であれば特に制限はないが、生産性の点から、液体窒素の充填された塔内に液状組成物を噴霧して行うことが好ましい。噴霧には、例えば、加圧式噴霧ノズル、回転式噴霧ノズル、回転円盤等が用いられ、好ましくは回転式噴霧ノズルである。回転式噴霧ノズルを用いる場合、好ましい回転数としては、２００〜１５０００ｒｐｍを例示できる。冷却の温度としては、−１９６〜−１５℃が好ましく、−１２０℃〜−２０℃がより好ましい。 The spraying and cooling solidification in the step (B) are not particularly limited as long as the liquid composition obtained in the step (A) is a method that can obtain fine particles in a frozen state. It is preferable to carry out by spraying the liquid composition into the packed tower. For spraying, for example, a pressurized spray nozzle, a rotary spray nozzle, a rotating disk or the like is used, and a rotary spray nozzle is preferable. In the case of using a rotary spray nozzle, examples of a preferable rotational speed include 200 to 15000 rpm. The cooling temperature is preferably -196 to -15 ° C, more preferably -120 ° C to -20 ° C.
〔工程（Ｃ）〕
工程（Ｃ）は、工程（Ｂ）で得た凍結粒子を品温−５〜３０℃で（好ましくは、品温−５〜３０℃のみで）乾燥する工程である。
[Process (C)]
Step (C) is a step of drying the frozen particles obtained in step (B) at a product temperature of -5 to 30 ° C (preferably, only at a product temperature of -5 to 30 ° C).
工程（Ｃ）では、より具体的には、工程（Ｂ）で得た凍結粒子を捕集し、これを棚段式通風乾燥機、流動層乾燥機、真空凍結乾燥機、振動真空乾燥機等の乾燥手段を用いて目的とする水分量まで品温−５〜３０℃で乾燥する。乾燥温度が品温−５〜３０℃であることにより、高密度且つ高分子皮膜の緻密性が向上した薬物含有粒子が得られる。 More specifically, in the step (C), the frozen particles obtained in the step (B) are collected, and this is a shelf-type air dryer, fluidized bed dryer, vacuum freeze dryer, vibration vacuum dryer, etc. The product is dried at a product temperature of -5 to 30 ° C. until the desired amount of water is obtained. When the drying temperature is −5 to 30 ° C., drug-containing particles with high density and improved polymer film density can be obtained.
ここで、上記乾燥手段は、凍結粒子の品温が−５〜３０℃となるように設定されるが、工程（Ｂ）における冷却固化は、通常−５℃未満で行われるため、工程（Ｂ）で得た凍結粒子を乾燥手段に供給して乾燥を開始する時点では、当該粒子の品温は実際には−５℃未満（例えば、−８〜−６℃程度）であり、その品温が−５〜３０℃に達するまでにある程度の時間（例えば、３０分間程度）を要する。そこで、本発明においては、凍結粒子の品温が−５〜３０℃となるように乾燥手段が設定されていても、工程（Ｂ）で得た凍結粒子の品温が−５℃未満から−５〜３０℃に達するまでの間は、工程（Ｃ）における乾燥に含まれないこととする。 Here, although the said drying means is set so that the article temperature of frozen particles may be -5-30 degreeC, since cooling solidification in a process (B) is normally performed at less than -5 degreeC, a process (B ) Is supplied to the drying means to start drying, the product temperature of the particles is actually less than −5 ° C. (for example, about −8 to −6 ° C.). It takes a certain amount of time (for example, about 30 minutes) to reach −5 to 30 ° C. Therefore, in the present invention, even if the drying means is set so that the product temperature of the frozen particles is −5 to 30 ° C., the product temperature of the frozen particles obtained in the step (B) is less than −5 ° C. Until the temperature reaches 5 to 30 ° C., it is not included in the drying in the step (C).
乾燥時間に特に制限はないが、水分量が通常１０質量％以下、好ましくは５質量％以下となるまで行われる。 Although there is no restriction | limiting in particular in drying time, It is carried out until a moisture content becomes 10 mass% or less normally, Preferably it is 5 mass% or less.
また、乾燥は、時間効率の観点から、段階的に実施することができ、例えば、「−５．０℃以上、０．０℃未満」、「０．０℃以上、１５℃未満」及び「１５℃以上、４０℃未満」の温度帯から選ばれる組合せのうち、品温が順次上がる組合せを選択することにより段階的に乾燥を実施することができる。より具体的には、例えば、「−５．０℃以上、０．０℃未満」で１５〜３６時間、「０．０℃以上、１５℃未満」で０．５〜２時間の乾燥を順次行った後、「１５℃以上、４０℃未満」で水分量が任意の割合になるまで乾燥することが好ましく行われる。 In addition, drying can be performed stepwise from the viewpoint of time efficiency. For example, “−5.0 ° C. or more and less than 0.0 ° C.”, “0.0 ° C. or more and less than 15 ° C.” and “ Drying can be performed stepwise by selecting a combination in which the product temperature sequentially increases from combinations selected from a temperature range of 15 ° C. or more and less than 40 ° C. More specifically, for example, “-5.0 ° C. or higher and lower than 0.0 ° C.” for 15 to 36 hours and “0.0 ° C. or higher and lower than 15 ° C.” for 0.5 to 2 hours in order. After being performed, drying is preferably performed until the water content reaches an arbitrary ratio at “15 ° C. or higher and lower than 40 ° C.”.
工程（Ｃ）における乾燥は、吸湿性成分（即ち、水や水蒸気を吸着する性質を有する成分）の存在下で及び／又は減圧条件下で行うことが好ましい。吸湿性成分の存在下で乾燥すると、粒子表面の水分を吸奪し、粒子の融解を防ぎつつ、高分子皮膜の形成を促進できるため好ましい。また、減圧条件下で乾燥すると、乾燥効率を促進し、乾燥後の薬物含有粒子の水分量を十分に低減できるため好ましい。 The drying in the step (C) is preferably performed in the presence of a hygroscopic component (that is, a component having a property of adsorbing water or water vapor) and / or under reduced pressure. Drying in the presence of a hygroscopic component is preferred because it can absorb the moisture on the particle surface and promote the formation of a polymer film while preventing the particles from melting. Further, it is preferable to dry under reduced pressure because the drying efficiency is promoted and the water content of the drug-containing particles after drying can be sufficiently reduced.
吸湿性成分の存在下における乾燥は、例えば、乾燥前に予め凍結粒子に対してクロスポビドン、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム、デンプン、デキストリン等の吸湿性成分を加えて混合することが好ましい。吸湿性成分の添加量は、例えば、凍結粒子１００質量％に対し、通常１〜６質量％である。 For drying in the presence of a hygroscopic component, for example, it is preferable to add a hygroscopic component such as crospovidone, croscarmellose sodium, sodium starch glycolate, starch, dextrin and the like to the frozen particles before drying. . The amount of the hygroscopic component added is usually 1 to 6% by mass with respect to 100% by mass of the frozen particles, for example.
減圧条件下における乾燥は、減圧機能を備えた乾燥手段を用いて、減圧時の圧力が通常０．５〜５０００Ｐａ、好ましくは１〜３０００Ｐａで行うことができる。 Drying under reduced pressure conditions can be carried out using a drying means having a reduced pressure function at a reduced pressure of usually 0.5 to 5000 Pa, preferably 1 to 3000 Pa.
工程（Ｃ）の後、必要に応じ、得られた乾燥物の表面に高分子の被膜を形成させ、薬物の放出制御の精度を高めるために、例えば品温２０〜４０℃で１０〜１２０時間静置しても良い。 After the step (C), if necessary, for example, a polymer film is formed on the surface of the obtained dried product to improve the accuracy of drug release control, for example, at a product temperature of 20 to 40 ° C. for 10 to 120 hours. It may be left still.
本発明の製造方法により得られる薬物含有粒子（以下、本発明の薬物含有粒子という。）１００質量％中の薬物の含有量は、通常０．１０〜９０質量％、好ましくは１．０〜８０質量％となるように調整するのが好ましい。また、当該薬物含有粒子の平均粒子径は、通常５０〜５００μｍであり、好ましくは１００〜３００μｍである。当該平均粒子径は、「第十七改正日本薬局方、粒度測定法 第２法 ふるい分け法」に記載の方法に準じて測定することが好ましい。 The content of the drug in 100% by mass of the drug-containing particles (hereinafter referred to as the drug-containing particles of the present invention) obtained by the production method of the present invention is usually 0.10 to 90% by mass, preferably 1.0 to 80%. It is preferable to adjust so that it may become mass%. Moreover, the average particle diameter of the said drug containing particle | grain is 50-500 micrometers normally, Preferably it is 100-300 micrometers. The average particle size is preferably measured according to the method described in “Seventeenth Revised Japanese Pharmacopoeia, Particle Size Measurement Method, Method 2, Screening Method”.
本発明の薬物含有粒子は、比較的高密度であることから、錠剤等の固形製剤を製造する際、機械圧力により破壊され難く、打錠適性に優れたものである。本発明の薬物含有粒子の密度は、例えば「かさ密度」及び／又は「タップ密度」として評価することができる。具体的な密度としては、非ゲル化性高分子の種類等により異なり一様ではないが、例えば、かさ密度が０．２０ｇ／ｍＬ以上であり、タップ密度が０．２４ｇ／ｍＬ以上である。本発明の薬物含有粒子のかさ密度及びタップ密度は、「第十七改正日本薬局方、３．粉体物性測定法、３．０１ かさ密度およびタップ密度測定法」に記載の方法に準じて測定することが好ましい。 Since the drug-containing particles of the present invention have a relatively high density, they are not easily broken by mechanical pressure when producing a solid preparation such as a tablet, and have excellent tableting suitability. The density of the drug-containing particles of the present invention can be evaluated as, for example, “bulk density” and / or “tap density”. The specific density varies depending on the type of non-gelling polymer and is not uniform. For example, the bulk density is 0.20 g / mL or more and the tap density is 0.24 g / mL or more. The bulk density and tap density of the drug-containing particles of the present invention are measured according to the method described in “17th revised Japanese pharmacopoeia, 3. Powder physical property measurement method, 3.01 bulk density and tap density measurement method”. It is preferable to do.
本発明の薬物含有粒子は、本発明の効果を阻害しない範囲で、他の任意の成分を含有してもよい。そのような成分としては、例えば、酸化防止剤、乳化剤、甘味料、香料等が挙げられる。 The drug-containing particles of the present invention may contain other optional components as long as the effects of the present invention are not impaired. Examples of such components include antioxidants, emulsifiers, sweeteners, and fragrances.
本発明の薬物含有粒子は、そのまま健康食品又は医薬品等として使用することもできるが、健康食品又は医薬品等に配合して好ましく使用することができる。本発明の薬物含有粒子を健康食品又は医薬品に配合して使用する場合、該健康食品又は医薬品の形態に特に制限はなく、該薬物含有粒子と共に医薬品添加物、食品添加物及び食品素材等を適宜配合し、常法に従い、例えば、散剤、顆粒剤、錠剤、ソフトカプセル、ハードカプセル等の形態の製剤として製造することができる。 The drug-containing particles of the present invention can be used as it is as a health food or a medicine, but can be preferably used by blending in a health food or a medicine. When the drug-containing particles of the present invention are used in combination with health foods or pharmaceuticals, there is no particular limitation on the form of the health foods or pharmaceuticals, and pharmaceutical additives, food additives, food materials, etc. are appropriately used together with the drug-containing particles. It can mix | blend and it can manufacture as a formulation of forms, such as a powder, a granule, a tablet, a soft capsule, a hard capsule, according to a conventional method.
以下、実施例をもって本発明を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。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
［実施例１］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを加えて溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌し、イブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）２５３．３ｇに上記イブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を−２．０℃に調整した。
上記捕集した粒子に質量比４．８７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３４０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、品温−２．０℃で３６時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、１２５ｇの薬物含有粒子１を得た。
得られた薬物含有粒子１について水分量及び平均粒子径を測定したところ、水分量は４．４質量％、平均粒子径は１００μｍであった。
[Example 1]
Purify 156.0 g of purified water into a 1 L capacity aluminum mug, add 4.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) and dissolve it, and add ibuprofen (manufactured by Shiratori Pharmaceutical Co., Ltd.). 80.0 g was added, and the mixture was stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare an ibuprofen dispersion.
Add the above ibuprofen dispersion to 253.3 g of ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mix evenly. The ethyl acrylate / methyl methacrylate copolymer and ibuprofen are in water A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 8500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated, and the internal temperature of the vibration dryer was adjusted to -2.0 ° C.
A total of 340.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.87% to the collected particles and mixing them uniformly was added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the inside of the vibration dryer was depressurized to 3000 Pa or less and dried at a product temperature of −2.0 ° C. for 36 hours.
Continuously, under the same reduced pressure, the product was dried in the order of 90 minutes at a product temperature of 5.0 ° C. and 60 minutes at a product temperature of 20.0 ° C.
When the water content and the average particle diameter of the obtained drug-containing particles 1 were measured, the water content was 4.4% by mass and the average particle diameter was 100 μm.
［実施例２］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを加えて溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌し、イブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）２５３．３ｇに上記イブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を−５．０℃に調整した。
上記捕集した粒子に質量比４．８７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３４０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、品温−５．０℃で４３時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、１２５ｇの薬物含有粒子２を得た。
得られた薬物含有粒子２について水分量及び平均粒子径を測定したところ、水分量は１．７質量％、平均粒子径は１００μｍであった。
[Example 2]
Purify 156.0 g of purified water into a 1 L capacity aluminum mug, add 4.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) and dissolve it, and add ibuprofen (manufactured by Shiratori Pharmaceutical Co., Ltd.). 80.0 g was added, and the mixture was stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare an ibuprofen dispersion.
Add the above ibuprofen dispersion to 253.3 g of ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mix evenly. The ethyl acrylate / methyl methacrylate copolymer and ibuprofen are in water A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 8500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated, and the internal temperature of the vibration dryer was adjusted to -5.0 ° C.
A total of 340.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.87% to the collected particles and mixing them uniformly was added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the inside of the vibration dryer was reduced to 3000 Pa or less and dried at a product temperature of -5.0 ° C. for 43 hours.
Subsequently, drying was performed in the order of 90 minutes at a product temperature of 5.0 ° C. and 60 minutes at a product temperature of 20.0 ° C. under the same reduced pressure to obtain 125 g of drug-containing particles 2.
When the water content and the average particle diameter of the obtained drug-containing particles 2 were measured, the water content was 1.7% by mass and the average particle diameter was 100 μm.
［実施例３］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを加えて溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌し、イブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）２５３．３ｇに上記イブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を−０．５℃に調整した。
上記捕集した粒子に質量比４．８７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３４０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、品温−０．５℃で２３時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、１２５ｇの薬物含有粒子３を得た。
得られた薬物含有粒子３について水分量及び平均粒子径を測定したところ、水分量は１．２質量％、平均粒子径は１００μｍであった。
[Example 3]
Purify 156.0 g of purified water into a 1 L capacity aluminum mug, add 4.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) and dissolve it, and add ibuprofen (manufactured by Shiratori Pharmaceutical Co., Ltd.). 80.0 g was added, and the mixture was stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare an ibuprofen dispersion.
Add the above ibuprofen dispersion to 253.3 g of ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mix evenly. The ethyl acrylate / methyl methacrylate copolymer and ibuprofen are in water A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 8500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated, and the internal temperature of the vibration dryer was adjusted to -0.5 ° C.
A total of 340.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.87% to the collected particles and mixing them uniformly was added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the inside of the vibration dryer was reduced to 3000 Pa or less and dried at a product temperature of −0.5 ° C. for 23 hours.
Subsequently, drying was performed in the order of 90 minutes at a product temperature of 5.0 ° C. and 60 minutes at a product temperature of 20.0 ° C. under the same reduced pressure to obtain 125 g of drug-containing particles 3.
When the water content and the average particle diameter of the obtained drug-containing particles 3 were measured, the water content was 1.2% by mass and the average particle diameter was 100 μm.
［実施例４］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを加えて溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌した後、適量の２５質量％クエン酸水溶液を加え、ｐＨ２．４のイブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）１１４．７ｇに適量の２５質量％クエン酸水溶液を加え、そのｐＨを２．４に調整した後、これにメタクリル酸コポリマーＬＤ（商品名：オイドラギットＬ３０ Ｄ−５５；ＥＶＯＮＩＫ社製）１１４．７ｇ、クエン酸トリエチル（和光純薬工業製）７．２g及び上記のイブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー、メタクリル酸コポリマーＬＤ及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を品温−２．０℃に調整した。
上記捕集した粒子に質量比４．９８％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３４０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、−２．０℃で３０時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、得られた乾燥物を内部温度４０℃の送風定温恒温器（型式：ＤＮＥ４００型；ヤマト科学社製）内に１２０時間静置して当該乾燥物表面に高分子の被膜を形成させ、１１５ｇの薬物含有粒子４を得た。
得られた薬物含有粒子４について水分量及び平均粒子径を測定したところ、水分量は１．６質量％、平均粒子径は１００μｍであった。
[Example 4]
Purify 156.0 g of purified water into a 1 L capacity aluminum mug, add 4.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) and dissolve it, and then add ibuprofen (manufactured by Shiratori Pharmaceutical). ) 80.0 g was added, and the mixture was stirred for 3 minutes at 10,000 rpm using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix), and then an appropriate amount of 25% by mass citric acid aqueous solution was added, and ibuprofen having a pH of 2.4 A dispersion was prepared.
An appropriate amount of a 25% by weight aqueous citric acid solution was added to 114.7 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK), and the pH was adjusted to 2.4. Add 114.7 g of acid copolymer LD (trade name: Eudragit L30 D-55; manufactured by EVONIK), 7.2 g of triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) and the above ibuprofen dispersion, and mix uniformly. A liquid composition in which ethyl / methyl methacrylate copolymer, methacrylic acid copolymer LD and ibuprofen were dispersed in water was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and sprayed in a spherical shape by rotating the rotary spray nozzle at 8,500 rpm. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated to adjust the internal temperature of the vibration dryer to a product temperature of -2.0 ° C.
A total of 340.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.98% to the collected particles and mixing them uniformly was added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the vibration dryer was dried at −2.0 ° C. for 30 hours while reducing the pressure to 3000 Pa or less.
Subsequently, under the same reduced pressure, the product was dried for 90 minutes at a product temperature of 5.0 ° C. and then at a product temperature of 20.0 ° C. for 60 minutes in order, and the resulting dried product was a constant temperature incubator (model number) with an internal temperature of 40 ° C. : DNE400 type; manufactured by Yamato Scientific Co., Ltd.) for 120 hours to form a polymer film on the surface of the dried product, and 115 g of drug-containing particles 4 were obtained.
When the water content and the average particle diameter of the obtained drug-containing particles 4 were measured, the water content was 1.6% by mass and the average particle diameter was 100 μm.
［実施例５］
１Ｌ容量のアルミ製ジョッキに精製水２３７．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）３．０ｇを加えて溶解し、これにファモチジン（陽進堂社製）６０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌撹拌し、ファモチジン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）１９０．０ｇに上記ファモチジン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びファモチジンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数５５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を−２．０℃に調整した。
上記捕集した粒子に質量比３．６７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３２０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、品温−２．０℃で３６時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、得られた乾燥物を内部温度４０℃の送風定温恒温器（型式：ＤＮＥ４００型；ヤマト科学社製）内に１２０時間静置して当該乾燥物表面に高分子の被膜を形成させ、９０ｇの薬物含有粒子５を得た。
得られた薬物含有粒子５について水分量及び平均粒子径を測定したところ、水分量は１．７質量％、平均粒子径は１５０μｍであった。
[Example 5]
237.0 g of purified water was put into a 1 L capacity aluminum mug, and 3.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) was added to dissolve it, and famotidine (Yoshidosha) 60.0 g was added, and the mixture was stirred and stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare a famotidine dispersion.
The above-mentioned famotidine dispersion is added to 190.0 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mixed uniformly. The ethyl acrylate / methyl methacrylate copolymer and famotidine are in water. A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 5500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated, and the internal temperature of the vibration dryer was adjusted to -2.0 ° C.
A total of 320.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 3.67% to the collected particles and mixing them uniformly was added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the inside of the vibration dryer was depressurized to 3000 Pa or less and dried at a product temperature of −2.0 ° C. for 36 hours.
Subsequently, under the same reduced pressure, the product was dried for 90 minutes at a product temperature of 5.0 ° C. and then at a product temperature of 20.0 ° C. for 60 minutes in order, and the resulting dried product was a constant temperature incubator (model number) with an internal temperature of 40 ° C. : DNE400 type; manufactured by Yamato Scientific Co., Ltd.) for 120 hours to form a polymer film on the surface of the dried product, and 90 g of drug-containing particles 5 were obtained.
When the water content and the average particle size of the obtained drug-containing particles 5 were measured, the water content was 1.7% by mass and the average particle size was 150 μm.
［実施例６］
１Ｌ容量のアルミ製ジョッキに精製水１９７．５ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）２．５ｇを溶解し、これにファモチジン（陽進堂社製）５０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌撹拌し、ファモチジン分散液を調製した。
精製水１４０．０ｇにラウリル硫酸ナトリウム２．０ｇ及びステアリン酸３．０ｇを溶解し、これにアミノアルキルメタクリレートコポリマーＥ（商品名：オイドラギットＥＰＯ；ＥＶＯＮＩＫ社製）２０．０ｇを加えて撹拌した後、これにアクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）７５．０ｇ及び上記のファモチジン分散液を加え、均一に混和させ、アミノアルキルメタクリレートコポリマーＥ、アクリル酸エチル・メタクリル酸メチルコポリマー及びファモチジンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数５５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
開放系冷却水循環装置（型式：ＣＴＰ−３０００型；東京理化器械社製）を用いて、振動乾燥機（型式：ＶＨ−１０型；中央化工機社製）のジャケットに冷媒〔水：ポリエチレングリコール＝１：１（質量比）〕を循環させ、当該振動乾燥機の内部温度を−２．０℃に調整した。
上記捕集した粒子に質量比３．０６％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計３５０．０ｇの粒子を上記振動乾燥機に投入し、小型空冷ドライ真空ポンプ（商品名：ＮｅｏＤｒｙ ６０Ｅ；樫山工業社製）を用いて当該振動乾燥機内を３０００Ｐａ以下に減圧しながら、品温−２．０℃で３６時間乾燥した。
続けて、同減圧下にて、品温５．０℃で９０分間、品温２０．０℃で６０分間の順に乾燥し、得られた乾燥物を内部温度４０℃の送風定温恒温器（型式：ＤＮＥ４００型；ヤマト科学社製）内に１２０時間静置して当該乾燥物表面に高分子の被膜を形成させ、７５ｇの薬物含有粒子６を得た。
得られた薬物含有粒子６について水分量及び平均粒子径を測定したところ、水分量は１．１質量％、平均粒子径は１５０μｍであった。
[Example 6]
Purified water (197.5 g) is put into a 1 L capacity aluminum mug, and hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) (2.5 g) is dissolved therein. 50.0 g was added, and the mixture was stirred and stirred at 10000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare a famotidine dispersion.
After dissolving 2.0 g of sodium lauryl sulfate and 3.0 g of stearic acid in 140.0 g of purified water, 20.0 g of aminoalkyl methacrylate copolymer E (trade name: Eudragit EPO; manufactured by EVONIK) was added and stirred, To this was added 75.0 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and the above-mentioned famotidine dispersion, and mixed uniformly to obtain an aminoalkyl methacrylate copolymer E, ethyl acrylate. A liquid composition in which methyl methacrylate copolymer and famotidine were dispersed in water was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 5500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
Using an open-system cooling water circulation device (model: CTP-3000 type; manufactured by Tokyo Rika Kikai Co., Ltd.), a refrigerant (water: polyethylene glycol = 1: 1 (mass ratio)] was circulated, and the internal temperature of the vibration dryer was adjusted to -2.0 ° C.
A total of 350.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 3.06% to the collected particles and mixing the particles uniformly is added to the vibration dryer. Then, using a small air-cooled dry vacuum pump (trade name: NeoDry 60E; manufactured by Kashiyama Kogyo Co., Ltd.), the inside of the vibration dryer was depressurized to 3000 Pa or less and dried at a product temperature of −2.0 ° C. for 36 hours.
Subsequently, under the same reduced pressure, the product was dried for 90 minutes at a product temperature of 5.0 ° C. and then at a product temperature of 20.0 ° C. for 60 minutes in order, and the resulting dried product was a constant temperature incubator (model number) with an internal temperature of 40 ° C. : DNE400 type; manufactured by Yamato Scientific Co., Ltd.) for 120 hours to form a polymer film on the surface of the dried product to obtain 75 g of drug-containing particles 6.
When the water content and average particle diameter of the obtained drug-containing particles 6 were measured, the water content was 1.1% by mass and the average particle diameter was 150 μm.
［比較例１］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌し、イブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）２５３．３ｇに上記イブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
上記捕集した粒子に質量比４．８７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計６０．０ｇの粒子を凍結乾燥機（型式：ＲＬＥＩＩ−１０３型；協和真空技術社製）に投入し、乾燥器内を４０Ｐａに減圧しながら、品温−２８℃の状態で、棚温度を０℃で６時間、５℃で６時間、１０℃で６時間、２０℃で６時間の順に上昇させて乾燥し、２２ｇの薬物含有粒子７を得た。
得られた薬物含有粒子７について水分量及び平均粒子径を測定したところ、水分量は１．７質量％、平均粒子径は１２０μｍであった。
[Comparative Example 1]
Purified water (156.0 g) is put in a 1 L capacity aluminum mug, and hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) (4.0 g) is dissolved in this. 0.0 g was added, and the mixture was stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare an ibuprofen dispersion.
Add the above ibuprofen dispersion to 253.3 g of ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mix evenly. The ethyl acrylate / methyl methacrylate copolymer and ibuprofen are in water A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 8500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
A total of 60.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.87% to the collected particles and mixing them uniformly was freeze-dried (model) : RLEII-103 type; manufactured by Kyowa Vacuum Technology Co., Ltd.), while reducing the pressure inside the dryer to 40 Pa, the product temperature is -28 ° C, the shelf temperature is 0 ° C for 6 hours, and 5 ° C for 6 hours. The temperature was raised in the order of 10 ° C. for 6 hours and 20 ° C. for 6 hours, followed by drying to obtain 22 g of drug-containing particles 7.
When the water content and the average particle size of the obtained drug-containing particles 7 were measured, the water content was 1.7% by mass and the average particle size was 120 μm.
［比較例２］
１Ｌ容量のアルミ製ジョッキに精製水１５６．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）４．０ｇを加えて溶解し、これにイブプロフェン（白鳥製薬社製）８０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌した後、適量の２５質量％クエン酸水溶液を加え、ｐＨ２．４のイブプロフェン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）１１４．７ｇに適量の２５質量％クエン酸水溶液を加え、そのｐＨを２．４に調整した後、これにメタクリル酸コポリマーＬＤ（商品名：オイドラギットＬ３０ Ｄ−５５；ＥＶＯＮＩＫ社製）１１４．７ｇ、クエン酸トリエチル（和光純薬工業製）７．２ｇ及び上記のイブプロフェン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー、メタクリル酸コポリマーＬＤ及びイブプロフェンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数８５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
上記捕集した粒子に質量比４．９８％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計６０．０ｇの粒子を凍結乾燥機（型式：ＲＬＥＩＩ−１０３型；協和真空技術社製）に投入し、乾燥器内を４０Ｐａに減圧しながら、品温−２８℃の状態で、棚温度を０℃で６時間、５℃で６時間、１０℃で６時間、２０℃で６時間の順に上昇させて乾燥し、２０ｇの薬物含有粒子８を得た。
得られた薬物含有粒子８について水分量及び平均粒子径を測定したところ、水分量は１．５質量％、平均粒子径は１２０μｍであった。
[Comparative Example 2]
Purify 156.0 g of purified water into a 1 L capacity aluminum mug, add 4.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) and dissolve it, and then add ibuprofen (manufactured by Shiratori Pharmaceutical). ) 80.0 g was added, and the mixture was stirred for 3 minutes at 10,000 rpm using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix), and then an appropriate amount of 25% by mass citric acid aqueous solution was added, and ibuprofen having a pH of 2.4 A dispersion was prepared.
An appropriate amount of a 25% by weight aqueous citric acid solution was added to 114.7 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK), and the pH was adjusted to 2.4. Add 114.7 g of acid copolymer LD (trade name: Eudragit L30 D-55; manufactured by EVONIK), 7.2 g of triethyl citrate (manufactured by Wako Pure Chemical Industries, Ltd.) and the above ibuprofen dispersion, and mix uniformly. A liquid composition in which ethyl / methyl methacrylate copolymer, methacrylic acid copolymer LD and ibuprofen were dispersed in water was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 8500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
A total of 60.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 4.98% to the collected particles and mixing them uniformly was freeze-dried (model) : RLEII-103 type; manufactured by Kyowa Vacuum Technology Co., Ltd.), while reducing the pressure inside the dryer to 40 Pa, the product temperature is -28 ° C, the shelf temperature is 0 ° C for 6 hours, and 5 ° C for 6 hours. The temperature was raised in the order of 10 hours at 10 ° C. and 6 hours at 20 ° C. and dried to obtain 20 g of drug-containing particles 8.
When the water content and the average particle diameter of the obtained drug-containing particles 8 were measured, the water content was 1.5% by mass and the average particle diameter was 120 μm.
［比較例３］
１Ｌ容量のアルミ製ジョッキに精製水２３７．０ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）３．０ｇを加えて溶解し、これにファモチジン（陽進堂社製）６０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＴＫロボミクス；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌撹拌し、ファモチジン分散液を調製した。
アクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）１９０．０ｇに上記ファモチジン分散液を加え、均一に混和させ、アクリル酸エチル・メタクリル酸メチルコポリマー及びファモチジンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数５５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
上記捕集した粒子に質量比３．６７％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計６０．０ｇの粒子を凍結乾燥機（型式：ＲＬＥＩＩ−１０３型；協和真空技術社製）に投入し、乾燥器内を４０Ｐａに減圧しながら、品温−２８℃の状態で、棚温度を０℃で６時間、５℃で６時間、１０℃で６時間、２０℃で６時間の順に上昇させて乾燥し、１７ｇの薬物含有粒子９を得た。
得られた薬物含有粒子９について水分量及び平均粒子径を測定したところ、水分量は１．６質量％、平均粒子径は１８０μｍであった。
[Comparative Example 3]
237.0 g of purified water was put into a 1 L capacity aluminum mug, and 3.0 g of hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) was added to dissolve it, and famotidine (Yoshidosha) 60.0 g was added, and the mixture was stirred and stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: TK Robotics; manufactured by Primix) to prepare a famotidine dispersion.
The above-mentioned famotidine dispersion is added to 190.0 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and mixed uniformly. The ethyl acrylate / methyl methacrylate copolymer and famotidine are in water. A dispersed liquid composition was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 5500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
A total of 60.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 3.67% to the collected particles and mixing them uniformly was freeze-dried (model) : RLEII-103 type; manufactured by Kyowa Vacuum Technology Co., Ltd.), while reducing the pressure inside the dryer to 40 Pa, the product temperature is -28 ° C, the shelf temperature is 0 ° C for 6 hours, and 5 ° C for 6 hours. The temperature was raised in the order of 10 ° C. for 6 hours and 20 ° C. for 6 hours, and dried to obtain 17 g of drug-containing particles 9.
When the water content and the average particle diameter of the obtained drug-containing particles 9 were measured, the water content was 1.6% by mass and the average particle diameter was 180 μm.
［比較例４］
１Ｌ容量のアルミ製ジョッキに精製水１９７．５ｇを入れ、これにヒドロキシプロピルセルロース（商品名：ＨＰＣ−Ｌ；日本曹達社製）２．５ｇを溶解し、これにファモチジン（陽進堂社製）５０．０ｇを加え、ＴＫホモミクサー（商品名；型式：ＭＡＲＫ２．５；プライミクス社製）を用いて１００００ｒｐｍにて３分間撹拌撹拌し、ファモチジン分散液を調製した。
精製水１４０．０ｇにラウリル硫酸ナトリウム２．０ｇ及びステアリン酸３．０ｇを溶解し、これにアミノアルキルメタクリレートコポリマーＥ（商品名：オイドラギットＥＰＯ；ＥＶＯＮＩＫ社製）２０．０ｇを加えて撹拌した後、これにアクリル酸エチル・メタ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；ＥＶＯＮＩＫ社製）７５．０ｇ及び上記のファモチジン分散液を加え、均一に混和させ、アミノアルキルメタクリレートコポリマーＥ、アクリル酸エチル・メタクリル酸メチルコポリマー及びファモチジンが水中に分散した液状組成物を調製した。
上記液状組成物を塔下部が液体窒素で冷却された噴霧冷却装置（試験機）に送液し、回転式噴霧ノズルを回転数５５００ｒｐｍで回転させて球状に噴霧した。噴霧された組成物は冷却されて塔下部に落下し、凍結状態の粒子として捕集した。
上記捕集した粒子に質量比３．０６％のクロスポビドン（商品名：Ｋｏｌｌｉｄｏｎ ＣＬ−ＳＦ；ＢＡＳＦ社製）を加えて均一に混合して得た計６０．０ｇの粒子を凍結乾燥機（型式：ＲＬＥＩＩ−１０３型；協和真空技術社製）に投入し、乾燥器内を４０Ｐａに減圧しながら、品温−２８℃の状態で、棚温度を０℃で６時間、５℃で６時間、１０℃で６時間、２０℃で６時間の順に上昇させて乾燥し、１３ｇの薬物含有粒子１０を得た。
得られた薬物含有粒子１０について水分量及び平均粒子径を測定したところ、水分量は１．６質量％、平均粒子径は１８０μｍであった。
[Comparative Example 4]
Purified water (197.5 g) is put into a 1 L capacity aluminum mug, and hydroxypropylcellulose (trade name: HPC-L; manufactured by Nippon Soda Co., Ltd.) (2.5 g) is dissolved therein. 50.0 g was added, and the mixture was stirred and stirred at 10,000 rpm for 3 minutes using a TK homomixer (trade name; model: MARK 2.5; manufactured by Primix) to prepare a famotidine dispersion.
After dissolving 2.0 g of sodium lauryl sulfate and 3.0 g of stearic acid in 140.0 g of purified water, 20.0 g of aminoalkyl methacrylate copolymer E (trade name: Eudragit EPO; manufactured by EVONIK) was added and stirred, To this was added 75.0 g of an ethyl acrylate / methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D; manufactured by EVONIK) and the above-mentioned famotidine dispersion, and mixed uniformly to obtain an aminoalkyl methacrylate copolymer E, ethyl acrylate. A liquid composition in which methyl methacrylate copolymer and famotidine were dispersed in water was prepared.
The liquid composition was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotational speed of 5500 rpm and sprayed in a spherical shape. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
A total of 60.0 g of particles obtained by adding crospovidone (trade name: Kollidon CL-SF; manufactured by BASF) having a mass ratio of 3.06% to the collected particles and mixing them uniformly was freeze-dried (model) : RLEII-103 type; manufactured by Kyowa Vacuum Technology Co., Ltd.), while reducing the pressure inside the dryer to 40 Pa, the product temperature is -28 ° C, the shelf temperature is 0 ° C for 6 hours, and 5 ° C for 6 hours. The temperature was raised in the order of 10 hours at 10 ° C. and 6 hours at 20 ° C. and dried to obtain 13 g of drug-containing particles 10.
When the water content and average particle diameter of the obtained drug-containing particles 10 were measured, the water content was 1.6% by mass and the average particle diameter was 180 μm.
上記実施例１〜６及び比較例１〜４における薬物の種類、非ゲル化性高分子の種類及び乾燥条件（乾燥温度・時間）について、実施例１〜６に関するものを表１に示し、比較例１〜４に関するものを表２に示す。 Table 1 shows the types of drugs, types of non-gelling polymers, and drying conditions (drying temperature / time) in Examples 1 to 6 and Comparative Examples 1 to 4 shown in Table 1. Those relating to Examples 1 to 4 are shown in Table 2.
［試験例：かさ密度及びタップ密度の測定］
上記実施例１〜６及び比較例１〜４で製造した薬物含有粒子１〜１０について、「かさ密度」及び「タップ密度」を測定した。測定は、「第十七改正日本薬局方、３．粉体物性測定法、３．０１ かさ密度およびタップ密度測定法」に記載の方法に準じて行った。結果を表３に示す。
[Test example: Measurement of bulk density and tap density]
For the drug-containing particles 1 to 10 produced in Examples 1 to 6 and Comparative Examples 1 to 4, “bulk density” and “tap density” were measured. The measurement was performed according to the method described in “17th revised Japanese Pharmacopoeia, 3. Powder physical property measurement method, 3.01 bulk density and tap density measurement method”. The results are shown in Table 3.
表３の結果から明らかなように、本発明の製造方法（実施例１〜６）により得られた薬物含有粒子１〜６は、比較例１〜４の製造方法により得られた薬物含有粒子７〜１０と比較してかさ密度及びタップ密度が高く、高密度であることが確認された。 As is clear from the results in Table 3, the drug-containing particles 1 to 6 obtained by the production method of the present invention (Examples 1 to 6) are the drug-containing particles 7 obtained by the production method of Comparative Examples 1 to 4. It was confirmed that the bulk density and the tap density were higher than those of -10 and a high density.
Claims (3)
（Ａ）非ゲル化性高分子及び薬物を水性成分に溶解及び／又は分散し、液状組成物を得る工程、
（Ｂ）前記液状組成物を噴霧及び冷却固化し、凍結粒子を得る工程、並びに
（Ｃ）前記凍結粒子を品温−５〜３０℃で乾燥する工程
を含む、薬物含有粒子の製造方法。 Next steps (A), (B) and (C):
(A) a step of dissolving and / or dispersing a non-gelling polymer and a drug in an aqueous component to obtain a liquid composition;
(B) A method for producing drug-containing particles, comprising the steps of spraying and cooling and solidifying the liquid composition to obtain frozen particles, and (C) drying the frozen particles at a product temperature of -5 to 30 ° C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2018015530A JP2019131511A (en) | 2018-01-31 | 2018-01-31 | Method for producing medicine-containing particle |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2018015530A JP2019131511A (en) | 2018-01-31 | 2018-01-31 | Method for producing medicine-containing particle |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2019131511A true JP2019131511A (en) | 2019-08-08 |
Family
ID=67544719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018015530A Pending JP2019131511A (en) | 2018-01-31 | 2018-01-31 | Method for producing medicine-containing particle |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2019131511A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030026842A1 (en) * | 2001-06-08 | 2003-02-06 | Prestrelski Steven J. | Production of hard, dense particles |
| JP2003509361A (en) * | 1999-09-10 | 2003-03-11 | アストラゼネカ・アクチエボラーグ | How to get fine particles |
| JP2006089381A (en) * | 2004-09-21 | 2006-04-06 | Riken Vitamin Co Ltd | Method for producing ubidecarenone-containing microcapsule |
| JP2008514644A (en) * | 2004-09-28 | 2008-05-08 | アルザ コーポレイション | Stabilization of alum adjuvant immunoactive agent |
| JP2017503641A (en) * | 2013-12-19 | 2017-02-02 | エアロゾル セラピューティクス， エルエルシー | Compositions and methods for atmospheric pressure spray freeze drying |
-
2018
- 2018-01-31 JP JP2018015530A patent/JP2019131511A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003509361A (en) * | 1999-09-10 | 2003-03-11 | アストラゼネカ・アクチエボラーグ | How to get fine particles |
| US20030026842A1 (en) * | 2001-06-08 | 2003-02-06 | Prestrelski Steven J. | Production of hard, dense particles |
| JP2006089381A (en) * | 2004-09-21 | 2006-04-06 | Riken Vitamin Co Ltd | Method for producing ubidecarenone-containing microcapsule |
| JP2008514644A (en) * | 2004-09-28 | 2008-05-08 | アルザ コーポレイション | Stabilization of alum adjuvant immunoactive agent |
| JP2017503641A (en) * | 2013-12-19 | 2017-02-02 | エアロゾル セラピューティクス， エルエルシー | Compositions and methods for atmospheric pressure spray freeze drying |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2021178871A (en) | Formulations of enzalutamide | |
| KR101443943B1 (en) | Solid dosage forms comprising an enteric coating with accelerated drug release | |
| JP4879351B2 (en) | Pharmaceutical solid formulation | |
| JP7471675B2 (en) | Porous silica particle composition | |
| JP4748839B2 (en) | Cilostazol preparation | |
| TW200302740A (en) | Immediate release dosage forms containing solid drug dispersions | |
| US10406107B2 (en) | Method of preparing composite granule comprising low-substituted hydroxypropyl cellulose and rapid release preparation | |
| JP2011063611A (en) | Cilostazol preparation | |
| KR100660072B1 (en) | Multiple unit controlled food effect-independent release pharmaceutical preparations and method for preparing the same | |
| TW200304377A (en) | Glycogen phosphorylase inhibitor | |
| JP2010525082A (en) | Solid dosage form | |
| TW200302739A (en) | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials | |
| JP2001172201A (en) | Use of film coating for masking the taste for oral administration, oral administration form and production thereof | |
| CN102238946B (en) | Pharmaceutical composition for the controlled release of methylphenidate | |
| WO2002096466A1 (en) | Medicinal composition | |
| JP2008539231A (en) | Cellulose film incorporating a pharmaceutically acceptable plasticizer with improved wettability | |
| JPH0819003B2 (en) | Nucleated granule and method for producing the same | |
| TW201609195A (en) | Solid antiviral dosage forms | |
| WO2016139683A2 (en) | Pharmaceutical compositions of lurasidone and process for preparing the same | |
| DHANDAPANI | Pelletization by Extrusion-Spheronization-A detailed review | |
| JP6361925B2 (en) | Solid preparation | |
| JP3910939B2 (en) | Single-substance spherical particles, foods and medicines using them, and methods for producing them | |
| JP2019131511A (en) | Method for producing medicine-containing particle | |
| JP5841609B2 (en) | Pharmaceutical composition for treating HCV infection | |
| US20180235913A1 (en) | An oral pharmaceutical formulation comprising sustained-release granules containing tamsulosin hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20201118 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210714 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210727 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220208 |