JPS58183621A - Dust preparation containing substance activating lung surface as active ingredient - Google Patents

Abstract

PURPOSE:A fine pwoder of water-soluble diluent is uniformly dispersed in a solution of a substance activating lung surfaces in an organic solvent, then the dispersion is evaporated to dryness to give a dust preparation which can develop sufficient effect as a remedy for hyperpnea syndromes without reduction in its specific surface activity. CONSTITUTION:A substance activating lung surfaces is dissolved in an organic solvent, preferably chloroform, methylene chloride, THF or ether and 20-30, preferably 5-20pts.wt. per 1pt.wt. of the substance, of a water-soluble diluent fine powder, which is insoluble or hard soluble in the organic solvent are added to the resultant solution to effect uniform dispersion. The resultant dispersion is evaporated to dryness rapidly at a temperature at which the substance is not deactivated to give the objective dust preparation. As water-soluble diluents, are used essential aminoacids such as glycine or alanine, saccharides such as glucose or galactose or antibiotics such as cefazolin or gentamycin.

Description

【発明の詳細な説明】[Detailed description of the invention]

本発明は、肺表面活性物質を有効成分とする粉末剤の調
製法に関する。その目的とするところは、呼吸器疾磨治
療剤と１−て経気道的に投与することのできる。肺表面
活性物質の粉末剤を提供することにある。 動物の肺胞には、肺表面活性物質と称するり／脂質を主
成分とする生理活性物′ａが存在する。 これは肺胞の内壁を覆い、肺胞土皮保験作用を廟すると
共Ｋ、動物が呼吸機能を維持−する上に重要な生理的機
能を有している。即ち肺表面活性物質は、呼気時、吸気
時における肺胞内面の表面張力を変化させると云った特
異な表面活伯を有しており、肺胞相互間の安定性に寄与
１−て、抗無気肺作用を示すと云われている。肺表面活
性物質については、従来種々の動物について多くの研究
がなされ、その全貌が明らかにされつ匁ある。即ち、こ
の活性物質はその成分と１．てリン脂質、中性脂質、蛋
白質等を含み、主成分はリン脂質の一つであるジパルミ
トイルレシチンであることが知られている。 最近、藤原らは生肝より抽出した活性物質にジパルミト
イルレシチン等を添加１．て、人ニ［的により活性の高
い肺表面活性物質を得、これを用いて新生児呼吸窮迫症
候群（ＩＲＩ）Ｓ　　）に経気道的に補充療法を行−り
て良好な結果を得たことを報告にている（小児科臨床、
第３２巻、第７号、＋３４３頁）。また、小林らは豚Ｑ
）肺洗浄液より活性物質を分離、更に活性を高める為に
Ｃａｉ＋　を共存させた肺表面活性物質を調製１１、Ｉ
Ｒｒ）Ｓの補充療法を行い成功している（日本界面医学
会雑誌１２巻第１号（１９８］））、、これらの方法に
於ては、天然より倚られた肺表面活性物質からＦｏｌｃ
ｈ　　の方法により脂質部を抽出（７て、牛や豚等に由
来する異種蛋白質を除去１−ているもの匁、その除去は
完全でなく１〜３φ前後の異種蛋白の混入が認められて
いる。また天然より得られた肺表面活性物質の中には、
通常の抑清蛋白とは異る肺固肩の蛋白の存在がＫｉｎｇ
らによって認められている（　Ｋｉｎｇら、　Ａｍ、　
Ｊ。 Ｐｈｙｓｌｏｌ　ｇ−２４，７８８〜７９５．１９７３
　：　　Ｆｅｄ、Ｐｒｏｃ、。 需−早、２２３８〜２２４１．１９７４　）。 これは分子量が３６，０００のものが主成分で、疎水性
のアミノ酸を多量に含む脂溶性蛋白であることが知られ
ている。このような事実から１゜て、上記の如く天然の
肺表面活性物質からＦｏｌｃｈ　の方法により有機溶剤
可溶部を抽出することにより肺表面活性物質を調製する
ことは、必要なリン脂質、中性脂質等のみなＬ−）ず肺
固有の蛋白も抽出され、その混入は逸れないと考えられ
る。そ１−て動物由来の蛋白の混入は抗原性を発現に、
アブフイラキシー等の副作用が惹起される可能性があり
、肺表面活性物質の医薬品化を考えた場合、こｔｌらは
好まＬ　＜ない。史にこ才１らは分散液状で注入膜力さ
れており、多量の液体を気管に注入すると云う問題点を
有The present invention relates to a method for preparing a powder containing a pulmonary surfactant as an active ingredient. Its purpose is to use it as a therapeutic agent for respiratory ailments so that it can be administered through the respiratory tract. The purpose of the present invention is to provide a powder of pulmonary surfactant. In the alveoli of animals, there is a physiologically active substance called lung surfactant 'a which is mainly composed of lipids. It covers the inner wall of the alveoli and has an important physiological function in maintaining the respiratory function of animals, as well as maintaining the protective function of the alveolar skin. In other words, pulmonary surfactants have a unique surface activity that changes the surface tension on the inner surface of the alveoli during exhalation and inspiration, and contributes to the stability between alveoli, thereby increasing the resistance to resistance. It is said to have an atelectasis effect. Regarding pulmonary surfactants, many studies have been conducted on various animals, and the full picture is still being clarified. That is, the active substance is combined with its constituents: 1. It is known that it contains phospholipids, neutral lipids, proteins, etc., and its main component is dipalmitoyl lecithin, which is one of the phospholipids. Recently, Fujiwara et al. added dipalmitoyl lecithin etc. to active substances extracted from raw liver. We obtained a pulmonary surfactant that is more active in humans, and used it to administer airway supplementation therapy to neonatal respiratory distress syndrome (IRI) with good results. In the report (pediatric clinical,
Volume 32, No. 7, +343 pages). Also, Kobayashi et al.
) Separate the active substance from the lung lavage fluid and prepare a lung surfactant with Cai+ coexisting to further increase the activity 11, I
Rr)S replacement therapy has been successfully carried out (Journal of the Japanese Society of Surface Medicine Vol. 12, No. 1 (198)). In these methods, Folc
Extract the lipid part using the method described in (7) to remove foreign proteins derived from cows, pigs, etc. However, the removal is not complete and foreign proteins of around 1 to 3 φ are found to be mixed in. Also, among the lung surfactants obtained from nature,
The presence of a lung stiffening protein that is different from normal suppressant proteins
(King et al., Am,
J. Physlol g-24, 788-795.1973
: Fed, Proc. Yu-haya, 2238-2241.1974). It is known that it is a fat-soluble protein whose main component has a molecular weight of 36,000 and contains a large amount of hydrophobic amino acids. Based on these facts, it is possible to prepare a lung surfactant by extracting the organic solvent-soluble part from a natural lung surfactant by Folch's method as described above. Not only lipids, etc., but also lung-specific proteins are extracted, and it is thought that their contamination will not be avoided. First, contamination with animal-derived proteins may cause antigenicity.
They may cause side effects such as ab-phylaxis, and when considering the commercialization of pulmonary surfactants, these are not preferred. Historically, Kosai 1 is in the form of a dispersed liquid and is injected into the membrane, which poses the problem of injecting a large amount of liquid into the trachea.

【２ている。Ｃ、Ｊ　、Ｍｏｒｌｅｙら（Ｔｈｅ　Ｌ
ａｎｃｅｔ　Ｊａｎ、　１０　＋１’ｉ８１．ｐ６４）
はこれら０）問題点を指摘し、異種蛋白を含まない粉末
合成肺表面活性物質の調製を試み、未熟児呼吸窮迫症候
群に適用（−１臨床的に成功ｔ２ている。従来、液状注
入でのみその効果が認められていたが、これは粉末投与
に於てもその薬効を充分に発現し得ることを示したもの
であり、授与形態の簡便さが充分期待出来るものである
。 最近、通常の呼吸器疾患治療剤は、局所効果に優れ、全
身効果が少−・ことを期待して吸入療法が試みられてお
り、ネブライザーによる工ρゾル投与と共にスピンヘラ
−によるより簡便な粉末製剤吸入投与方法が臨床に於い
て採用されつつある。本発明者ら（す、この様な事実に
鑑み、　５−− 肺表面活性物質の粉末化の方法の検討を続けて来た。天
然の粗肺炎面活性物質よりＦ’ｏｌｃｈ　Ｏ−＋方法で
得られた脂質部は、有機溶剤雰囲気下より乾燥１．た場
合は、軟性の膠質となり、また凍結乾燥等水溶液雰囲気
下より乾燥１．た場合は、綿状となる等粉末化１．にく
い物質である。また、本発明者らはリン脂質を主成分と
［−だ合成肺表面活性物質と１．て、い（っがの高活性
組成物を得ているが、これらはいずれも、ろう状或いは
ワックス状で、粉末形態になりＫくい。本発明者らは、
肺表面活性物質の特異的な表面活性を下げることな（粉
末化する方法を鋭意検討の結果、本発明に到達した。 即ち、本発明は、肺表面活性物質を有機溶剤に溶解させ
、これに該有機溶剤に不溶又は難溶で医学的に許容され
る水溶性賦形剤の微粉末を均一に分散させ、その後得ら
れた分散液を蒸発乾固させることを特徴とする、肺表面
活性物質を有効成分とする粉末剤の調製法であ４）。 本発明に於ける粉末状の賦形剤は、アミノ酸。 　６− ｆｆｉ　９　、裳いは抗生物質等の水溶性のもので、肺
表面活性物質を溶かす有機溶剤に不溶又は難溶で医学的
に許容される様なものである１、肺表面活性物質】重量
部に対に２〜３０重険、好ま１゜くけ５〜２０重量部が
使用される。アミノ酸と１、ては、必須アミノ酸のグリ
シン、アラニン。 ｌ・リプトファ／、シスチン等があり、糖と１−てはグ
ルフース、ガラクトース、マンニトール。 ンルキトール、ザツカρ−ズ等がある。抗生物質と１．
ては、セファゾリン、ゲンタマイシン。 エリスロマイシン、フ・イトマイシン等がある。 Ｖ形削と１．て抗生物質を用いた場合には、肺表面活性
物質の薬効と同時に抗生物質の薬効も期待でき、目的に
よっては好ま１．い粉末剤となろ３゜粉末化の方法と１
．ては、肺表面活性物質を有機溶剤、好まｌ、　（は、
り＋＝＋ｐホルム、塩化メチレン、テトラヒドロフラン
、二一ヴル等に溶解［２、該溶液に微粉末化１．た賦形
剤の一種或いは二種以」二を重層加え、均一に分散させ
る。そし。 て、肺表面活性物質の活性を失活させない様な温度です
みやかに蒸発乾固させる。好ましくけ、ロータリーエバ
ポレーター等で室温、減圧下。 回転攪拌になが１ｌ−）蒸発ψ固する。必要ルｒ　ｔｌ
げ（＋）らねた粉末を更に均一な微粉末と１．製剤化す
４）、。 また、これら暉゛形削り外に、医学的に許容される無機
塩例えば塩化カッ１シウム、場化すｌリウム、リン酸ナ
トリウＪ−等を混合添加すイ）ことも出来る。肺表面活
性物質は、これら粉末状財形剤の表面に均一に伺着せ１
．めらｔｌており、粉末の形態をとる製剤と１、て使用
さｉ１４．。 祷らすまた粉末剤の表面活性を、後述のウィルヘルミー
バランスによって測定すると、最小表面張力は］　Ｏｄ
ｙｎｅ　／　ｃｍ　Ｊソ］・で、最大表面張力は′（６
〜ｓ　５　ｄｙｎｅ　／　ｃｍ　、またスタビリテイ・
インデックスは１．２旬上であり、第１図に示１．たり
［１ぎ％界的ｔ「ヒステリ／スループを描き、高い表面
活性４・有１．ている。この様に、本発明に」、れげ、
表面活性を損うことなく、天然又は自戒肺表面活性物質
を粉末化することができ、祷られる粉末剤は天然の肺表
面活性物質とＳｌ等の表面活性をＩＡｌ、ている。本発
明で得らねた粉末化肺表面活性物質は、天然由来或いは
合成にか匁わりなく本来の活性を維持１、ていることよ
り、吸入等の簡便な投与方法により、ＩＲＤＳ等の呼吸
窮迫症候群治療薬とにてその薬効を充分発現することが
期待出来るもＱ）である。 以下、実施例により本発明を詳述する。なお肺表面活性
物質の表面活性は以下の如き方法で測定１．た。 〔合成肺表面活性物質の表面張力の測定とスタビ１１テ
イ・インデックスの算出〕 測定にはアフマ社製のウイルヘルミ−バランスを使用１
１、このテフｐ／水槽に生理食塩水を５０　ｍ／入れ、
その上に被検試料の１多分散液或いは粉末体を静かにの
せた。試料が分散液の購ｒは５ｄを静かに重層１．た。 そ１．て、０．３サイクル／分の速度で液体の表面積を
４ｏｃＪから１３〜の間で連続的にサイクリングさせ、
Ｘ−Ｙレコーダーで第１図に示（また如き表１１ｉｌｉ
ｆ＊−表面張力ダイアグラムを記録した。サイクリング
開始　９　− 後５〜６回目で一宇に収束またヒステリ／スループから
最小表面張力（ｒ龍）の値と最大表面張力（１ｒｎａｘ
　）の値及びヒステリシスループで囲まわた面積を求め
た。安定性の指標であるスタビリテイ・インデックス（
Ｓ、Ｉ　）を下記式から求めた。 実施例Ｉ Ｌ−α−ジパルｊ）イルホスファチジルフリン１．２ｖ
どシリルインｏ、ｓ　ｙをりｐｐホルムに溶解し、均一
な溶液と１．た。次に該溶液を室漉減圧下ｐ−タリーエ
バポレーターで蒸発乾固し、四に高真空下に乾燥１．白
色ろう状の固形物を得た（合成肺表面活性物Ｗ）。この
もα−ノを微畦とり、ウィルヘルミーバ→ンスで表面活
性ヲ測定１．た。結果は第１表に示す々１１（で高（゛
表面活性を示したが、このものを■鉢にて粉砕１−ｔ′
が粘り着（・て粉末状にブＪらなが−った。１−１０− このもの０，５りをりｐロホルム５０−に溶解１２、こ
れに微粉化したグリシン５２を添加、均一な分散液とに
た。次に１−タリーエバポレーターで減圧下、室温で回
転蒸発乾燥させ、更にＩｌ！ｉ貫空下で乾燥１．た。得
られた粉末体を史に微粉化１１、均一なさらさらｊ−た
微粉体を得た。このもの−表面活性は第１表の如くであ
った３、このもの又氷表面に於ける分散性は非常に良好
であり、犬きｔ「ヒステリシスループを描きグリシンに
よる微粉化によって活性の低下は認められなかった。 実施例２ 実施例１で得られた白色ろう状物質１２をクロルホルム
ＢＯｍ７！に溶解１５、こねに予め微粉化１、たアラニ
ン］Ｏｆを添加１２、均一な分散油ど１２だ。次に実施
例１と同様に乾燥粉末化１．て白色微粉体を得た。この
もの−表面活性は第１表に示１．た如くで、アラニンに
よる粉末化により活性の低下は認められなかった。 実施例３ Ｍ、Ｆ２．Ａｂｒａｍｓの方法（Ｊ、Ａｐｐｌ　、Ｐｈ
ｙｓｉｏｌ　２　ｒ　：　７　］　８〜７２０）に基き
、下記に示す方法で天然の肺表面活性物質を分＃また１
、 豚の肺臓２　ＫｆをＮＩ切１−１生理食塩水５ｔを用い
てホモジナイザーでポモジナイズシ、ガーゼにて濾過に
て抽出液ケ得た。次１ｃ　＋　０００ｒｐｒｎ　Ｘ３０
分の低速遠心分離で上清をとり、得られた一ヒ清を７０
０　Ｏｒｐｍの高速回転で１時間遠心分離［、沈渣を得
た。予め冷却調製した飽和食塩水（比重１，２　］　）
に沈渣を分散り一、７０００ｒｐｍＸ３０分の遠心分離
を行い、上層の白い薄層を分増１．た。この白い薄層部
を冷却蒸留水で透析１５、凍結乾燥を行うことＫより天
然の精製肺表面活性物質を得た。 次に、Ｆｏｌｃｈ　　らの方法に準じて、りρｐホルム
／メタノール（２：　］　ｖ／ｖ　）混合溶謀に得られ
た天然の肺表面活性物質を溶％ｌ、０．５％の食塩水に
接触ｍ置することにより脂質部を得た。 このものを少濱とり、蒸留水で１％の分散液を訓ｆｆ＋
、、ウイルヘルミーバランスで表面活性を測定１．た５
、結果は第１表に示す如くで、界面への分散性が良好で
’＋Ｗい表面活性を示１．た。 次にこのもの１ｆを１００　ｍｌのりｐρポルムニ溶解
１、こ１に予め僚粉化１．たマンニトール５ｖを分散さ
せ、均一な分散液を調製１．た。次にｐ−タリーエバポ
レータで減圧下、室温で回転蒸発乾燥させ、更に高真空
下で乾燥１．て淡白黄色の粉末を得た。このもの〜表面
活性は第１表に示１−だ如くで、高い表面活性を示ｌ２
、粉末化肺表面活性物質ｋｌることか出来た。 実施例４ ■・−α−ホスファチジルコリンジパルミトイル６００
Ｍ＋ｇ、　　シリルイン３００肩９．リノール酸１００
１９をりＩ：ＩＩ：Ｉホルム］ＯＯｍｅに溶解し、こね
に予め微粉化したマンニトール５２を分散１、て、均一
フ（、分散液を得た。この分散液を実施例Ｊと同様な方
法で乾燥１．て、粉末体とＬ−更に１３− 微粉化にて白色の均一な微粉末をイ（１だ。 このもの−表面活性は第１表に示にだ如（で、良好な界
面分散性と高い表向活性を示１．た。 実施例５ ＤＬ−α−ボスファチジルコリンジパルミトイル３００
ｍｇ、　　シリ／　ｌ／イア２００ｍ１／をりｐａホル
Ａ　３０　ｒｒｄ’、に溶解１１、これに予め微粉化１
−たセファゾリンナトリウ、１−．２．Ｂｆを分散１−
て、均一な分散液を得た。この分散液を実施例１と同様
な方法で乾燥１−て、粉末体とに、更に微粉化１−て白
色の均一な微粉末を得た。このもの瓦表面活性は第１表
に示（また如（で、置い表面活性を示ｊ−た。 　１４−[There are 2. C, J., Morley et al.
ancet Jan, 10 +1'i81. p64)
pointed out these problems and attempted to prepare a powdered synthetic pulmonary surfactant that does not contain foreign proteins, and applied it to respiratory distress syndrome of prematurity (-1), which has been clinically successful. Conventionally, only liquid injection was performed. Although its effectiveness was recognized, this shows that the medicinal effects can be fully expressed even when administered as a powder, and the simplicity of the form of administration can be fully expected. Inhalation therapy has been attempted for respiratory disease therapeutic agents in the hope that they will have excellent local effects and little systemic effects. In view of these facts, the present inventors have continued to study methods for powderizing pulmonary surfactants.Natural crude pulmonary surfactants When the lipid part obtained by the F'olch O-+ method is dried under an organic solvent atmosphere, it becomes a soft gelatinous substance, and when it is dried under an aqueous solution atmosphere such as freeze-drying, it becomes flocculent. It is a substance that is difficult to powderize.The present inventors also obtained a highly active composition using phospholipids as the main component and a synthetic pulmonary surfactant. However, all of these are waxy or wax-like and in powder form.The present inventors have
As a result of extensive research into a method for powdering lung surfactants without lowering their specific surface activity, the present invention has been achieved by dissolving lung surfactants in an organic solvent, A pulmonary surfactant characterized by uniformly dispersing fine powder of a medically acceptable water-soluble excipient that is insoluble or sparingly soluble in the organic solvent, and then evaporating the resulting dispersion to dryness. 4). The powdered excipient in the present invention is an amino acid. 6-ffi 9, the material is a water-soluble substance such as an antibiotic, which is medically acceptable and insoluble or sparingly soluble in organic solvents that dissolve pulmonary surfactants. 1. Pulmonary surfactants] The amount used is 2 to 30 parts by weight, preferably 5 to 20 parts by weight. Amino acids include the essential amino acids glycine and alanine. Examples of sugars include glufus, galactose, and mannitol. Examples include Nurkitol and Zatsuka Rhozu. Antibiotics and 1.
For example, cefazolin and gentamicin. Examples include erythromycin and fuitomycin. V-shaping and 1. When antibiotics are used, the medicinal efficacy of the antibiotic can be expected at the same time as the pulmonary surfactant, and depending on the purpose, 1. Powder and Naro 3゜Powdering method and 1
．． For pulmonary surfactants, organic solvents, preferably l, (are
Dissolve in +=+p form, methylene chloride, tetrahydrofuran, 21 Vr, etc. [2. Finely powdered in the solution1. One or more excipients are added in layers and dispersed uniformly. stop. and quickly evaporate to dryness at a temperature that does not deactivate the activity of the pulmonary surfactant. Preferably, use a rotary evaporator or the like at room temperature under reduced pressure. Rotate and stir to evaporate and solidify (1 liter). Necessary r tl
1. Add the ground powder to a uniform fine powder. Formulation 4). In addition to these shapes, medically acceptable inorganic salts such as potassium chloride, sodium chloride, sodium phosphate, etc. can also be mixed and added. Pulmonary surface active substances are uniformly deposited on the surface of these powdered substances.
．． The formulation is in the form of a powder and is used in 14. . When the surface activity of the powder agent is measured by the Wilhelmy balance described below, the minimum surface tension is ] Od
yne / cm J so]・, and the maximum surface tension is ′(6
~s 5 dyne/cm, also stability
The index is 1.2 months above, as shown in Figure 1. [1% limit "Hysteria/sloop is drawn and has high surface activity 4.1. Thus, the present invention", Rege,
It is possible to powderize natural or self-administered pulmonary surfactants without loss of surface activity, and the desired powder contains natural pulmonary surfactants and surface activities such as Sl. The powdered pulmonary surfactant obtained in the present invention maintains its original activity regardless of whether it is derived from natural sources or synthetically. Q) It is expected that the drug will fully exhibit its medicinal efficacy as a therapeutic drug. Hereinafter, the present invention will be explained in detail with reference to Examples. The surface activity of lung surface active substances is measured by the following method: 1. Ta. [Measurement of surface tension of synthetic lung surfactant and calculation of stability index] Wilhelmy balance manufactured by Afuma was used for measurement1.
1. Pour 50 m of physiological saline into this Teff p/aquarium,
A polydispersion liquid or powder of the test sample was gently placed thereon. If the sample is a dispersion liquid, gently overlay 1. Ta. Part 1. continuously cycling the surface area of the liquid between 4 and 13 ocJ at a rate of 0.3 cycles/min;
With an X-Y recorder, as shown in Figure 1 (Table 11ili
An f*-surface tension diagram was recorded. Starting cycling 9 - After 5th to 6th cycle, it converges to Ichiu, and from hysteria/sloop, the value of minimum surface tension (rryu) and maximum surface tension (1rnax)
) and the area surrounded by the hysteresis loop were determined. Stability index (
S, I ) was determined from the following formula. Example I L-α-dipal j)yl phosphatidylfurin 1.2v
Dissolve dosilylin o, sy in PP form and make a homogeneous solution.1. Ta. Next, the solution was filtered and evaporated to dryness in a p-tally evaporator under reduced pressure, and 4. dried under high vacuum. A white waxy solid was obtained (synthetic lung surfactant W). 1. Make a slight ridge on this α-no and measure the surface activity using Wilhelmy balance. Ta. The results are shown in Table 1.11() showed high (゛surface activity.
1-10- This was dissolved in 0.5% of proform 50-12, and pulverized glycine 52 was added to it to form a uniform powder. The dispersion was then dried by rotary evaporation at room temperature under reduced pressure in a 1-tally evaporator, and further dried under an Il!i air flow. A smooth fine powder was obtained.The surface activity of this powder was as shown in Table 1.This powder also had very good dispersibility on the ice surface, and no hysteresis loop was observed. No decrease in activity was observed after micronization with glycine.Example 2 The white waxy substance 12 obtained in Example 1 was dissolved in chloroform BOm7! Add 12, uniformly dispersed oil, etc. 12. Next, dry powder 1. was carried out in the same manner as in Example 1 to obtain a white fine powder. The surface activity of this powder was as shown in Table 1. No decrease in activity was observed upon powdering by M. F. Abrams method (J. Appl., Ph.
ysiol2r:7]8-720), natural lung surfactant was prepared by the method shown below.
, 2 Kf of pig lungs were pomogenized using a homogenizer using 5 tons of 1-1 physiological saline and filtered through gauze to obtain an extract. Next 1c + 000rprn X30
The supernatant was removed by low-speed centrifugation for 70 minutes, and the resulting human supernatant was
Centrifugation was performed for 1 hour at high speed rotation at 0 Orpm to obtain a precipitate. Saturated saline solution (specific gravity 1,2) prepared by cooling in advance
Disperse the sediment, centrifuge at 7000 rpm for 30 minutes, and remove the upper white thin layer by 1. Ta. This white thin layer was dialyzed against cold distilled water and freeze-dried to obtain a naturally purified pulmonary surfactant. Next, the natural lung surfactant obtained by mixing lypform/methanol (2: ] v/v) was dissolved in 0.5% saline solution according to the method of Folch et al. A lipid portion was obtained by contacting the mixture with each other. Take a small amount of this and make a 1% dispersion with distilled waterff+
,,Measuring surface activity with Wilhelmy balance1. 5
The results are shown in Table 1, showing good dispersibility at the interface and high surface activity. Ta. Next, dissolve 1f of this in 100 ml of paste (pρ) and pre-powder 1. 1. Disperse 5v of mannitol and prepare a uniform dispersion. Ta. Next, rotary evaporation drying was carried out under reduced pressure in a p-Tally evaporator at room temperature, and further drying was carried out under high vacuum. A pale yellow powder was obtained. This product has a high surface activity as shown in Table 1.
, powdered lung surfactant was also produced. Example 4 ■・-α-phosphatidylcholine dipalmitoyl 600
M+g, Shiriruin 300 shoulder 9. linoleic acid 100
19 was dissolved in [I:II:I form]OOme, and the pre-pulverized mannitol 52 was dispersed in the kneaded mixture to obtain a uniform dispersion.This dispersion was prepared in the same manner as in Example J. After drying the powder with It exhibited dispersibility and high surface activity.Example 5 DL-α-bosphatidylcholine dipalmitoyl 300
mg, Siri/l/Ia 200ml/lipa hol A 30 rrd', dissolved in 11, pre-pulverized in this 1
- Cefazolin sodium, 1-. 2. Distribute Bf 1-
A uniform dispersion was obtained. This dispersion was dried in the same manner as in Example 1 to obtain a powder, and further pulverized to obtain a white uniform fine powder. The surface activity of this roof tile is shown in Table 1.

【図面の簡単な説明】[Brief explanation of the drawing]

第１図は、肺表面活性物質の表面槍−表曲張力ダイアグ
ラムを示す。FIG. 1 shows a surface lance-curvature tension diagram of pulmonary surfactant.

Claims (1)

【特許請求の範囲】 ！　肺表面活性物質を有機溶剤に溶解させ、これに該有
機溶剤に不溶又は難溶で医学的に許容さねる水溶性賦形
剤の微粉末を均一に分散させ、その後得られた分散液を
蒸発乾固させることを特徴とする、肺表面活性物質を有
効成分とする粉末剤の調製法。 ２　肺表面活性物質１電鉄部に対１−１賦形剤が２〜３
０重州部でちることを特徴とする特許請求の範囲第１項
記載の肺表面活性物質を有効成分とする粉末剤の調製法
、 ３　有機溶剤に不溶又は難溶で医学的に許容さ才する水
溶性賦形剤が、必須アミノ酸であることを特徴とする特
許請求の範囲第１項記載の肺表面活性物質を有効成分と
する粉末剤の調製法。 ４　有機溶剤に不溶又は難溶で医学的にＲ１ｆ容されろ
水溶性賦形剤か、糖類であることを特徴とする特許請求
の範囲第１項記載の肺と自活性物質を有効成分とする粉
末剤の調製法。 ５　有機溶剤に不溶又は郁溶で医学的に許容される水溶
性賦形剤が、抗生物質であることを特徴とする特許請求
の範囲第１項記載の肺表面活性物質を有効成分とする粉
末剤の、ＩＡｌＮ法。[Claims]! A pulmonary surfactant is dissolved in an organic solvent, a fine powder of a medically unacceptable water-soluble excipient that is insoluble or poorly soluble in the organic solvent is uniformly dispersed therein, and the resulting dispersion is then evaporated. A method for preparing a powder containing a pulmonary surfactant as an active ingredient, which comprises drying. 2 Pulmonary surfactant 1 train part to 1-1 excipient 2-3
3. A method for preparing a powder containing a pulmonary surfactant as an active ingredient according to claim 1, characterized in that the powder is a powder that is insoluble or sparingly soluble in organic solvents and is medically acceptable. A method for preparing a powder containing a pulmonary surfactant as an active ingredient according to claim 1, wherein the water-soluble excipient is an essential amino acid. 4. The active ingredient is the lung and self-active substance described in claim 1, which is insoluble or sparingly soluble in organic solvents and is medically R1f soluble, water-soluble excipient, or saccharide. Preparation of powder. 5. A powder containing a pulmonary surfactant as an active ingredient according to claim 1, wherein the medically acceptable water-soluble excipient that is insoluble or soluble in organic solvents is an antibiotic. agent, IAlN method.