JP2842647B2 - Drug sustained release granules and method for producing the same - Google Patents
Drug sustained release granules and method for producing the sameInfo
- Publication number
- JP2842647B2 JP2842647B2 JP1343421A JP34342189A JP2842647B2 JP 2842647 B2 JP2842647 B2 JP 2842647B2 JP 1343421 A JP1343421 A JP 1343421A JP 34342189 A JP34342189 A JP 34342189A JP 2842647 B2 JP2842647 B2 JP 2842647B2
- Authority
- JP
- Japan
- Prior art keywords
- granules
- drug
- sustained
- organic polymer
- release
- 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.)
- Expired - Fee Related
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Description
【発明の詳細な説明】 「利用分野」 本発明は、薬剤を含浸させた薬剤徐放性顆粒及びその
製造方法に関する。Description: FIELD OF THE INVENTION The present invention relates to drug sustained-release granules impregnated with a drug and a method for producing the same.
「従来技術及びその問題点」 化学療法には、効果ができるだけ長時間持続する徐放
性薬剤が望まれる。殊に、近年、肝腫瘍などの治療法と
して、経血管化学療法が注目され、この療法に有効な徐
放性薬剤が検討されている。従来、このような目的に使
用する徐放性薬剤として、ゼラチンなどの生体由来物質
のスポンジ状粒子に薬剤を含浸したものやリピオドール
（小玉（株）製ヨード化ケシ油脂肪酸エチルエステルの
商品名）などの油脂に懸濁した薬剤粒子が知られてい
る。しかしながら、これらの薬剤粒子では、粒径を一定
にできないので、患部に薬剤を集中できないこと、生体
中に拡散、吸収されやすいので、効果の持続性が充分で
ないこと及びＸ線や超音波造影性がないので、投与後の
捕捉ができないなどの欠点がある。"Prior art and its problems" For chemotherapy, a sustained-release drug having an effect that lasts as long as possible is desired. In particular, in recent years, transvascular chemotherapy has attracted attention as a treatment for liver tumors and the like, and sustained-release drugs effective for this therapy have been studied. Conventionally, sustained release drugs used for such purposes include sponge-like particles of biological substances such as gelatin impregnated with the drug and Lipiodol (trade name of ethyl iodide poppy oil fatty acid ethyl ester manufactured by Kodama Co., Ltd.) Drug particles suspended in fats and oils are known. However, with these drug particles, the particle size cannot be made constant, so that the drug cannot be concentrated on the affected area, and it is easily diffused and absorbed into the living body, so that the effect is not sufficiently maintained, and the X-ray and ultrasonic contrast properties are poor. However, there is a drawback such that capture after administration is not possible.
また、特開昭60−106459号公報には、可燃性物質のビ
ーズにリン酸カルシウムをコーティングし、得られたビ
ーズに抗生物質を充填するための小孔をあけ、その後、
焼成して可燃性物質を除去して中空ビーズを作製し、小
孔から抗生物質を充填した後に、小孔を密封することに
より、抗生物質を含むリン酸カルシウム質充填剤を製造
することが開示されている。しかしながら、この方法で
は、ビーズに小孔をあけなければならないため、直径が
２〜40mmという比較的大きいものしか製造できず、ま
た、抗生物質の充填及び小孔の密封など、極めて煩雑な
操作を必要とする。Also, JP-A-60-106459 discloses that beads of flammable substances are coated with calcium phosphate, and the obtained beads are perforated with small holes for filling with antibiotics.
It is disclosed to produce a calcium phosphate-based filler containing an antibiotic by baking to remove flammable substances to produce hollow beads, filling the pores with an antibiotic, and then sealing the pores. I have. However, in this method, since a small hole must be formed in the beads, only a relatively large one having a diameter of 2 to 40 mm can be manufactured.In addition, extremely complicated operations such as antibiotic filling and sealing of the small hole are performed. I need.
「発明の目的」 本発明は、気孔率、細孔径、比表面積などを適宜、選
択することによって徐放効果を制御でき、Ｘ線や超音波
による造影性のよい薬剤徐放性顆粒及びこのような顆粒
を容易に製造しうる方法を提供することを目的とする。"Object of the Invention" The present invention can control the sustained-release effect by appropriately selecting the porosity, pore diameter, specific surface area, etc., and provide a drug-sustained release granule having good contrast by X-rays and ultrasonic waves. It is an object of the present invention to provide a method capable of easily producing fine granules.
「発明の構成」 本発明の薬剤徐放性顆粒は、200〜1400℃の温度で焼
成されたCa/P比1.3〜1.8、気孔率0.1〜70％、比表面積
0.1〜50m2/g及び細孔径1nm〜10μｍの多孔質リン酸カル
シウム系化合物顆粒の孔内に薬剤を含有し、顆粒表面に
可溶性の有機有機高分子化合物から成るコーティング層
を有することを特徴とする。"Constitution of the Invention" The sustained-release drug granules of the present invention have a Ca / P ratio of 1.3 to 1.8 calcined at a temperature of 200 to 1400C, a porosity of 0.1 to 70%, and a specific surface area.
The present invention is characterized in that a drug is contained in the pores of a porous calcium phosphate compound granule having a particle size of 0.1 to 50 m 2 / g and a pore diameter of 1 nm to 10 μm, and the granule surface has a coating layer made of a soluble organic organic polymer compound.
また、本発明による薬剤徐放性顆粒の製造方法は、上
記のような多孔質リン酸カルシウム系化合物顆粒に薬剤
を含浸させ、その顆粒を−70℃以下の温度で凍結させ、
凍結物を10-4〜10-7Torrの減圧で脱水することによって
凍結乾燥することを特徴とする。Further, the method for producing drug sustained-release granules according to the present invention impregnates the drug into the porous calcium phosphate compound granules as described above, and freezes the granules at a temperature of −70 ° C. or less,
It is characterized by freeze-drying by dehydrating the frozen product at a reduced pressure of 10 -4 to 10 -7 Torr.
本発明において、顆粒の原料として用いるリン酸カル
シウム系化合物は、Ca/P比1.3〜1.8のリン酸カルシウム
系化合物であれば、特に制限はなく、Ca/P比が1.35〜1.
75のものが好ましく、Ca/P比が1.4〜1.7のものがより好
ましい。例えば、ハイドロキシアパタイト、フッ素アパ
タイトなどの各種アパタイト、α−及びβ−リン酸三カ
ルシウム、リン酸四カルシウムなどが挙げられる。顆粒
は、上記のようなリン酸カルシウム系化合物のうちの１
種以上を含むものであってよい。本発明に用いる多孔質
顆粒は、例えば、過酸化水素などの発泡剤を用いる方法
や加熱により消失する物質の粒子と混合して造粒し、加
熱して多孔質化する方法など、自体公知の方法により製
造することができる。In the present invention, the calcium phosphate compound used as a raw material of the granules is not particularly limited as long as the calcium phosphate compound has a Ca / P ratio of 1.3 to 1.8, and the Ca / P ratio is 1.35 to 1.
Those having a ratio of 75 are preferable, and those having a Ca / P ratio of 1.4 to 1.7 are more preferable. For example, various apatites such as hydroxyapatite and fluorapatite, α- and β-tricalcium phosphate, tetracalcium phosphate and the like can be mentioned. Granules are one of the above calcium phosphate compounds.
It may contain more than one species. The porous granules used in the present invention include, for example, a method using a foaming agent such as hydrogen peroxide and a method of mixing and granulating with particles of a substance which disappears by heating, and granulating and heating to form a porous material. It can be manufactured by a method.
本発明に用いる多孔質顆粒は200〜1400℃、好ましく
は500〜1300℃、より好ましくは700〜1200℃の温度で焼
成したものである。200℃未満であると、粒子の結合が
弱く、生理食塩水や血液中で崩れてしまい、使用に耐え
なくなる。一方、焼成温度が1400℃を超えると、ハイド
ロキシアパタイトなど、リン酸カルシウム系化合物の分
解が起こり、好ましくない。The porous granules used in the present invention are those calcined at a temperature of 200 to 1400C, preferably 500 to 1300C, more preferably 700 to 1200C. If the temperature is lower than 200 ° C., the binding of the particles is weak, and the particles are broken in physiological saline or blood, and cannot be used. On the other hand, if the firing temperature exceeds 1400 ° C., decomposition of calcium phosphate compounds such as hydroxyapatite occurs, which is not preferable.
本発明に用いる多孔質顆粒は、気孔率0.1〜70％であ
ることを必要とする。気孔率が0.1％未満では、薬剤の
含有率が少なすぎて実用的でなく、70％を超えると、強
度が弱くなり、使用に耐えなくなる。気孔率が１〜60％
の顆粒が好ましく、10〜50％の顆粒はより好ましい。The porous granules used in the present invention need to have a porosity of 0.1 to 70%. When the porosity is less than 0.1%, the content of the drug is too small to be practical, and when the porosity exceeds 70%, the strength becomes weak and the product cannot be used. Porosity 1-60%
Are preferred, and 10-50% of the granules are more preferred.
さらに、比表面積は、0.1〜50m2/gであることを必要
とする。比表面積が0.1m2/g未満であると、薬剤の付着
する表面積が小さすぎるため薬剤の含有率が少なく、実
用的でなく、50m2/gを超えると、強度が弱くなり、使用
に耐えなくなる。比表面積は好ましくは１〜40m2/g、よ
り好ましくは１〜30m2/gである。Furthermore, the specific surface area needs to be 0.1 to 50 m 2 / g. If the specific surface area is less than 0.1 m 2 / g, the surface area to which the drug adheres is too small, so the content of the drug is small and impractical.If the specific surface area exceeds 50 m 2 / g, the strength becomes weak and it can withstand use. Disappears. The specific surface area is preferably 1 to 40 m 2 / g, more preferably 1 to 30 m 2 / g.
本発明に用いる多孔質顆粒は、薬剤の保持能力の観点
から1nm〜10μｍの細孔径を有するものとするのが好ま
しく、10nm〜８μｍの細孔径を有するのがより好まし
く、50nm〜５μｍの細孔径を有するのが最も好ましい。
細孔径が1nm未満であると、薬剤が孔内に浸透すること
ができず、10μｍを超えると、薬剤が孔内に保持され難
くなるので好ましくない。The porous granules used in the present invention preferably have a pore size of 1 nm to 10 μm, more preferably 10 nm to 8 μm, and more preferably 50 nm to 5 μm, from the viewpoint of the ability to retain a drug. Is most preferred.
If the pore diameter is less than 1 nm, the drug cannot penetrate into the pores, and if it exceeds 10 μm, it becomes difficult to hold the drug in the pores, which is not preferable.
また、本発明に使用する多孔質顆粒の粒径は、１μｍ
〜10mmであるのが好ましい。本発明の薬剤徐放性顆粒を
血管塞栓術に用いる場合には、毛細血管の直径が５μｍ
以上と言われており、カテーテルの内径が1000μｍであ
るので、顆粒径は５〜1000μｍであるのが好ましい。ま
た、実際には、顆粒が腫瘍組織に近い血管に留まってい
るのが理想的であるので、５〜500μｍがより好まし
く、10〜100μｍが最も好ましい。他方、本発明の薬剤
徐放性顆粒を補填材に用いる場合には、欠損部の大きさ
によっても異なるが、１μｍ未満であると、生体内で拡
散しやすく、マクロファージ等による貧食もされやす
い。また、顆粒径が10mmをこえると、欠損部に充填した
ときに顆粒間の間隙が大きくなり、骨の再生が起こり難
くなる。したがって、補填材としては顆粒径は１μｍ〜
10mmが好ましく、５μｍ〜5mmがより好ましく、10μｍ
〜4mmが最も好ましい。粒径や粒径分布は、セラミック
スの造粒技術により適宜調節することができる。The particle size of the porous granules used in the present invention is 1 μm
Preferably it is 10 mm. When the drug sustained-release granules of the present invention are used for vascular embolization, the diameter of the capillaries is 5 μm.
Since it is said that the inner diameter of the catheter is 1000 μm, the granule diameter is preferably 5 to 1000 μm. Also, in practice, it is ideal that the granules stay in the blood vessels near the tumor tissue, so that the particle size is more preferably 5 to 500 μm, most preferably 10 to 100 μm. On the other hand, when the sustained-release drug granules of the present invention are used as a filling material, depending on the size of the defective portion, if it is less than 1 μm, they are easily diffused in a living body and are easily eroded by macrophages and the like. . On the other hand, if the granule diameter exceeds 10 mm, the gap between the granules becomes large when filling the defective part, and bone regeneration becomes difficult to occur. Therefore, as a filler, the granule diameter is 1 μm or more.
10 mm is preferable, 5 μm to 5 mm is more preferable, and 10 μm
~ 4 mm is most preferred. The particle size and the particle size distribution can be appropriately adjusted by a ceramic granulation technique.
本発明に使用する多孔質顆粒は、中空になっていても
よいが、中空顆粒の殻は顆粒径の1/10以上の厚さを有す
ることが必要である。このような多孔質中空顆粒は、公
知の方法で、焼失性物質ビーズの周囲に多孔質リン酸カ
ルシウム系化合物の層を形成させた後、焼成の過程で焼
失性物質を加熱除去することによって得ることができ
る。The porous granules used in the present invention may be hollow, but the shell of the hollow granules needs to have a thickness of 1/10 or more of the granule diameter. Such a porous hollow granule can be obtained by forming a layer of a porous calcium phosphate compound around the burnable substance beads by a known method, and then heating and removing the burnable substance in the firing process. it can.
本発明の薬剤徐放性顆粒は、上記のような多孔質リン
酸カリシウム系化合物の顆粒に薬剤を含浸させ、乾燥す
ることによって製造することができる。The sustained-release drug granules of the present invention can be produced by impregnating the above-mentioned porous potassium phosphate compound granules with a drug and drying.
薬剤の含浸は、液体薬剤の場合には、そのままあるい
は希釈剤で薬剤を希釈した希釈液に浸漬することによっ
て行われ、固体薬剤の場合には、適切な溶剤に溶解又は
懸濁した薬液に浸漬することによって行われる。希釈液
あるいは薬液に浸漬する場合には、これらの濃度は、顆
粒に含浸させたい薬剤の量に応じて適宜選定するが、一
般には、できるだけ高濃度の液とし、顆粒への薬剤の含
浸量をできるだけ多くするのが好ましい。In the case of a liquid drug, the impregnation of the drug is performed as it is or by immersing it in a diluent obtained by diluting the drug with a diluent, and in the case of a solid drug, immersing in a drug solution dissolved or suspended in an appropriate solvent. It is done by doing. When immersed in a diluting solution or a drug solution, these concentrations are appropriately selected according to the amount of the drug to be impregnated into the granules. Preferably, it is as large as possible.
本発明においては、上記のようにして薬剤を含浸した
顆粒を乾燥する。乾燥は、常法で、例えば加熱又は凍結
乾燥法により行うことができる。加熱乾燥は、含浸顆粒
を高温乾燥機内で100℃以下で行うことができる。しか
し、高温で変質する薬剤もあるので、凍結乾燥が好まし
い。凍結乾燥は、自体公知の方法で行うことができる。
例えば、薬剤を含浸した顆粒を−70℃以下で凍結させ、
凍結物を真空容器に入れて10-4〜10-7Torrの真空度に減
圧して脱水することによって凍結乾燥を行うことができ
る。In the present invention, the granules impregnated with the drug as described above are dried. Drying can be performed in a conventional manner, for example, by heating or freeze-drying. Heat drying can be performed on the impregnated granules at 100 ° C. or lower in a high-temperature dryer. However, lyophilization is preferred because some drugs are degraded at high temperatures. Freeze-drying can be performed by a method known per se.
For example, granules impregnated with a drug are frozen at -70 ° C or less,
Freeze-drying can be performed by placing the frozen product in a vacuum vessel and decompressing the vacuum at a degree of vacuum of 10 -4 to 10 -7 Torr.
本発明の薬剤徐放性顆粒においては、気孔率、比表面
積及び細孔径を適宜、選択することによって薬剤の徐放
効果を制御することができる。In the drug sustained release granules of the present invention, the drug sustained release effect can be controlled by appropriately selecting the porosity, specific surface area and pore diameter.
さらに、本発明の薬剤徐放性顆粒に可溶性有機高分子
化合物をコーティングすることによって、薬剤の徐放効
果を向上させると共に、顆粒の比重を制御することがで
きる。Furthermore, by coating the drug sustained-release granules of the present invention with a soluble organic polymer compound, the drug sustained-release effect can be improved and the specific gravity of the granules can be controlled.
薬剤徐放性顆粒を経血管療法に使用する場合に、その
比重が高いと、チューブの途中に詰まり、投与目的の患
部に到達し難い。リン酸カルシウム系化合物の粒子自体
は、水に比べて比重の高いものであるから、使用するリ
ン酸カルシウム系化合物に比べて比重の低い物質で粒子
をコーティングすることによって、薬剤徐放性顆粒の比
重を低下させることができ、これによって患部への顆粒
の到達を容易にすることができる。When drug sustained-release granules are used for transvascular therapy, if their specific gravity is high, they will be clogged in the middle of the tube, making it difficult to reach the diseased part targeted for administration. Since the particles of the calcium phosphate compound itself have a higher specific gravity than water, coating the particles with a substance having a lower specific gravity than the calcium phosphate compound used reduces the specific gravity of the drug sustained release granules. This can facilitate the access of the granules to the affected area.
コーティングされた物質は、血液や体液中で徐々に溶
けることが望ましいので、有機高分子化合物としては、
可溶性で、生体に無害のものが好ましい。使用する有機
高分子化合物としては、例えばアルブミン、デキストラ
ン、ヨード化ケシ油脂肪酸エチルエステル、ゼラチン、
カルボキシメチルキチン、グリコールキチン等が挙げら
れる。It is desirable that the coated substance gradually dissolves in blood and body fluids.
Those which are soluble and harmless to living organisms are preferred. Examples of the organic polymer compound to be used include albumin, dextran, iodized poppy oil fatty acid ethyl ester, gelatin,
Carboxymethyl chitin, glycol chitin and the like can be mentioned.
コーティングは、自体公知の方法で行うことができ
る。例えば、乾燥した顆粒と上記のような有機高分子
化合物あるいはその溶液との混合により行う方法、顆
粒への有機高分子化合物あるいはその溶液の噴霧により
行う方法、顆粒とその粒径の1/10以下の粒径の有機高
分子化合物並びに必要に応じて結合剤及び水とを混合し
た後、高速で攪拌することにより行う方法等によってコ
ーティングを行うことができる。コーティング層の厚さ
は、目的とする顆粒の比重、徐放効果の程度に応じて適
宜、決定することができる。The coating can be performed by a method known per se. For example, a method of mixing dried granules and an organic polymer compound or a solution thereof as described above, a method of spraying an organic polymer compound or a solution thereof to granules, 1/10 or less of the particle size and the particle size The coating can be carried out by a method of mixing an organic polymer compound having a particle size of, and if necessary, a binder and water, followed by stirring at a high speed. The thickness of the coating layer can be appropriately determined according to the specific gravity of the target granules and the degree of the sustained release effect.
本発明においては、含浸させる薬剤は、制ガン剤、抗
生物質など、各種のものであってよく、特に制限はな
い。また、本発明の薬剤徐放性顆粒は投与方法において
も、経血管化学療法に限定されるものではなく、局所注
射、植込錠、充填材などとして適用することもできる。
例えば、溶解度の高いリン酸カルシウム系化合物、例え
ばリン酸三カルシウム（Ca/P＝1.5）を用いて顆粒自体
が消失することが望ましい用途に適用することができ、
また、溶解度の低いリン酸カルシウム系化合物、例えば
ハイドロキシアパタイト（Ca/P＝1.67）を用いて骨の欠
損部などに適用すれば、補填材としても機能させること
ができる。In the present invention, the drug to be impregnated may be various drugs such as an anticancer drug and an antibiotic, and is not particularly limited. In addition, the drug sustained-release granules of the present invention are not limited to transvascular chemotherapy in the administration method, and can be applied as local injections, implants, fillers, and the like.
For example, it can be applied to a use in which it is desirable that the granules themselves disappear using a calcium phosphate compound having high solubility, for example, tricalcium phosphate (Ca / P = 1.5).
In addition, if a calcium phosphate-based compound having low solubility, for example, hydroxyapatite (Ca / P = 1.67) is applied to a bone defect or the like, it can function as a filler.
「発明の実施例」 次に、実施例に基づいて本発明をさらに詳しく説明す
るが、本発明はこれに限定されるものではない。"Examples of the Invention" Next, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.
実施例１ 700℃の温度で焼成したCa/P比1.67、平均粒径30μ
ｍ、気孔率50％、平均細孔径90nm、比表面積23.0m2/gの
多孔質ハイドロキシアパタイト顆粒を用いた。この顆粒
100mgをアドリアシン（協和醗酵（株）製制ガン剤、硫
酸ドキソルビシンの商品名、以下ADRと略記する）10mg
を水2mlに溶解した水溶液と混合して、この薬剤で含浸
した。得られた含浸顆粒を日酸エドワーズ真空（株）製
MODULYOを用い、−70℃の温度で凍結させ、真空度10-4
〜10-7Torrで水分を除去することにより凍結乾燥し、次
いで解砕した顆粒をヨード系造影剤コンレイ（第一製薬
（株）製イオタラム酸ナトリウム注射液の商品名）1ml
とリピオドール（小玉（株）製ヨード化ケシ油脂肪酸エ
チルエステルの商品名）1mlの混合液中に懸濁してリピ
オドール中の顆粒懸濁液（以下、HAL顆粒の懸濁液と略
記する）を製造した。Example 1 Ca / P ratio 1.67 calcined at a temperature of 700 ° C, average particle size 30μ
m, a porosity of 50%, an average pore diameter of 90 nm, and a specific surface area of 23.0 m 2 / g porous hydroxyapatite granules were used. This granule
10 mg of adriacin (trade name of doxorubicin sulfate, a cancer drug manufactured by Kyowa Hakko Co., Ltd .; hereinafter abbreviated as ADR)
Was mixed with an aqueous solution dissolved in 2 ml of water and impregnated with the drug. The obtained impregnated granules are manufactured by Nippon Acid Edwards Vacuum Co., Ltd.
Using MODULYO, freeze at a temperature of -70 ° C and vacuum degree of 10 -4
Lyophilized by removing water at で 10 −7 Torr, and then crushed granules 1 ml of iodine-based contrast agent Conley (trade name of sodium iotalamate injection solution, manufactured by Daiichi Pharmaceutical Co., Ltd.)
And Lipiodol (trade name of ethyl ester of iodized poppy oil fatty acid manufactured by Kodama Co., Ltd.) to produce a granule suspension in Lipiodol (hereinafter abbreviated as HAL granule suspension). did.
実施例２ 700℃で焼成したCa/P比1.67、平均粒径400μm/粒径範
囲300〜500μｍ）、気孔率40％、平均細孔径80nm、比表
面積25m2/gの多孔質ハイドロキシアパタイト顆粒を実施
例１と同様の方法でアドリアシンで含浸し、凍結乾燥
後、解砕してADR含浸顆粒を得た。Example 2 Porous hydroxyapatite granules having a Ca / P ratio of 1.67, average particle diameter of 400 μm / particle diameter range of 300 to 500 μm, porosity of 40%, average pore diameter of 80 nm and specific surface area of 25 m 2 / g fired at 700 ° C. It was impregnated with adriacin in the same manner as in Example 1, freeze-dried, and crushed to obtain ADR-impregnated granules.
この顆粒50gに300rpmの攪拌機内で攪拌しながら10％
デキストラン水溶液100mlをスプレーで噴霧した後、室
温で乾燥させ、厚さ20〜100μｍ（乾燥状態）の被覆層
を有するデキストラン被覆顆粒を作製した。10% while stirring 50g of these granules in a stirrer at 300rpm
After spraying 100 ml of an aqueous dextran solution with a spray, it was dried at room temperature to produce dextran-coated granules having a coating layer having a thickness of 20 to 100 μm (dry state).
実施例３ 実施例２で調製したADR含浸顆粒50gに実施例２と同じ
攪拌条件下で、70℃で溶解し、室温に冷却した５％ゼラ
チン水溶液100mlを噴霧した後、室温で乾燥させ、厚さ5
0〜200μｍ（乾燥状態）の被覆層を有するゼラチン被覆
顆粒を作製した。Example 3 To 50 g of the ADR-impregnated granules prepared in Example 2, 100 ml of a 5% gelatin aqueous solution dissolved at 70 ° C. and cooled to room temperature was sprayed under the same stirring conditions as in Example 2, and then dried at room temperature. 5
Gelatin-coated granules having a coating layer of 0 to 200 μm (dry state) were prepared.
実施例４ 実施例２で調製したADR含浸顆粒100gとカルボキシメ
チルキチン（平均粒径20μｍ）100gの混合物に攪拌機内
で蒸留水50gを噴霧し、5000rpmで高速攪拌した後、室温
で乾燥させ、厚さ100〜300μｍ（乾燥状態）の被覆層を
有するカルボキシメチルキチン被覆顆粒を作製した。Example 4 A mixture of 100 g of the ADR-impregnated granules prepared in Example 2 and 100 g of carboxymethylchitin (average particle size: 20 μm) was sprayed with 50 g of distilled water in a stirrer, stirred at 5,000 rpm at a high speed, and dried at room temperature. Carboxymethyl chitin-coated granules having a coating layer of 100 to 300 μm (dry state) were prepared.
実施例５ 1100℃で焼成したCa/P比1.5、平均粒径20μｍ（粒径
範囲10〜30μｍ）、気孔率40％、平均細孔径500nm、比
表面積4.2m2/gの多孔質リン酸三カルシウム顆粒を実施
例１と同様の方法でアドリアシンで含浸し、凍結乾燥
後、解砕してADR含浸顆粒を得た。Example 5 Porous phosphoric acid having a Ca / P ratio of 1.5, an average particle diameter of 20 μm (particle diameter range of 10 to 30 μm), a porosity of 40%, an average pore diameter of 500 nm, and a specific surface area of 4.2 m 2 / g fired at 1100 ° C. The calcium granules were impregnated with adriacin in the same manner as in Example 1, freeze-dried, and crushed to obtain ADR-impregnated granules.
この顆粒50gを２％グリコールキチン水溶液100mlと混
合し、乾燥後、解砕して、厚さ10〜100μｍ（乾燥状
態）の被覆層を有するグリコールキチン被覆顆粒を作製
した。50 g of the granules were mixed with 100 ml of a 2% aqueous solution of glycol chitin, dried and crushed to prepare glycol chitin-coated granules having a coating layer having a thickness of 10 to 100 μm (dry state).
実施例６ 平均粒子径50μｍの球状アクリルビーズを平均粒径0.
8μｍのCa/P比1.67のハイドロキシアパタイト粉末と攪
拌機内で混合し、蒸留水を噴霧しながら5000rpmで高速
攪拌してアクリルビーズを核とし、これをハイドロキシ
アパタイト粉末で被覆した顆粒を作製し、900℃で焼成
し、平均粒径90μｍ（粒径範囲60〜120μｍ）の中空顆
粒を得た。この顆粒は気孔率50％、平均細孔径200nm、
比表面積14.5m2/gであった。この中空顆粒を用いて実施
例２と同様の方法でADR含浸顆粒を作製した。Example 6 Spherical acrylic beads having an average particle size of 50 μm were prepared using an average particle size of 0.
8μm Ca / P ratio 1.67 mixed with hydroxyapatite powder in a stirrer, high-speed stirring at 5000 rpm while spraying distilled water with acrylic beads as nuclei, producing granules coated with hydroxyapatite powder, 900 C. to obtain hollow granules having an average particle size of 90 .mu.m (particle size range: 60 to 120 .mu.m). This granule has a porosity of 50%, an average pore diameter of 200 nm,
The specific surface area was 14.5 m 2 / g. Using the hollow granules, ADR-impregnated granules were produced in the same manner as in Example 2.
この顆粒50gに実施例２と同じ攪拌条件下で５％アル
ブミン水溶液100mlを噴霧した後、室温で乾燥させ、厚
さ10〜100μｍ（乾燥状態）の被覆層を有するデキスト
ラン被覆顆粒を作製した。After spraying 100 ml of a 5% aqueous solution of albumin on 50 g of the granules under the same stirring conditions as in Example 2, the granules were dried at room temperature to prepare dextran-coated granules having a coating layer having a thickness of 10 to 100 μm (dry state).
試験例１ 実施例１で製造したHAL顆粒の懸濁液を体重約200gの
雄のウィスターラットの総肝動脈から各ラットに0.1ml
ずつ注入した。次いで、経時的（注入直後、６時間後、
24時間後、48時間後）に肝臓を摘出し、肝臓内のADR量
を高速液体クロマトグラフィー（HPLC法）で測定し、第
１表及び第１図に示した結果を得た。なお、ラットは各
群５匹とした。また、ADR量は、肝臓内のADRの濃度を注
入直後の値を100％とした残存率で示す。Test Example 1 0.1 ml of the suspension of the HAL granules prepared in Example 1 was added to each rat from the common hepatic artery of a male Wistar rat weighing about 200 g.
Was injected at a time. Then, over time (immediately after injection, 6 hours later,
The liver was removed 24 hours and 48 hours later), and the ADR content in the liver was measured by high performance liquid chromatography (HPLC method), and the results shown in Table 1 and FIG. 1 were obtained. Each group consisted of 5 rats. In addition, the ADR amount is represented by a residual ratio with the value of the ADR concentration in the liver immediately after injection as 100%.
試験例２ この例は比較例である。Test Example 2 This example is a comparative example.
比較のためADR10mgとコンレイ1mlとの混合物（以下、
ADR混合物と略記する）を同様に注入した場合及びADR10
mgをリピオドール1ml及びコンレイ1ml中に懸濁したもの
（以下、ALCと略記する）を注入した場合についても、A
DR量を測定し、結果を第１表及び第１図に示す。For comparison, a mixture of 10 mg of ADR and 1 ml of Konrei (hereinafter, referred to as
ADR mixture) and ADR10
mg was suspended in 1 ml of Lipiodol and 1 ml of Conley (hereinafter abbreviated as ALC).
The DR amount was measured, and the results are shown in Table 1 and FIG.
第１表に示した結果から、HAL顆粒の懸濁液は、肝組
織内ADR残存率が最も高く、注入してから６時間後では4
9.8％という高濃度で残存し、従来の方法に比べて薬剤
の徐放効果が著しく向上していることが判る。 From the results shown in Table 1, the suspension of HAL granules has the highest ADR retention rate in the liver tissue, and 4 hours after injection, 4 hours after injection.
It remains at a concentration as high as 9.8%, indicating that the sustained release effect of the drug is significantly improved as compared with the conventional method.
試験例３ この例は、本発明によるHAL顆粒の懸濁液を使用する
ことによって肝機能障害が軽減されることを示すもので
ある。比較のため、試験例２に使用したADR混合物及びA
LCを用いた。Test Example 3 This example shows that hepatic dysfunction is reduced by using a suspension of HAL granules according to the present invention. For comparison, the ADR mixture used in Test Example 2 and A
LC was used.
ウィスターラットの総肝動脈を結紮して各薬剤を注入
した場合の血清GOT（アスパラギン酸アミノトランスフ
ェラーゼ）及びGPT（アラニンアミノトランスフェラー
ゼ）の経時変化を測定し、結果をそれぞれ第２図及び第
３図並びに第２表に示す。The time course of serum GOT (aspartate aminotransferase) and GPT (alanine aminotransferase) when each drug was injected by ligating the common hepatic artery of Wistar rats was measured, and the results were shown in FIGS. 2 and 3, respectively. It is shown in Table 2.
対照として、肝動脈を結紮しただけで、何も注入しな
かったときのGOT及びGPTを示す。As a control, GOT and GPT when only the hepatic artery was ligated but nothing was injected are shown.
第２表の結果から、本発明のHAL顆粒の懸濁液を用い
た場合には、従来のALCを用いた場合に比べて肝機能障
害は著しく軽度であることが判る。これは、顆粒の材料
として用いたハイドロキシアパタイトが、生体親和性を
有する物質であるためと、顆粒の粒径を血管の大きさと
同じか、あるいは少し大きめに調節できたためと思われ
る。 From the results shown in Table 2, it can be seen that when the suspension of the HAL granules of the present invention was used, liver dysfunction was remarkably mild as compared with the case where the conventional ALC was used. This is presumably because the hydroxyapatite used as the material of the granules is a substance having biocompatibility, and the particle size of the granules could be adjusted to be equal to or slightly larger than the size of blood vessels.
実施例７ 700℃で焼成したCa/P比1.67、粒径300〜500μｍ、気
孔率40％、平均細孔径80nm、比表面積25m2/gの多孔質ハ
イドロキシアパタイト顆粒（実施例２で用いたもの）50
gを茶色インク（中外化成（株）製レコーダーインク）5
0ml中に入れ、色素を含浸させた後、50℃の恒温乾燥器
で水分を除去し、色素含浸顆粒（これを顆粒Ａと称す
る）を作製した。Example 7 Porous hydroxyapatite granules having a Ca / P ratio of 1.67, a particle diameter of 300 to 500 μm, a porosity of 40%, an average pore diameter of 80 nm, and a specific surface area of 25 m 2 / g fired at 700 ° C. (the one used in Example 2) ) 50
g to brown ink (Recorder ink manufactured by Chugai Kasei Co., Ltd.) 5
After being placed in 0 ml and impregnated with the pigment, water was removed with a thermostatic oven at 50 ° C. to produce pigment-impregnated granules (referred to as granules A).
この顆粒を実施例２と同様にしてデキストランでコー
ティングし、デキストラン被覆顆粒（これを顆粒Ｂと称
する）を作製した。The granules were coated with dextran in the same manner as in Example 2 to prepare dextran-coated granules (referred to as granules B).
実施例８ 実施例７と同様にして作製した色素含浸顆粒50gを用
いて実施例３と同様の方法でゼラチン被覆顆粒（これを
顆粒Ｃと称する）を作製した。Example 8 Gelatin-coated granules (referred to as granules C) were produced in the same manner as in Example 3 using 50 g of the dye-impregnated granules produced in the same manner as in Example 7.
実施例９ 実施例７と同様にして作製した色素含浸顆粒100gを用
いて実施例４と同様の方法でカルボキシメチルキチン被
覆顆粒（これを顆粒Ｄと称する）を作製した。Example 9 Carboxymethyl chitin-coated granules (referred to as granules D) were produced in the same manner as in Example 4 using 100 g of the dye-impregnated granules produced in the same manner as in Example 7.
実施例10 実施例５で用いたのと同じリン酸三カルシウム顆粒を
用いて実施例７と同様の方法で色素含浸顆粒を得た。こ
の顆粒50gに実施例５と同様の方法でグリコールキチン
をコーティングし、グリコールキチン被覆顆粒（これを
顆粒Ｅと称する）を作製した。Example 10 Pigment-impregnated granules were obtained in the same manner as in Example 7, using the same tricalcium phosphate granules as used in Example 5. 50 g of the granules were coated with glycol chitin in the same manner as in Example 5 to prepare glycol chitin-coated granules (referred to as granules E).
実施例11 実施例６で調製したハイドロキシアパタイト中空顆粒
を用いて実施例７と同様の方法で色素含浸顆粒を得た。
この顆粒に実施例６と同様の方法でアルブミンをコーテ
ィングし、アルブミン被覆顆粒（これを顆粒Ｆと称す
る）を作製した。Example 11 Using the hydroxyapatite hollow granules prepared in Example 6, pigment-impregnated granules were obtained in the same manner as in Example 7.
The granules were coated with albumin in the same manner as in Example 6 to prepare albumin-coated granules (referred to as granules F).
試験例４ 実施例７〜11で作製した顆粒Ａ〜Ｆの各1gをそれぞれ
透析チューブ（VISKASE SALES社製、シームレスセルロ
ースチュービング8/32）に入れ、このチューブの両端を
糸を縛って閉じた後、蒸留水200mlの入ったビーカーに
入れ、スターラーで攪拌した。蒸留水中に溶出したイン
クの量を１時間後、３時間後、６時間後、12時間後及び
24時間後に測定した。Test Example 4 1 g of each of granules A to F prepared in Examples 7 to 11 was put into a dialysis tube (Seamless Cellulose Tubing 8/32, manufactured by VISKASE SALES), and both ends of the tube were tied with a thread and closed. Was placed in a beaker containing 200 ml of distilled water and stirred with a stirrer. After 1 hour, 3 hours, 6 hours, 12 hours and
Measured 24 hours later.
顆粒から溶出したインクの量は、各時間経過後に顆粒
の入ったチューブを取り出し、ビーカー中の水分を蒸発
させた後、10mlの蒸留水を加えて再びインクを水に溶解
させ、この液中のインクの濃度を分光光度計（島津製作
所UV−100−01）により620nmの波長の光の透過率として
測定した。なお、蒸留水の光の透過率を100％とした。The amount of ink eluted from the granules is determined by removing the tube containing the granules after each time has elapsed, evaporating the water in the beaker, adding 10 ml of distilled water to dissolve the ink again in water, The density of the ink was measured as a transmittance of light having a wavelength of 620 nm using a spectrophotometer (Shimadzu Corporation UV-100-01). The light transmittance of distilled water was set to 100%.
また、比較のため、顆粒1g当たりに含浸したと推定さ
れる色素1mlを顆粒と同様に透析チューブに入れ、200ml
の蒸留水の入ったビーカーに入れ、スターラーで攪拌
し、前記と同様の方法で水中に溶出したインクの量を測
定し、これを対照とした。For comparison, 1 ml of the dye presumed to be impregnated per 1 g of granules was placed in a dialysis tube in the same manner as the granules, and 200 ml
Was placed in a beaker containing distilled water, stirred with a stirrer, and the amount of ink eluted in water was measured in the same manner as described above, and this was used as a control.
測定結果を第４図に示す。 FIG. 4 shows the measurement results.
この結果から、含浸した多孔質リン酸カルシウム顆粒
は、色素をゆっくりと水中に放出し、水中の色素濃度が
徐々に高くなり、光の透過率が徐々に低下することが判
る。すなわち、本発明の薬剤含浸多孔質リン酸カルシウ
ム顆粒は、薬剤の徐放効果を有する。さらに、有機高分
子化合物でコーティングした顆粒は、コーティングする
物質や顆粒の構造にも左右されるが、よりゆるやかな薬
剤の徐放効果を有することが判る。The results show that the impregnated porous calcium phosphate granules slowly release the pigment into water, the pigment concentration in water gradually increases, and the light transmittance gradually decreases. That is, the drug-impregnated porous calcium phosphate granules of the present invention have a sustained drug release effect. Further, it can be seen that the granules coated with the organic polymer compound have a gentler sustained release effect of the drug, although it depends on the substance to be coated and the structure of the granules.
上記の実施例及び試験例においては、リン酸カルシウ
ム系化合物としてハイドロキシアパタイト及びリン酸三
カルシウムを用いたが、他のリン酸カルシウム系化合物
を用いても同様の効果が達成されることは明らかであ
る。In the above Examples and Test Examples, hydroxyapatite and tricalcium phosphate were used as calcium phosphate compounds, but it is clear that similar effects can be achieved by using other calcium phosphate compounds.
「発明の効果」 本発明の薬剤徐放性顆粒は、本発明方法によれば容易
に製造することができ、多孔質顆粒の孔内に薬剤を含浸
して含むので、薬剤徐放性に優れている。粒径、粒径分
布、気孔率、比表面積、細孔径などを必要に応じて制御
することができるので、徐放効果を制御することができ
る。また、リン酸カルシウム系化合物の顆粒を用いてい
るので、生体に対して無害であり、Ｘ線や超音波による
造影性に優れており、投与後の捕捉が容易であるという
利点がある。さらに、有機高分子化合物でコーティング
することにより、徐放効果を向上させると共に、比重を
調節することができ、経血管塞栓療法に対しても好適に
適用することができる。[Effects of the Invention] The drug sustained-release granules of the present invention can be easily produced according to the method of the present invention, and contain a drug impregnated in the pores of the porous granules. ing. Since the particle size, the particle size distribution, the porosity, the specific surface area, the pore size and the like can be controlled as required, the sustained release effect can be controlled. In addition, since granules of a calcium phosphate compound are used, they are harmless to living organisms, have excellent contrast by X-rays and ultrasonic waves, and have the advantage of being easy to capture after administration. Furthermore, by coating with an organic polymer compound, the sustained release effect can be improved and the specific gravity can be adjusted, so that it can be suitably applied to transvascular embolization therapy.
また、本発明の薬剤徐放性顆粒は、経血管塞栓療法ば
かりでなく、様々な薬剤を含浸させて、各種の投与方式
で投与することができ、溶解性の高いリン酸カルシウム
系化合物を用いれば、顆粒自体が消失することが望まし
い用途に好適であり、溶解性の低いリン酸カルシウム系
化合物を用いて骨の欠損部などに適用すれば、充填材と
しても機能させることができる。Further, the drug sustained-release granules of the present invention can be administered not only by transvascular embolization therapy but also by various administration methods impregnated with various drugs, and by using a highly soluble calcium phosphate compound, It is suitable for applications in which it is desirable that the granules themselves disappear, and if a calcium phosphate compound having low solubility is applied to a bone defect or the like, it can function as a filler.
第１図は肝組織内ADR残存率の経時変化を示すグラフ、
第２図は血清GOT濃度の経時変化を示すグラフ、第３図
は血清GPT濃度の経時変化を示すグラフ、第４図は透析
チューブから溶出した色素の水溶液の光透過率の経時変
化を示すグラフである。 符号の説明 ○……HAL顆粒、●……ALC、▲……ADR混合物、■……
対照FIG. 1 is a graph showing the change over time in the ADR residual rate in liver tissue,
FIG. 2 is a graph showing the change over time in serum GOT concentration, FIG. 3 is a graph showing the change over time in serum GPT concentration, and FIG. 4 is a graph showing the change over time in the light transmittance of the aqueous solution of the dye eluted from the dialysis tube. It is. Explanation of symbols ○ …… HAL granules, ● …… ALC, ▲ …… ADR mixture, △ ……
Contrast
───────────────────────────────────────────────────── フロントページの続き (72)発明者 市塚 健司 東京都板橋区前野町２丁目36番９号 旭 光学工業株式会社内 (56)参考文献 特開 昭61−47401（ＪＰ，Ａ) 特開 昭59−101145（ＪＰ，Ａ) 特開 昭57−4915（ＪＰ，Ａ) 特開 昭54−163807（ＪＰ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 9/16,9/18,9/50 A61K 9/52,47/00 - 47/02 A61K 47/30 - 47/42 A61L 27/00──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Kenji Ichizuka 2-36-9 Maeno-cho, Itabashi-ku, Tokyo Asahi Optical Co., Ltd. (56) References JP-A-61-47401 (JP, A) JP-A-59-101145 (JP, A) JP-A-57-4915 (JP, A) JP-A-54-163807 (JP, A) (58) Fields investigated (Int. Cl. 6 , DB name) A61K 9 / 16,9 / 18,9 / 50 A61K 9 / 52,47 / 00-47/02 A61K 47/30-47/42 A61L 27/00
Claims (12)
〜1.8、気孔率0.1〜70％、比表面積0.1〜50m2/g及び細
孔径1nm〜10μｍの多孔質リン酸カルシウム系化合物顆
粒の孔内に薬剤を含有し、顆粒表面に可溶性の有機高分
子化合物から成るコーティング層を有することを特徴と
する薬剤徐放性顆粒。1. A Ca / P ratio of 1.3 calcined at a temperature of 200-1400 ° C.
~ 1.8, porosity 0.1 ~ 70%, specific surface area 0.1 ~ 50m 2 / g and pore diameter 1nm ~ 10μm from the organic polymer compound containing a drug in the pores of the granules and soluble in the surface of the granules Sustained-release granules having a coating layer comprising:
薬剤徐放性顆粒。2. The sustained-release drug granule according to claim 1, wherein the particle size is 1 μm to 10 mm.
る請求項１記載の薬剤徐放性顆粒。3. The sustained-release drug granule according to claim 1, wherein the granule is hollow and contains a drug in the space.
ラン、ヨード化ケシ油脂肪酸エチルエステル、ゼラチ
ン、カルボキシメチルキチン又はグリコールキチンであ
る請求項１記載の薬剤徐放性顆粒。4. The sustained-release drug granule according to claim 1, wherein the organic polymer compound is albumin, dextran, ethyl ester of iodized poppy oil fatty acid, gelatin, carboxymethyl chitin or glycol chitin.
〜1.8、気孔率0.1〜70％、比表面積0.1〜50m2/g及び細
孔径1nm〜10μｍの多孔質リン酸カルシウム系化合物顆
粒に薬剤を含浸させ、その顆粒を−70℃以下の温度で凍
結させ、凍結物を10-4〜10-7Torrの減圧で脱水すること
によって凍結乾燥することを特徴とする薬剤徐放性顆粒
の製造方法。5. A Ca / P ratio of 1.3 calcined at a temperature of 200-1400 ° C.
1.8, porosity from 0.1 to 70%, is impregnated with a drug specific surface area 0.1 to 50 m 2 / g and pore diameter 1nm~10μm porous calcium phosphate-based compound granules, frozen the granules at -70 ° C. below the temperature, A method for producing sustained-release drug granules, comprising freeze-drying a dehydrated product by dehydration at a reduced pressure of 10 -4 to 10 -7 Torr.
ウム系化合物粒子で被覆し、被覆されたビーズを加熱し
て焼失性物質を除去することにより中空構造を有する顆
粒を製造し、該顆粒に薬剤を含浸させる請求項５記載の
薬剤徐放性顆粒の製造方法。6. A granule having a hollow structure is produced by coating beads of a burnable substance with porous potassium phosphate compound particles and heating the coated beads to remove the burnable substance. 6. The method for producing drug sustained-release granules according to claim 5, wherein the drug is impregnated with the drug.
５記載の薬剤徐放性顆粒の製造方法。7. The method for producing sustained-release drug granules according to claim 5, wherein granules having a particle size of 1 μm to 10 mm are produced.
でコーティングする請求項５記載の薬剤徐放性顆粒の製
造方法。8. The method for producing sustained-release drug granules according to claim 5, wherein the dried granules are coated with a soluble organic polymer compound.
物又はその水溶液との混合によって行う請求項８記載の
薬剤徐放性顆粒の製造方法。9. The method according to claim 8, wherein the coating is performed by mixing with a soluble organic polymer compound or an aqueous solution thereof.
合物又はその水溶液の噴霧によって行う請求項８記載の
薬剤徐放性顆粒の製造方法。10. The method according to claim 8, wherein the coating is performed by spraying a soluble organic polymer compound or an aqueous solution thereof.
粒径の1/10以下の粒径の有機高分子化合物並びに必要に
応じて結合剤及び水とを混合した後、高速で攪拌するこ
とによって行う請求項８記載の薬剤徐放性顆粒の製造方
法。11. The coating is mixed by mixing the dried granules with an organic polymer compound having a particle size of 1/10 or less of the particle size and, if necessary, a binder and water, followed by stirring at a high speed. The method for producing sustained-release drug granules according to claim 8, which is performed.
キストラン、ヨード化ケシ油脂肪酸エチルエステル、ゼ
ラチン、カルボキシメチルキチン又はグリコールキチン
を使用する請求項８記載の薬剤徐放性顆粒の製造方法。12. The method for producing sustained-release drug granules according to claim 8, wherein albumin, dextran, ethyl ester of iodized poppy oil fatty acid, gelatin, carboxymethyl chitin or glycol chitin is used as the organic polymer compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1343421A JP2842647B2 (en) | 1988-12-29 | 1989-12-28 | Drug sustained release granules and method for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-335355 | 1988-12-29 | ||
| JP33535588 | 1988-12-29 | ||
| JP1343421A JP2842647B2 (en) | 1988-12-29 | 1989-12-28 | Drug sustained release granules and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03218310A JPH03218310A (en) | 1991-09-25 |
| JP2842647B2 true JP2842647B2 (en) | 1999-01-06 |
Family
ID=26575148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1343421A Expired - Fee Related JP2842647B2 (en) | 1988-12-29 | 1989-12-28 | Drug sustained release granules and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2842647B2 (en) |
Cited By (1)
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|---|---|---|---|---|
| JP2015154809A (en) * | 2014-02-20 | 2015-08-27 | 学校法人東京理科大学 | Artificial bone and production method thereof |
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|---|---|---|---|---|
| GB0020610D0 (en) * | 2000-08-21 | 2000-10-11 | Dytech Corp Ltd | Uses of porous carriers |
| JP3915001B2 (en) * | 2003-06-18 | 2007-05-16 | 独立行政法人科学技術振興機構 | Sustained release microparticle preparation of human growth hormone and method for producing the same |
| AU2004249032A1 (en) * | 2003-06-18 | 2004-12-29 | Ltt Bio-Pharma Co.,Ltd. | Drug-containing sustained release microparticle, process for producing the same and preparation containing the microparticle |
| JP2007001865A (en) * | 2003-09-16 | 2007-01-11 | Ltt Bio-Pharma Co Ltd | Fine particle enclosing fat-soluble medicine, method for producing the same and preparation containing the same |
| CA2557397A1 (en) * | 2004-02-26 | 2005-09-09 | Japan Science And Technology Agency | Protein drug sustained-release microparticle preparation for injection and process for producing the same |
| GB2436067A (en) * | 2006-03-17 | 2007-09-19 | Apatech Ltd | A flowable biomedical filler resisiting flow at higher shear stress or compressive force |
| WO2008007796A1 (en) * | 2006-07-10 | 2008-01-17 | National Institute For Materials Science | Controlled-release drug preparation and method for producing the same |
| NZ596876A (en) * | 2009-05-06 | 2014-01-31 | Lab Skin Care Inc | Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same |
| JP2013510862A (en) | 2009-11-10 | 2013-03-28 | ラボラトリー スキン ケア インコーポレイテッド | Sunscreen composition comprising uniform, hard, spherical nanoporous calcium phosphate particles, and methods for making and using the same |
| WO2020065753A1 (en) * | 2018-09-26 | 2020-04-02 | オリンパス株式会社 | Drug administration body, drug administration system, and drug administration method |
-
1989
- 1989-12-28 JP JP1343421A patent/JP2842647B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015154809A (en) * | 2014-02-20 | 2015-08-27 | 学校法人東京理科大学 | Artificial bone and production method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03218310A (en) | 1991-09-25 |
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