JP2023151957A - Method for producing medicine-containing particles - Google Patents
Method for producing medicine-containing particles Download PDFInfo
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- JP2023151957A JP2023151957A JP2022061844A JP2022061844A JP2023151957A JP 2023151957 A JP2023151957 A JP 2023151957A JP 2022061844 A JP2022061844 A JP 2022061844A JP 2022061844 A JP2022061844 A JP 2022061844A JP 2023151957 A JP2023151957 A JP 2023151957A
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- JP
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- Prior art keywords
- drug
- particles
- containing particles
- liquid composition
- drying
- 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
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- 239000002245 particle Substances 0.000 title claims abstract description 53
- 239000003814 drug Substances 0.000 title claims abstract description 49
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- 239000007788 liquid Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 13
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- 235000010489 acacia gum Nutrition 0.000 claims abstract description 9
- 238000005507 spraying Methods 0.000 claims abstract description 6
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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。 BACKGROUND ART Conventionally, one of the methods for manufacturing fine particles containing a drug is to use a polymer having gelling ability (gelling agent) such as gelatin or agar as a base. This method requires heating to, for example, 40 to 90° C. in order to prepare a solution in which the gelling agent is dissolved, and there is a problem that it cannot be applied to drugs whose decomposition is accelerated by heat. In addition, this method also has the problem that the types of applicable drugs are further restricted because production becomes impossible if the raw materials contain drugs that inhibit gelation, such as strong acids and strong bases.
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、得られた粒子を乾燥するというものである（特許文献１及び２）。 On the other hand, a spray freeze-drying method is known as a method capable of producing fine particles containing a drug without using a gelling agent as a base. In this method, a liquid mixture containing a drug and a non-gelling polymer as a base is sprayed onto liquid nitrogen, etc., rapidly cooled and solidified, and the resulting particles are dried (Patent Document 1 and 2).
この方法において、非ゲル化性の高分子としてポリビニルアルコールを用いた場合、保形性やバリア性に優れた粒子が得られるが、乾燥した粒子が帯電して製造装置や器具等に付着し、生産性が低下する問題があった。 In this method, when polyvinyl alcohol is used as a non-gelling polymer, particles with excellent shape retention and barrier properties can be obtained, but the dried particles become electrically charged and adhere to manufacturing equipment, instruments, etc. There was a problem of decreased productivity.
本発明は、ポリビニルアルコールを基剤とする薬物含有粒子を噴霧凍結乾燥法により製造する際に生じる粒子の帯電を防止する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 preventing the charging of particles that occurs when producing drug-containing particles based on polyvinyl alcohol by a spray freeze-drying method.
本発明者は、上記課題に対して鋭意検討を行った結果、ポリビニルアルコールと共にポリエチレングリコール及び／又はアラビアガムを用いることにより、粒子の帯電を防止できることを見出し、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-mentioned problem, the present inventor discovered that by using polyethylene glycol and/or gum arabic together with polyvinyl alcohol, charging of particles can be prevented, and based on this knowledge, the present invention was made. reached.
すなわち、本発明は、以下の工程１、２及び３を含む、薬物含有粒子の製造方法からなっている。
工程１：以下の成分（Ａ）、（Ｂ）及び（Ｃ）を成分（Ｄ）に溶解及び／又は分散し、液状組成物を得る工程
（Ａ）ポリビニルアルコール
（Ｂ）ポリエチレングリコール及び／又はアラビアガム
（Ｃ）薬物
（Ｄ）水性成分
工程２：前記工程１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
工程３：前記工程２で得た凍結粒子を乾燥する工程
That is, the present invention consists of a method for producing drug-containing particles, which includes the following steps 1, 2, and 3.
Step 1: Step of obtaining a liquid composition by dissolving and/or dispersing the following components (A), (B) and (C) in component (D) (A) polyvinyl alcohol (B) polyethylene glycol and/or arabic Gum (C) Drug (D) Aqueous component Step 2: Spraying and solidifying the liquid composition obtained in Step 1 to obtain frozen particles Step 3: Drying the frozen particles obtained in Step 2
本発明の製造方法は、得られる薬物含有粒子の帯電が防止されているため、製造装置や器具等への該粒子の付着が少なく、生産性が高い。 In the production method of the present invention, since the obtained drug-containing particles are prevented from being charged, there is little adhesion of the particles to production equipment, instruments, etc., and productivity is high.
本発明の薬物含有粒子の製造方法は、以下の工程１、２及び３を含む。 The method for producing drug-containing particles of the present invention includes the following steps 1, 2, and 3.
〔工程１〕
工程１は、以下の成分（Ａ）、（Ｂ）及び（Ｃ）を成分（Ｄ）に溶解及び／又は分散し、液状組成物を得る工程である。
（Ａ）ポリビニルアルコール
（Ｂ）ポリエチレングリコール及び／又はアラビアガム
（Ｃ）薬物
（Ｄ）水性成分
[Step 1]
Step 1 is a step of dissolving and/or dispersing the following components (A), (B), and (C) in component (D) to obtain a liquid composition.
(A) Polyvinyl alcohol (B) Polyethylene glycol and/or gum arabic (C) Drug (D) Aqueous component
成分（Ａ）のポリビニルアルコールは、医薬品添加物規格２０１８に収載されている医薬品添加物であり、ポリ酢酸ビニルをけん化して得られる水溶性の高分子である。ポリビニルアルコールは、ポリビニルアルコール完全けん化物（けん化度：９７ｍｏｌ％以上）及びポリビニルアルコール部分けん化物（けん化度：７８～９６ｍｏｌ％）に大別されるが、本発明においては、部分けん化物が好ましい。 Component (A) polyvinyl alcohol is a pharmaceutical additive listed in the Pharmaceutical Excipients Standard 2018, and is a water-soluble polymer obtained by saponifying polyvinyl acetate. Polyvinyl alcohol is broadly classified into completely saponified polyvinyl alcohol (saponification degree: 97 mol% or more) and partially saponified polyvinyl alcohol (saponification degree: 78 to 96 mol%), but partially saponified products are preferred in the present invention.
成分（Ｂ）のポリエチレングリコールは、エチレングリコールが重合した構造をもつ高分子化合物である。ポリエチレングリコールの分子量に特に制限はないが、例えば、数平均分子量が１００～１０００００、好ましくは２００～５００００のものを用いることができる。尚、数平均分子量は、日本薬局方及び医薬部外品原料規格に記載の平均分子量試験における末端基定量法に基づき、滴定により水酸基価を求めることにより測定される。 Component (B) polyethylene glycol is a polymer compound having a structure in which ethylene glycol is polymerized. Although there is no particular restriction on the molecular weight of polyethylene glycol, for example, polyethylene glycol having a number average molecular weight of 100 to 100,000, preferably 200 to 50,000 can be used. The number average molecular weight is measured by determining the hydroxyl value by titration based on the terminal group determination method in the average molecular weight test described in the Japanese Pharmacopoeia and the Standards for Quasi-drug Ingredients.
また、成分（Ｂ）のアラビアガムは、マメ科アラビアゴムノキ（Ａｃａｃｉａ Ｓｅｎｅｇａｌ Ｗｉｌｌｄｅｎｏｗ）又は他同属植物の分泌物を乾燥して得られたもの又はこれを脱塩して得られるものであり、多糖類を主成分とするものである。 In addition, gum arabic, which is component (B), is obtained by drying the secretion of Acacia Senegal Wildenow or other plants of the same genus, or is obtained by desalting it, and is a polysaccharide. The main component is
成分（Ｃ）の薬物は、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 of component (C) is not particularly limited as long as it is a therapeutically or prophylactically effective active ingredient, and examples include ibuprofen, naproxen, ketoprofen, acetaminophen, indomethacin, bufexamac, aspirin, diclofenac, Non-steroidal anti-inflammatory drugs such as alclofenac, fenclofenac, etodolac, flurbiprofen, mefenamic, meclofenamic, piroxicam, hypnotic/sedative drugs such as nitrazepam, triazolam, phenobarbital, amibarbital, phenytoin, Antiepileptic drugs such as metalvital, primidone, clonazepam, carbamazepine, valproic acid, antidepressants such as meclizine hydrochloride, dimenhydrinate, antidepressants such as imiplanin, noxyputyline, phenelzine, haloperidol, meprobamate, chlordiazepoxide, diazebam, oxazebam , neuropsychiatric agents such as sulpiride, antispasmodics such as papaverine, atropine, etomidrine, cardiotonic agents such as digoxin, digitoxin, methyldigoxin, ubidecarenone, arrhythmic agents such as pindolol, ajmaline, disopyramide, hydrochlorothiazide, spironolactone, triamterene, furosemide, Diuretics such as bumetanide, antihypertensive agents such as reserpine, dihydroergotoxin mesylate, prazosin hydrochloride, metoprolol, propranolol, atenolol, coronary vasodilators such as nitroglycerin, isosorbide nitrate, diltiazem, nifedipine, dipyridamole, noscapine, salbutamol, Antitussives such as procaterol, tulopterol, tranilast, and ketotifen, expectorants such as bromhexine hydrochloride and guaifenesin, cerebral circulation improvers such as nicardipine and pinpocetine, antibiotics such as erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, and griseofulvin, and diphenhydramine. , antihistamines such as promethazine, mequitazine, and clemastine fumarate; steroids such as triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, and chlormadinone acetate; vitamins A, vitamin D, vitamin E, vitamin K, and folic acid ( Vitamin preparations such as vitamin M), drugs for treating digestive system diseases such as famotidine, dimethicone, cimetidine, nizatidine, metoclopramide, omeprazole, sulpiride, trepibutone, sucralfate, caffeine, dicumarol, cinnarizine, clofibrate, gefarnate, brobenecid, mercapto Examples include purine, methotrexate, ursodesoxycholic acid, dihydroergotamine mesylate, and the like.
成分（Ｄ）の水性成分としては、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 of component (D) include "water" or "aqueous solution containing one or more selected from aqueous solvents, sugar alcohols, and polyhydric alcohols", among others, those that are easy to manufacture and easily available From the viewpoint of properties, water is preferably used. Examples of water include distilled water, purified water such as ion exchange resin treated water, reverse osmosis membrane treated water, and 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 sugar alcohols include sorbitol, mannitol, maltitol, reduced starch syrup, and the like. Examples of polyhydric alcohols include propylene glycol, glycerin, polyglycerin, and the like.
上記液状組成物は、成分（Ａ）、（Ｂ）及び（Ｃ）が成分（Ｄ）に溶解及び／又は分散したものである。該液状組成物１００質量％中の成分（Ａ）、（Ｂ）、（Ｃ）及び（Ｄ）の配合割合は、薬物の種類等により異なり一様ではないが、例えば、成分（Ａ）が２．５～３０質量％、好ましくは２．５～２０質量％、成分（Ｂ）のポリエチレングリコールが０．０１～３０質量％、好ましくは０．０１～２０質量％、成分（Ｂ）のアラビアガムが０．５～３０質量％、好ましくは０．５～２０質量％、成分（Ｃ）が５～７５質量％、好ましくは５～５０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 liquid composition has components (A), (B), and (C) dissolved and/or dispersed in component (D). The blending ratio of components (A), (B), (C), and (D) in 100% by mass of the liquid composition varies depending on the type of drug, etc., but for example, if component (A) is 2 .5 to 30% by weight, preferably 2.5 to 20% by weight, component (B) polyethylene glycol, 0.01 to 30% by weight, preferably 0.01 to 20% by weight, gum arabic as component (B) is 0.5 to 30% by mass, preferably 0.5 to 20% by mass, component (C) is 5 to 75% by mass, preferably 5 to 50% by mass, and the remainder is an aqueous component. can.
上記液状組成物は、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、ソルビタン脂肪酸エステル、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類等が挙げられる。 In addition to the above-mentioned components, the liquid composition may optionally contain a dispersant, a pH adjuster, a plasticizer, etc. Examples of the dispersant include polysaccharides such as hydroxypropylcellulose, sorbitan fatty acid esters, 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, and glyceryl monostearate.
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１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１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 production method of the present invention does not require the use of a gelling agent, it is preferable that the liquid composition in step 1 does not substantially contain a polymer having gelling ability. Substantially not containing a polymer having a gelling ability does not mean not only that it does not contain a polymer having a gelling ability at all, but also means that the liquid composition in Step 1 contains a polymer having a gelling ability. It also means that the content is sufficiently low to the extent that it 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。 Note that examples of polymers having gelling ability include gelatin, agar, carrageenan, gellan gum, and the like.
成分（Ａ）、（Ｂ）及び（Ｃ）を成分（Ｄ）に溶解及び／又は分散する方法に特に制限はないが、例えば、成分（Ａ）、（Ｄ）及び必要により分散剤を加え、４０～７５℃に加温及び撹拌して成分（Ａ）を成分（Ｄ）に溶解し、必要によりこれを２０～４０℃に冷却し、これに成分（Ｂ）及び（Ｃ）を加えて撹拌し、成分（Ｂ）及び（Ｃ）を成分（Ｄ）に溶解及び／又は分散することが好ましい。 There are no particular limitations on the method of dissolving and/or dispersing components (A), (B), and (C) in component (D), but for example, components (A), (D) and, if necessary, a dispersing agent are added, Dissolve component (A) in component (D) by heating and stirring to 40-75°C, cool this to 20-40°C if necessary, add components (B) and (C) to this, and stir. However, it is preferable to dissolve and/or disperse components (B) and (C) in component (D).
上記の成分（Ｂ）及び（Ｃ）を加えた後の撹拌は、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）、ホモディスパー（プライミクス社製）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。 Stirring after adding the above components (B) and (C) can be carried out using a high-speed rotating device such as TK Homomixer (manufactured by Primix), Clearmix (manufactured by M Techniques), or HomoDisper (manufactured by Primix). It is preferable to stir using a dispersing/emulsifying machine. As for the stirring conditions, it is preferable that the rotation speed is 3000 to 10000 rpm and the stirring time is 5 to 60 minutes.
〔工程２〕
工程２は、工程１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。
[Step 2]
Step 2 is a step in which the liquid composition obtained in Step 1 is sprayed and solidified by cooling to obtain frozen particles.
工程２の噴霧及び冷却固化は、工程１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 step 2 are not particularly limited as long as the liquid composition obtained in step 1 can obtain fine particles in a frozen state, but from the viewpoint of productivity, a tower filled with liquid nitrogen is used. It is preferable to spray the liquid composition into the inside of the container. For the spraying, for example, a pressurized spray nozzle, a rotary spray nozzle, a rotating disk, etc. are used, and preferably a rotary spray nozzle. When using a rotary spray nozzle, a preferable rotation speed is 200 to 15,000 rpm. The cooling temperature is preferably -196°C to -15°C, more preferably -120°C to -20°C.
〔工程３〕
工程３は、工程２で得た凍結粒子を乾燥する工程である。
[Step 3]
Step 3 is a step of drying the frozen particles obtained in Step 2.
工程３では、より具体的には、例えば、工程２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（例えば、１０質量％以下、好ましくは５質量％以下）まで品温－５～４０℃で乾燥することが好ましい。 More specifically, in step 3, for example, the frozen particles obtained in step 2 are collected and dried using a tray type ventilation dryer, a fluidized bed dryer, a vacuum freeze dryer, a vibration vacuum dryer, etc. It is preferable to dry the product to a desired moisture content (for example, 10% by mass or less, preferably 5% by mass or less) using a method at a temperature of -5 to 40°C.
また、工程３の乾燥は、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、「－５．０～１５℃」の温度帯による乾燥を１～２４時間実施した後、「１５～４０℃」の温度帯による乾燥を目的とする水分量まで実施することができる。 In addition, the drying in step 3 can be carried out in stages from the viewpoint of time efficiency. For example, after carrying out drying in a temperature range of "-5.0 to 15 degrees Celsius" for 1 to 24 hours, Drying can be carried out in a temperature range of 40°C up to the desired moisture content.
工程３の乾燥は、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する観点から、減圧条件下で行うことが好ましい。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０．５～５０００Ｐａ、好ましくは１～３０００Ｐａで行うことができる。 The drying in step 3 is preferably performed under reduced pressure conditions from the viewpoint of promoting drying efficiency and sufficiently reducing the moisture content of the drug-containing particles after drying. Drying under reduced pressure conditions can be carried out at a pressure of 0.5 to 5000 Pa, preferably 1 to 3000 Pa, using a drying means equipped with a reduced pressure function.
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、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、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 drug content in 100% by mass of drug-containing particles obtained by the production method of the present invention (hereinafter referred to as drug-containing particles of the present invention) is 0.10 to 90% by mass, preferably 1.0 to 80% by mass. %. Further, the average particle diameter of the drug-containing particles is 50 to 500 μm, preferably 100 to 300 μm. The average particle diameter is preferably measured according to the method described in "Particle Size Measurement Method, Method 2, Sieving Method, 17th Edition Japanese Pharmacopoeia."
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 they are as health foods or medicines, but they can also be preferably used by blending them into health foods or medicines. When the drug-containing particles of the present invention are used in a health food or medicine, there is no particular restriction on the form of the health food or medicine, and pharmaceutical additives, food additives, food materials, etc. are appropriately added to the drug-containing particles. They can be blended and manufactured according to conventional methods into preparations in the form of powders, granules, tablets, soft capsules, hard capsules, and the like.
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。 EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.
［薬物含有粒子の製造］
（１）原材料
１）水
２）ポリビニルアルコール（商品名：ゴーセルノール ＥＧ－０５Ｐ；三菱ケミカル社製）
３）ソルビタン脂肪酸エステル（商品名：Ｌ－３００；理研ビタミン社製）
４）アセトアミノフェン（商品名：アセトアミノフェン；山本化学工業社製）
５）ポリエチレングリコール１（商品名：マクロゴール４００；数平均分子量４００；日油社製）
６）ポリエチレングリコール２（商品名：マクロゴール４０００；数平均分子量４０００；日油社製）
７）ポリエチレングリコール３（商品名：マクロゴール６０００；数平均分子量６０００；日油社製）
８）ポリエチレングリコール４（商品名：ＰＥＧ♯２００００；数平均分子量２００００；日油社製）
９）アラビアガム（商品名：局方アラビアゴム末「Ｓ」 ＳＤ品；鈴粉末薬品社製）
１０）デキストリン（商品名：サンデック♯１００；三和澱粉工業社製）
１１）ポリビニルピロリドン（商品名：Ｋｏｌｌｉｄｏｎ３０；ＢＡＳＦ社製）
１２）ヒドロキシプロピルセルロース（商品名：ＨＰＣ－ＳＳＬ；日本曽達社製）
[Manufacture of drug-containing particles]
(1) Raw materials 1) Water 2) Polyvinyl alcohol (Product name: Gosselnol EG-05P; manufactured by Mitsubishi Chemical Corporation)
3) Sorbitan fatty acid ester (product name: L-300; manufactured by Riken Vitamin Co., Ltd.)
4) Acetaminophen (trade name: acetaminophen; manufactured by Yamamoto Chemical Co., Ltd.)
5) Polyethylene glycol 1 (trade name: Macrogol 400; number average molecular weight 400; manufactured by NOF Corporation)
6) Polyethylene glycol 2 (trade name: Macrogol 4000; number average molecular weight 4000; manufactured by NOF Corporation)
7) Polyethylene glycol 3 (trade name: Macrogol 6000; number average molecular weight 6000; manufactured by NOF Corporation)
8) Polyethylene glycol 4 (trade name: PEG #20000; number average molecular weight 20000; manufactured by NOF Corporation)
9) Gum arabic (Product name: Pharmacopoeia gum arabic powder “S” SD product; manufactured by Suzu Powder Yakuhin Co., Ltd.)
10) Dextrin (product name: Sandek #100; manufactured by Sanwa Starch Industries Co., Ltd.)
11) Polyvinylpyrrolidone (trade name: Kollidon 30; manufactured by BASF)
12) Hydroxypropyl cellulose (product name: HPC-SSL; manufactured by Nippon Soda)
上記原材料を用いて製造した薬物含有粒子１～１２の配合組成を表１及び２に示す。このうち、表１に示す薬物含有粒子１～８の製造は、本発明に係る実施例であり、表２に示す薬物含有粒子９～１２の製造は、それらに対する比較例である。 Tables 1 and 2 show the formulation compositions of drug-containing particles 1 to 12 produced using the above raw materials. Among these, the production of drug-containing particles 1 to 8 shown in Table 1 are examples according to the present invention, and the production of drug-containing particles 9 to 12 shown in Table 2 are comparative examples thereto.
（２）薬物含有粒子の製造方法
１０００ｍＬ容量のガラス製ビーカーに、表１又は２に示した配合量に従って（Ｉ）の原材料を加え、これを６０℃に加熱し、均一に混合及び溶解し、３０℃に冷却した。ここに表１又は２に示した配合量に従って（ＩＩ）の原材料を加え、高速分散機ホモディスパー（型式：２．５型；プライミクス社製）で５０００ｒｐｍにて５分間撹拌し、原料を均一に分散し、液状組成物を得た。
次に、該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５０００ｒｐｍ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。
捕集した粒子を、凍結乾燥機（型式：ＤＲＣ－１０００，ＦＤＵ－１１１０；東京理化器械社製）を用いて、５０Ｐａ以下の減圧下で、設定温度－５℃で１時間乾燥した後、粒子の品温が２７℃以上になるまで設定温度３０℃で乾燥した。得られた乾燥物を３０号篩（目開き５００μｍ）で篩い、平均粒子径２００μｍの薬物含有粒子１～１２を各々得た。
(2) Method for manufacturing drug-containing particles Add the raw materials (I) according to the amounts shown in Table 1 or 2 to a 1000 mL glass beaker, heat this to 60°C, mix and dissolve uniformly, Cooled to 30°C. Add the raw material (II) according to the blending amount shown in Table 1 or 2, and stir for 5 minutes at 5000 rpm using a high-speed disperser homodisper (model: 2.5 type; manufactured by Primix) to uniformly distribute the raw material. The mixture was dispersed to obtain a liquid composition.
Next, the liquid composition was sent to a spray cooling device (testing machine) whose lower part of the tower was cooled with liquid nitrogen, and a rotary spray nozzle was rotated at a rotation speed of 5000 rpm to spray it into a spherical shape. The sprayed composition was cooled and fell to the bottom of the tower, where it was collected as frozen particles.
The collected particles were dried using a freeze dryer (model: DRC-1000, FDU-1110; manufactured by Tokyo Rikakikai Co., Ltd.) under reduced pressure of 50 Pa or less at a set temperature of -5°C for 1 hour, and then the particles were dried. The product was dried at a set temperature of 30°C until the product temperature reached 27°C or higher. The obtained dried product was sieved with a No. 30 sieve (mesh opening 500 μm) to obtain drug-containing particles 1 to 12 each having an average particle diameter of 200 μm.
（３）帯電防止効果の評価
上記（２）の製造において３０号篩（目開き５００μｍ）により篩過済みの薬物含有粒子１～１２の各々について同篩で再度の篩過を実施した。試験では、当該再度の篩過前後の粒子の質量を測定し、次式に基づき通過率（％）を求めた。また、その結果を以下の基準に従って記号化した。ここで、通過率（％）は、その値が高いほど、帯電により篩に付着した薬物含有粒子が少なく、薬物含有粒子の帯電が防止されていることを表す。結果を表３に示す。
通過率（％）＝Ａ／Ｂ×１００
Ａ：篩過後の薬物含有粒子の質量
Ｂ：篩過前の薬物含有粒子の質量
(3) Evaluation of antistatic effect Each of the drug-containing particles 1 to 12 that had been sieved through a No. 30 sieve (mesh opening 500 μm) in the production of (2) above was sieved again using the same sieve. In the test, the mass of the particles before and after the second sieving was measured, and the passage rate (%) was determined based on the following formula. In addition, the results were coded according to the following criteria. Here, the higher the pass rate (%), the fewer drug-containing particles adhere to the sieve due to electrification, and the more the drug-containing particles are prevented from being electrified. The results are shown in Table 3.
Passage rate (%) = A/B x 100
A: Mass of drug-containing particles after sieving B: Mass of drug-containing particles before sieving
［記号化基準］
◎：極めて良好 通過率９０％以上
○：良好 通過率８０％以上、９０％未満
×：悪い 通過率８０％未満
[Symbolization standards]
◎: Very good Passage rate 90% or more ○: Good Passage rate 80% or more, less than 90% ×: Poor Passage rate less than 80%
表３の結果から明らかなように、本発明の製造方法により得られた薬物含有粒子１～８は、比較例の製造方法により得られた薬物含有粒子９～１２と比較して透過率が高く、帯電が防止されていることが確認された。 As is clear from the results in Table 3, drug-containing particles 1 to 8 obtained by the production method of the present invention have higher transmittance than drug-containing particles 9 to 12 obtained by the production method of the comparative example. It was confirmed that charging was prevented.
Claims (1)
工程１：以下の成分（Ａ）、（Ｂ）及び（Ｃ）を成分（Ｄ）に溶解及び／又は分散し、液状組成物を得る工程
（Ａ）ポリビニルアルコール
（Ｂ）ポリエチレングリコール及び／又はアラビアガム
（Ｃ）薬物
（Ｄ）水性成分
工程２：前記工程１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
工程３：前記工程２で得た凍結粒子を乾燥する工程 A method for producing drug-containing particles, comprising the following steps 1, 2 and 3.
Step 1: Step of obtaining a liquid composition by dissolving and/or dispersing the following components (A), (B) and (C) in component (D) (A) polyvinyl alcohol (B) polyethylene glycol and/or arabic Gum (C) Drug (D) Aqueous component Step 2: Spraying and solidifying the liquid composition obtained in Step 1 to obtain frozen particles Step 3: Drying the frozen particles obtained in Step 2
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