JP2789115B2 - Process for producing granular pharmaceutical sustained-release agent using soluble collagen powder as carrier - Google Patents
Process for producing granular pharmaceutical sustained-release agent using soluble collagen powder as carrierInfo
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- JP2789115B2 JP2789115B2 JP1230421A JP23042189A JP2789115B2 JP 2789115 B2 JP2789115 B2 JP 2789115B2 JP 1230421 A JP1230421 A JP 1230421A JP 23042189 A JP23042189 A JP 23042189A JP 2789115 B2 JP2789115 B2 JP 2789115B2
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- release agent
- collagen
- drug
- soluble collagen
- carrier
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Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、生体内で薬物を徐々に放出する医薬徐放剤
の製造方法に関し、特に、可溶性コラーゲン及び／又は
可溶性コラーゲン誘導体を担体とした平均粒径が0.1〜5
0μｍの粒状医薬徐放剤の製造方法に関する。Description: FIELD OF THE INVENTION The present invention relates to a method for producing a sustained-release drug for gradually releasing a drug in a living body, and particularly to a method using soluble collagen and / or a soluble collagen derivative as a carrier. Average particle size is 0.1-5
The present invention relates to a method for producing a 0 μm granular sustained release drug.
（従来の技術及び解決しようとする課題） コラーゲン又はコラーゲン誘導体は、生体内において
溶解・吸収されるために従来より生体内で薬物を徐々に
放出する医薬徐放剤の担体（運搬体）として使用される
ことは良く知られている。(Prior art and problems to be solved) Collagen or a collagen derivative is conventionally used as a carrier (carrier) of a pharmaceutical sustained-release agent that gradually releases a drug in a living body because it is dissolved and absorbed in the living body. It is well known that
これらの医薬除法剤は、薄膜状或いは三層構造もしく
は医薬品を含有させた中心部と、その外周囲にコラーゲ
ンを配した球状を呈し、又は、コラーゲンとしては、例
えば、分子末端部分のテロペプタイドを除去し、抗原性
のないアテロコラーゲンを用いたり（特開昭56−122317
号及び特開昭57−55146号公報）、或いはコラーゲンを
サクシニル化、アクセル化又はメチル化或いはエチル化
などのアルキル化を行なったコラーゲン誘導体が用いら
れている。These pharmaceutical removers exhibit a thin film or a three-layer structure or a central portion containing a drug and a spherical shape with collagen disposed around the central portion, or as collagen, for example, telopeptide at the molecular terminal portion Removed and used atelocollagen without antigenicity (Japanese Patent Application Laid-Open No. 56-122317)
And JP-A-57-55146), or collagen derivatives obtained by subjecting collagen to succinylation, acceleration, methylation, or ethylation.
しかし、この医薬徐放剤に要求される特性としては、
薬物を一定の割合で放出すると共に生体内に埋入した
際、安全性は勿論、異物感を与えるようなことがあって
はならない。殊に、眼科用医薬徐放剤の場合には、眼に
は適用した場合に異物感を与えやすく、又、適用する場
合が限られているために埋入しにくく、使用部位も限定
されるという難しさを有する。更に、症状による薬剤量
を任意に選択できないという点もある。However, the properties required for this pharmaceutical sustained release agent include:
When a drug is released at a fixed rate and implanted in a living body, it must not give a foreign body sensation, of course, not only safety. In particular, in the case of an ophthalmic pharmaceutical sustained-release agent, it is easy to give a foreign body sensation when applied to the eye, and it is difficult to embed due to the limited application, and the use site is also limited. It has the difficulty of. Further, there is also a point that the amount of the drug depending on the symptoms cannot be arbitrarily selected.
そこで、これらの要求を満足すべき医薬徐放剤につい
て種々検討した結果、微細な粉末状の可溶性コラーゲン
パウダーを担体とし、平均粒径0.1〜50μｍの粒状の医
薬徐放剤とすることが極めて有効であることを見出し、
本発明を完成するに至ったもので、本発明の目的は、微
細な可溶性コラーゲンパウダーを担体とした平均粒径0.
1〜50μｍの粒状の医薬徐放剤を提供することにある。Therefore, as a result of various investigations on a pharmaceutical sustained release agent that satisfies these requirements, it is extremely effective to use a fine powdered soluble collagen powder as a carrier and a granular pharmaceutical sustained release agent having an average particle size of 0.1 to 50 μm. Heading,
The present invention has been accomplished, and an object of the present invention is to provide a fine soluble collagen powder having an average particle diameter of 0.
An object of the present invention is to provide a granular drug sustained release agent having a particle size of 1 to 50 μm.
（課題を解決するための手段） 本発明の要旨は１種又は２種以上の薬剤を含有した可
溶性コラーゲン及び／又は可溶性コラーゲン誘導体の溶
液又は分散液を最終工程として噴霧乾燥を行い平均粒径
が0.1〜50μｍの粒状医薬徐放剤とすることを特徴とす
る粒状医薬徐放剤の製造方法である。(Means for Solving the Problems) The gist of the present invention is to spray-dry a solution or a dispersion of a soluble collagen and / or a soluble collagen derivative containing one or more drugs as a final step to perform spray drying to obtain an average particle size. A method for producing a granular drug sustained release agent, characterized in that the drug is a 0.1 to 50 μm granular drug sustained release agent.
即ち、本発明は、薬剤と可溶性コラーゲン及び／又は
可溶性コラーゲン誘導体とよりなる医薬徐放剤を微細な
粒子の状態とすることによって、使用部位も限定される
ことなく、特に眼科領域において極めて優れた効果のあ
ることを見出したのである。That is, the present invention provides a pharmaceutical sustained release agent comprising a drug and a soluble collagen and / or a soluble collagen derivative in the form of fine particles. I found it to be effective.
本発明について詳細に説明する。 The present invention will be described in detail.
本願発明において担体として使用する一般に可溶性コ
ラーゲンは、動物の真皮から得られるものである。この
真皮部分に、タンパク質分解酵素を作用させ、テロペプ
タイド部分を選択的に消化除去することによって、抗原
性の少ないアテロコラーゲンを得ることができる。Generally, soluble collagen used as a carrier in the present invention is obtained from the dermis of an animal. A proteolytic enzyme is allowed to act on the dermis portion to selectively digest and remove the telopeptide portion, whereby atelocollagen with low antigenicity can be obtained.
本発明で使用する可溶性コラーゲンには、上述のアテ
ロコラーゲン、その他、酸可溶性コラーゲン、アルカリ
抽出コラーゲンなどが挙げられ、コラーゲン誘導体には
アシル化、サクシニル化、または、メチル化、エチル化
などのアルキル化等の化学修飾を行ったものがあげられ
るが、用途にあわせて選択する。一般に抗原性のないア
テロコラーゲンが好ましく、また、眼科用医薬徐放剤の
担体としては中性で可溶性コラーゲンが好ましい。The soluble collagen used in the present invention includes the above-mentioned atelocollagen, other acid-soluble collagen, alkali-extracted collagen, and the like. The collagen derivative is acylated, succinylated, or alkylated such as methylated or ethylated. Can be mentioned, but it is selected according to the application. In general, atelocollagen having no antigenicity is preferable, and neutral and soluble collagen is preferable as a carrier of the ophthalmic pharmaceutical sustained-release agent.
また、医薬徐放剤に用いられる薬剤としては、特に、
制限はないが、例えば、５−フルオロウラシル、ペプレ
オマイシン等の制癌剤やプレドニゾロン、エストラジー
ル等のステロイド系ホルモン或は、ゲンタマイシン等が
ある。In addition, as the drug used in the pharmaceutical sustained release agent, in particular,
Although there is no limitation, examples thereof include anticancer drugs such as 5-fluorouracil and pepeomycin, steroid hormones such as prednisolone and estragil, and gentamicin.
そして、医薬徐放剤中に含有される薬剤の量として
は、通常の医薬徐放剤の場合と異ならず、徐放剤全重量
の50％以下の量である。The amount of the drug contained in the pharmaceutical sustained-release agent is not different from that of the usual pharmaceutical sustained-release agent, and is 50% or less of the total weight of the sustained-release agent.
本発明にかかる医薬徐放剤は、平均粒径が0.1〜50μ
ｍの粒状である。大きな粒状の医薬徐放剤は、使用時に
異物感を与えるので好ましくなく、また、小さすぎると
操作しにくく、また徐放効果も期待できないのである。
そのため、平均粒径が0.1〜50μｍの範囲の粒状物でな
ければならず、特に、眼科用医薬徐放剤は約５μｍ程度
の物が、使用者に異物感を与えないので好ましい。The pharmaceutical sustained-release agent according to the present invention has an average particle size of 0.1 to 50 μm.
m. A large granular drug sustained release agent is not preferred because it gives a foreign body sensation during use, and if it is too small, it is difficult to operate and no sustained release effect can be expected.
Therefore, it must be a granular material having an average particle size in the range of 0.1 to 50 μm. In particular, an ophthalmic sustained-release agent having a particle size of about 5 μm is preferable because it does not give a user a foreign-body sensation.
本発明にかかる医薬徐放剤は、微細なコラーゲン担体
と薬剤とが混合した状態で粒状を形成しているものと考
えられる。It is considered that the pharmaceutical sustained release agent according to the present invention forms a granule in a state where the fine collagen carrier and the drug are mixed.
次に本発明の医薬徐方材の製造方法について述べる。 Next, the method for producing the medicinal material according to the present invention will be described.
本発明に係る医薬徐放剤の製造方法としては、通常、
次の方法が考えられる。As a method for producing the pharmaceutical sustained release agent according to the present invention, usually,
The following methods are conceivable.
（１）コラーゲン溶液を等電点で沈澱させて得たコラー
ゲン沈澱物と薬剤とを混合後、凍結乾燥し、得られた複
合体を粉砕する。(1) After mixing a collagen precipitate obtained by precipitating a collagen solution at an isoelectric point with a drug, freeze-drying and pulverizing the resulting complex.
（２）コラーゲン溶液中に薬剤を添加、混合後凍結乾燥
し、その後粉砕する。(2) A drug is added to the collagen solution, mixed, freeze-dried, and then pulverized.
（３）（１）の方法における凍結乾燥の代りにアルコー
ル脱水行ない、しかる後、粉砕する。(3) Alcohol dehydration is performed instead of freeze-drying in the method of (1), and then pulverization is performed.
これらの方法において、粉砕工程として、機械的な粉
砕方法を採用すると、発熱のためのコラーゲンが変性す
る危険性があり、また、得られた徐放剤の形状が、いび
つであったり、或は繊維状できれいな粒状とはなりにく
い。更に、（３）の方法は、上記の外にコラーゲンと薬
剤との混合が困難であるという問題がある。In these methods, when a mechanical pulverization method is employed as a pulverization step, there is a risk that collagen for heat generation is denatured, and the shape of the obtained sustained-release agent is irregular, or It is difficult to be fine and fibrous. Further, the method (3) has a problem that it is difficult to mix collagen and a drug in addition to the above.
本発明では、噴霧乾燥手段を採用することによって、
きれいな粒状の医薬徐放剤が得られる。In the present invention, by employing a spray drying means,
A clean granular drug sustained release agent is obtained.
使用する可溶性コラーゲンの溶液は、pHなどを調整し
てコラーゲンを溶解し、その濃度を0.01〜10％、好まし
くは0.1〜２％になるように調整する。The soluble collagen solution to be used is prepared by dissolving collagen by adjusting the pH and the like, and adjusting the concentration to 0.01 to 10%, preferably 0.1 to 2%.
このコラーゲン溶液又は分散液に添加する薬剤の濃度
としては、得ようとする徐放剤の用途により、その割合
は異なる。通常、可溶性コラーゲン及び／又は可溶性コ
ラーゲン誘導体と薬剤との混合割合は、薬剤が50％以下
である。The concentration of the drug added to the collagen solution or dispersion varies depending on the intended use of the sustained release agent to be obtained. Usually, the mixing ratio of the soluble collagen and / or the soluble collagen derivative to the drug is 50% or less for the drug.
噴霧乾燥の条件としては、可溶性コラーゲンが編成又
は分解しないような低温で行うことが好ましく、通常、
出口温度が80℃以下の温度範囲で行うのがよい。The spray drying is preferably performed at a low temperature such that the soluble collagen is not knitted or decomposed.
It is preferable to carry out the reaction in a temperature range where the outlet temperature is 80 ° C. or less.
そして、噴霧乾燥の結果、得られる医薬徐放剤の粒径
は、その条件によって任意に作ることができるが、平均
粒径が0.1〜50μｍの範囲の粒状物に成るようにする。
又、酸性溶液より得られたパウダーをアンモニアガス等
により中和しても良い。The particle size of the pharmaceutical sustained-release agent obtained as a result of the spray drying can be arbitrarily determined depending on the conditions, but the average particle size is in the range of 0.1 to 50 μm.
Further, the powder obtained from the acidic solution may be neutralized with ammonia gas or the like.
更に、目的に応じて、可溶性コラーゲン、特に、アテ
ロコラーゲンをサクシニル化、アシル化等の化学修飾を
行なったコラーゲン誘導体を噴霧乾燥して同様のパウダ
ーを得ることができる。Further, depending on the purpose, a similar powder can be obtained by spray-drying soluble collagen, particularly a collagen derivative obtained by chemically modifying atelocollagen such as succinylation and acylation.
本発明にかかる担体である微細なコラーゲン担体の形
状を示すと第１図の通りであり、医薬徐放剤の場合も同
様な形状を示している。FIG. 1 shows the shape of the fine collagen carrier which is the carrier according to the present invention, and the pharmaceutical sustained release agent shows the same shape.
次に、実施例をもって、更に具体的に本発明を説明す
るが、本発明は、これによって制限されるものではな
い。Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
実施例１ 牛真皮より得られたアテロコラーゲンの１％水溶液10
0mlに脱塩したα型インターフェロン（10MU/ml）5.0ml
を加え均一に攪拌混合した。Example 1 1% aqueous solution of atelocollagen obtained from bovine dermis 10
0ml desalted α-type interferon (10MU / ml) 5.0ml
Was added and uniformly stirred and mixed.
得られたアテロコラーゲンとα型インターフェロンと
の混合溶液を、噴霧乾燥器（ヤマト科学（株）製DL41）
を使用し、出口温度約45℃の温度のもとで、噴霧乾燥す
ることにより、平均粒径５μｍの粒状のアテロコラーゲ
ンとα型インターフェロンとの複合体パウダーを得た。The obtained mixed solution of atelocollagen and α-type interferon is spray-dried (DL41 manufactured by Yamato Scientific Co., Ltd.).
Was spray-dried at an outlet temperature of about 45 ° C. to obtain a composite powder of granular atelocollagen having an average particle diameter of 5 μm and α-type interferon.
実施例２ 牛真皮より得られたアテロコラーゲン2.5gをpH3を精
製水１に溶解した後、pH9.0になるようにNaOHで調整
した。Example 2 2.5 g of atelocollagen obtained from bovine dermis was dissolved in purified water 1 at pH 3 and adjusted to pH 9.0 with NaOH.
これに無水コハク酸1gを添加し、コラーゲンをサクシ
ニル化した。To this was added 1 g of succinic anhydride to succinylate the collagen.
得られたサクシニル化コラーゲンの１％水溶液１に
500μｇのゲンタマイシンを加え、均一に撹拌混合した
後、出口温度60℃の条件のもとで、噴霧乾燥を行なうこ
とによって平均粒径2.5μｍの粒状のサクシニル化コラ
ーゲンとゲンタマイシンとの複合体パウダーを得た。In the obtained 1% aqueous solution 1 of succinylated collagen
After adding 500 μg of gentamicin and uniformly stirring and mixing, spray drying is performed under the condition of an outlet temperature of 60 ° C. to obtain a granular succinylated collagen having an average particle size of 2.5 μm and a complex powder of gentamicin. Was.
この方法と同様の方法で得られた8.0×105dpm/mlの放
射性ゲンタマイシンを含むサクシニル化コラーゲンパウ
ダー、放射性ゲンタマイシンを含むサクシニル化コラー
ゲンフィルム及び放射性ゲンタマイシン注射剤を用い
て、涙液中の放射性ゲンタマイシンの量を測定した。Using a succinylated collagen powder containing 8.0 × 10 5 dpm / ml of radioactive gentamicin obtained by the same method as this method, a succinylated collagen film containing radioactive gentamicin, and a radioactive gentamicin injection, radioactive gentamicin in tears was used. Was measured.
即ち、上記のパウダー、フイルム及び注射剤を兎の眼
の下瞼に挿入し、経時的に涙液のサンプルを取った。サ
ンプリイングの時間は5,10,20,30分及び1,2,4,6時間で
行ない、それぞれ涙液に溶出してくるゲンタマイシンの
量を測定した。ゲンタマイシンは14Cゲンタマイシンを
用いた。That is, the above-mentioned powder, film and injection were inserted into the lower eyelid of a rabbit eye, and samples of tears were taken with time. The sampling time was 5, 10, 20, 30 minutes and 1, 2, 4, 6 hours, respectively, and the amount of gentamicin eluted in tears was measured. Gentamicin used was 14 C gentamicin.
その結果を第２図に示す。第２図より徐放速度は、パ
ウダーの場合がフイルムの場合よりはやく、また、薬剤
濃度は、注射剤の場合より長時間維持することができ
る。The result is shown in FIG. As shown in FIG. 2, the sustained release rate is faster in the case of powder than in the case of film, and the drug concentration can be maintained for a longer time than in the case of injection.
実施例３ 実施例２と同様の方法によって、牛真皮より得られた
サクシニル化コラーゲンを得た。Example 3 Succinylated collagen obtained from bovine dermis was obtained in the same manner as in Example 2.
得られたサクシニル化コラーゲンの２％水溶液を噴霧
乾燥することにより平均粒径3.0μｍの粒状のサクシニ
ル化コラーゲンパウダーを得た。The obtained 2% aqueous solution of succinylated collagen was spray-dried to obtain granular succinylated collagen powder having an average particle size of 3.0 μm.
次にサクシニル化コラーゲンパウダーによる異物感の
有無を調べた。Next, the presence or absence of foreign body sensation due to the succinylated collagen powder was examined.
得られたサクシニル化コラーゲンパウダーを生理用食
塩水に0.01w/v％になるように添加した場合をＡ、生理
用食塩水の場合をＢとし、サクシニル化コラーゲンフィ
ルムをＣとして、パネラー10人にそれぞれ使用してもら
い、パウダーによる異物感の有無を調べた。A: A case where the obtained succinylated collagen powder was added to physiological saline to a concentration of 0.01 w / v%, B: a case of physiological saline, C: a succinylated collagen film, and 10 panelists Each of them was used, and the presence or absence of foreign matter sensation due to powder was examined.
サクシニル化コラーゲンフィルムの場合は、５〜20mg
の楕円型のものを下瞼に挿入した。5-20 mg for succinylated collagen film
Was inserted into the lower eyelid.
その結果を次の表に示す。 The results are shown in the following table.
この結果より、サクシニル化コラーゲンフィルムは、
異物感を感じる人が多かったが、パウダーについては、
異物感を感じる人は少なく、生理食塩水の場合と有意な
差はなかった。 From these results, the succinylated collagen film was
Many people felt a foreign body, but for powder,
There were few people who felt a foreign body sensation, and there was no significant difference from the physiological saline solution.
（発明の効果） 以上述べたように、本発明は、噴霧乾燥によって得ら
れた平均粒径が0.1〜50μｍの粒状の医薬徐放剤である
ので、使用者に異物感を与えることなく使用でき、ま
た、従来の医薬徐放剤のような適応部位を選択する必要
はなく、油に懸濁するなどして患部に直接注入すること
ができるばかりでなく、コラーゲンパウダーの量を変え
ることによって患者の病状にあった投薬量を調整するこ
とが出来る。(Effect of the Invention) As described above, the present invention is a granular pharmaceutical sustained-release agent having an average particle size of 0.1 to 50 µm obtained by spray drying, and thus can be used without giving a user a foreign-body sensation. In addition, there is no need to select an indication site as in the case of a conventional pharmaceutical sustained release agent, and it can be directly injected into the affected area by suspending in oil, etc., and also by changing the amount of collagen powder in patients. The dosage can be adjusted to suit the condition of the patient.
更に、医薬除放剤は、乾燥状態で保存でき、従って、
薬剤を安定に保つことができる。In addition, the medicinal release agent can be stored in a dry state,
Drugs can be kept stable.
特に眼科用の薬剤と混合し、平均粒径５μｍ以下にな
るように造粒したものは、先の実施例で示すように、眼
に適用した場合、殆ど異物感はない等の効果を奏する。In particular, those mixed with an ophthalmic drug and granulated so as to have an average particle size of 5 μm or less, when applied to the eyes, as described in the previous examples, have an effect such as almost no foreign-body sensation.
第１図は、本発明で使用する担体であるコラーゲンパウ
ダーの電子顕微鏡写真であり、第２図は、実施例２によ
って得られたパウダーの徐放性を示す図面である。FIG. 1 is an electron micrograph of collagen powder as a carrier used in the present invention, and FIG. 2 is a drawing showing the sustained release of the powder obtained in Example 2.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 9/14,9/16 A61K 47/30,47/42,47/46──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. 6 , DB name) A61K 9 / 14,9 / 16 A61K 47 / 30,47 / 42,47 / 46
Claims (1)
コラーゲン及び／又は可溶性コラーゲン誘導体の溶液又
は分散液を最終工程として噴霧乾燥を行い平均粒径が0.
1〜50μｍの粒状医薬徐放剤とすることを特徴とする粒
状医薬徐放剤の製造方法。A solution or a dispersion of a soluble collagen and / or a soluble collagen derivative containing one or more drugs is spray-dried as a final step to obtain an average particle size of 0.1.
A method for producing a granular drug sustained release agent, which is a granular drug sustained release agent having a particle size of 1 to 50 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1230421A JP2789115B2 (en) | 1989-09-07 | 1989-09-07 | Process for producing granular pharmaceutical sustained-release agent using soluble collagen powder as carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1230421A JP2789115B2 (en) | 1989-09-07 | 1989-09-07 | Process for producing granular pharmaceutical sustained-release agent using soluble collagen powder as carrier |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04855998A Division JP3240593B2 (en) | 1998-02-16 | 1998-02-16 | Pharmaceutical sustained-release agent using soluble collagen powder as carrier |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0393716A JPH0393716A (en) | 1991-04-18 |
| JP2789115B2 true JP2789115B2 (en) | 1998-08-20 |
Family
ID=16907626
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1230421A Expired - Fee Related JP2789115B2 (en) | 1989-09-07 | 1989-09-07 | Process for producing granular pharmaceutical sustained-release agent using soluble collagen powder as carrier |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2789115B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL122802A0 (en) * | 1995-07-03 | 1998-08-16 | Koken Kk | Gene preparations |
| US6998268B2 (en) | 1995-07-03 | 2006-02-14 | Dainippon Sumitomo Pharma Co. Ltd. | Gene preparations |
| IT1317832B1 (en) * | 2000-02-15 | 2003-07-15 | Eurores S R L | PROCEDURE FOR THE PREPARATION OF MICRONIZED COLLAGEN AND THERAPEUTIC APPLICATIONS. |
| DK1407787T3 (en) | 2001-06-20 | 2009-06-02 | Dainippon Sumitomo Pharma Co | Process for promoting nucleic acid transfer |
| JP2003206448A (en) * | 2002-01-15 | 2003-07-22 | Nitta Gelatin Inc | Method of producing gelatin |
-
1989
- 1989-09-07 JP JP1230421A patent/JP2789115B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0393716A (en) | 1991-04-18 |
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