JPS61191609A - Slow-releasing medicinal preparation - Google Patents
Slow-releasing medicinal preparationInfo
- Publication number
- JPS61191609A JPS61191609A JP3233085A JP3233085A JPS61191609A JP S61191609 A JPS61191609 A JP S61191609A JP 3233085 A JP3233085 A JP 3233085A JP 3233085 A JP3233085 A JP 3233085A JP S61191609 A JPS61191609 A JP S61191609A
- Authority
- JP
- Japan
- Prior art keywords
- pva
- phase
- active substance
- concentration
- pharmacologically active
- 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.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は薬理活性物質を高含水高強度のポリビニルアル
コール多孔質ゲル中に含む徐放性製剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a sustained-release preparation containing a pharmacologically active substance in a highly water-containing, high-strength polyvinyl alcohol porous gel.
［従来の技術］
近年、製薬分野において新しい薬剤投与系（ドラッグデ
リバリ−システム）に対する関心が非常に高まっている
。これは、既存の医薬の薬効を最大限に高めると同時に
、副作用を最小限に抑制することを目的とするものであ
る。そのために採用されている手段の一つとして、高分
子材料を用いた医薬の徐放化があり、種々の高分子材料
が用いられている。ハイドロゲル材料もその一つである
。[Prior Art] In recent years, there has been a great deal of interest in new drug delivery systems in the pharmaceutical field. The purpose of this is to maximize the efficacy of existing drugs while minimizing side effects. As one of the means adopted for this purpose, there is sustained release of medicines using polymeric materials, and various polymeric materials are used. Hydrogel materials are one such material.
ハイドロゲルとは、水に溶けずに水を包含しているゲル
のことである。そうしたハイドロゲルは古くから知られ
ているが、近年、機能性材料に対する関心が高まるとと
もにその性質が注目ざ゛れるようになってきている。た
とえば、ソフトコンタクトレンズや医薬の徐放性担体の
ような医用材料として、または酵素や菌体の固定化担体
、保冷用熱媒体、芳香剤の徐放性担体などとして用いら
れている。Hydrogel is a gel that does not dissolve in water but contains water. Such hydrogels have been known for a long time, but in recent years, as interest in functional materials has increased, their properties have been receiving more and more attention. For example, they are used as medical materials such as soft contact lenses and sustained-release carriers for medicines, as immobilized carriers for enzymes and microbial cells, as heat carriers for cold storage, and as sustained-release carriers for fragrances.
ハイドロゲル用の高分子材料としては、ゼラチン、カラ
ギーナン、アルギン酸、ポリメタクリル酸２−ヒドロキ
シエチル、架橋カルボキシル化メチルデンプン、アクリ
ロニトリル、グラフト化デンプン加水分解物、ポリアク
リロニトリル誘導体、ポリアクリル酸塩、酢酸ビニル−
アクリル酸メチル共重合体ケン化物、ポリオキシエチレ
ン、ポリビニルピロリドン、ポリスチレンスルホン酸、
ポリビニルアルコールなどが知られている。Polymeric materials for hydrogels include gelatin, carrageenan, alginic acid, poly 2-hydroxyethyl methacrylate, cross-linked carboxylated methyl starch, acrylonitrile, grafted starch hydrolyzate, polyacrylonitrile derivatives, polyacrylates, and vinyl acetate. −
Saponified methyl acrylate copolymer, polyoxyethylene, polyvinylpyrrolidone, polystyrene sulfonic acid,
Polyvinyl alcohol and the like are known.
ポリビニルアルコール（以下、ＰＶＡと略す）の濃厚水
溶液を室温以下で放置すると粘度が次第に増大し、つい
にはゲル化することはよく知られている。しかし、その
結果えられるゲルは粘着性を示すものであり、機械的強
度に劣るものである。It is well known that when a concentrated aqueous solution of polyvinyl alcohol (hereinafter abbreviated as PVA) is left at room temperature or below, its viscosity gradually increases and eventually gels. However, the resulting gel is sticky and has poor mechanical strength.
そこでＰＶＡハイドロゲルの機械的強度を向上させるた
め、ホルムアルデヒドやグルタルアルデヒドなどの架橋
剤を用いて化学的にＰＶＡを架橋させる方法や、ホウ酸
、コンゴーレッド、グリセリンなどの増粘剤を添加して
ＰＶＡ水溶液をゲル化させる方法、γ線、電子線、紫外
線などを照射してＰＶＡを架橋する方法、チタン、銅、
コバルトなどの金属化合物を添加して配位結合化する方
法などが提案されている。しかしながら、これらの方法
でえられたＰＶＡハイドロゲルは高含水性と高強度との
バランスがよくない。Therefore, in order to improve the mechanical strength of PVA hydrogel, methods of chemically cross-linking PVA using cross-linking agents such as formaldehyde and glutaraldehyde, and adding thickeners such as boric acid, Congo red, and glycerin have been proposed. A method of gelling a PVA aqueous solution, a method of crosslinking PVA by irradiating with γ rays, electron beams, ultraviolet rays, etc., titanium, copper,
A method of adding a metal compound such as cobalt to form a coordinate bond has been proposed. However, PVA hydrogels obtained by these methods do not have a good balance between high water content and high strength.
すなわち、機械的強度を高めようとすると含水率が低下
し、また含水率を高めようとすると機械的強度を犠牲に
せざるをえない。That is, if an attempt is made to increase the mechanical strength, the moisture content decreases, and if an attempt is made to increase the moisture content, the mechanical strength must be sacrificed.
添加剤を用いずに高含水率を保持したままＰＶＡハイド
ロゲルの機械的強度を高める試みとして、ＰＶＡ濃厚水
溶液を低温にて短時間で凍結し、ついで室温にて短時間
で解凍する方法が提案されている（特開昭５０−５２２
９６号公報）。しかし、この方法でえられるＰＶＡハイ
ドロゲルの機械的強度は満足のいくものではなく、しか
も水中に浸漬すると大きく膨潤してしまうという欠点を
有している。In an attempt to increase the mechanical strength of PVA hydrogel while maintaining a high water content without using additives, a method was proposed in which a concentrated aqueous PVA solution was frozen at low temperature for a short time and then thawed at room temperature for a short time. (Japanese Unexamined Patent Publication No. 50-522
Publication No. 96). However, the mechanical strength of the PVA hydrogel obtained by this method is not satisfactory, and furthermore, it has the disadvantage that it swells significantly when immersed in water.
また、凍結後凍結体を融解させることなく真空乾燥させ
る方法も提案されている（特開昭５７−１３０５４３号
公報）。この方法は、ケン化度９５モル％以上、粘度平
均重合度ｉ、ｓｏｏ以上のＰＶＡの水溶液を注型したの
ち一６℃よりも低い温度で凍結成形し、この凍結成形体
を融解させることなく真空乾燥をするものである。かか
る方法によるときは、真空乾燥という処理が必要である
。Furthermore, a method has also been proposed in which the frozen product is vacuum-dried after freezing without being thawed (Japanese Patent Application Laid-open No. 130543/1983). This method involves casting an aqueous solution of PVA with a saponification degree of 95 mol% or more and a viscosity average polymerization degree of i, soo or more, and then freeze-molding it at a temperature lower than -6°C, without melting the frozen molded product. It is used for vacuum drying. When using such a method, a process called vacuum drying is required.
本発明者らは、従来のＰＶＡハイドロゲルの欠点を解消
するべく鋭意研究を重ねた結果、ＰＶＡ水溶液を氷点以
下の温度にて凍結させて氷層と高分子相に分離したのち
０〜１０℃の低温にて高分子相を結晶化させると、高含
水率でかつ高強度性の多孔質ＰＶＡハイドロゲルがえら
れ、ざらにＰＶＡ水溶液に薬理活性物質を加えておくと
すぐれた徐放性製剤となることを見出し、本発明を完成
するに至った。As a result of extensive research in order to resolve the drawbacks of conventional PVA hydrogels, the present inventors have found that after freezing a PVA aqueous solution at a temperature below the freezing point and separating it into an ice layer and a polymer phase, 0 to 10 °C When the polymer phase is crystallized at low temperatures, a porous PVA hydrogel with high water content and high strength is obtained, and when a pharmacologically active substance is added to an aqueous PVA solution, it can be used as an excellent sustained-release preparation. The present invention has been completed based on the discovery that the following is true.
［発明が解決しようとする問題点］
本発明は、高含水率でかつ高強度の多孔質ＰＶＡハイド
ロゲルと薬理活性物質との複合体からなる徐放性製剤を
提供することを目的とする。[Problems to be Solved by the Invention] An object of the present invention is to provide a sustained-release preparation comprising a complex of a porous PVA hydrogel with high water content and high strength and a pharmacologically active substance.
［問題点を解決するための手段］
本発明は、薬理活性物質を含むＰＶＡ水溶液を氷点以下
の温度にて凍結させて氷相と高分子相に分離したのち、
単に０〜１０℃の低温にて高分子相を結晶化させてえら
れる、薬理活性物質をＰＶＡの多孔質ハイドロゲル中に
含む徐放性製剤に関する。[Means for Solving the Problems] The present invention involves freezing a PVA aqueous solution containing a pharmacologically active substance at a temperature below the freezing point and separating it into an ice phase and a polymer phase.
The present invention relates to a sustained release preparation containing a pharmacologically active substance in a porous hydrogel of PVA, which is obtained by simply crystallizing a polymer phase at a low temperature of 0 to 10°C.
［作 用］
本発明の徐放性製剤における多孔質のＰＶＡハイドロゲ
ルは含水性および機械的強度のいずれにもすぐれたもの
である。かかるすぐれた多孔質ゲルがえられる理由は、
まず薬理活性物質を含むＰＶＡ水溶液が氷点以下で凍結
することにより、ＰＶＡの高分子相と氷相とに分離して
相分離構造体が形成され、その結果ＰＶＡ分子鎖の局所
濃度が高まると共にＰＶＡ分子鎖間で二次結合が生じて
結晶核が形成されるためと考えられる。[Function] The porous PVA hydrogel in the sustained release preparation of the present invention is excellent in both water absorption and mechanical strength. The reason why such an excellent porous gel can be obtained is as follows.
First, when a PVA aqueous solution containing a pharmacologically active substance is frozen below the freezing point, it separates into a PVA polymer phase and an ice phase, forming a phase-separated structure.As a result, the local concentration of PVA molecular chains increases and PVA This is thought to be because secondary bonds occur between molecular chains and crystal nuclei are formed.
ついでこの凍結体を０〜１０℃にて１０時間以上放置す
ると、氷相の解凍と同時にＰＶＡの結晶化が進み、その
際形成される微結晶が架橋点となってＰＶＡの強固な三
次元綱目構造（多孔質構造）が形成され、それらの間隙
に薬理活性物質を含む水相が充填しているものと考えら
れる。Then, when this frozen body is left at 0 to 10°C for 10 hours or more, PVA crystallization progresses at the same time as the ice phase thaws, and the microcrystals formed at this time become crosslinking points and form a strong three-dimensional network of PVA. It is thought that a structure (porous structure) is formed, and the gaps between them are filled with an aqueous phase containing a pharmacologically active substance.
［実施例］
本発明の徐放性製剤は、前記のごとく強固な三次元網目
構造を有する多孔質のＰＶＡに薬理活性物質および水が
包含されたものである。[Example] The sustained release preparation of the present invention is one in which a pharmacologically active substance and water are contained in porous PVA having a strong three-dimensional network structure as described above.
本発明に用いるＰＶＡは、ケン化度９５モル％以上、好
ましくは９７モル％以上、とくに９９モル％以上のもの
が好ましい。これより低いケン化度、たとえば８５モル
％以下では、軟弱なゲルかえられるにすぎない。平均重
合度は粘度平均でｉ 、 ｏｏｏ以上、とくに１ 、７
００以上のものが好ましい。ＰＶＡの重合度が低下する
と共に、えられるゲルの強度も低下するため、通常市販
されている重合度１，７００〜２，０００程度の高重合
度品を用いるのがよい。The PVA used in the present invention preferably has a saponification degree of 95 mol% or more, preferably 97 mol% or more, particularly 99 mol% or more. If the degree of saponification is lower than this, for example 85 mol% or less, only a weak gel will be formed. The average degree of polymerization is viscosity average of i, ooo or more, especially 1, 7
00 or more is preferable. As the degree of polymerization of PVA decreases, the strength of the resulting gel also decreases, so it is best to use a commercially available product with a high degree of polymerization of about 1,700 to 2,000.
本発明においては、まず薬理活性物質を含むＰＶＡの濃
厚水溶液が調製されるのであるが、濃度としては１０〜
３０重量％の範囲にするのがよい。In the present invention, a concentrated aqueous solution of PVA containing a pharmacologically active substance is first prepared;
The content is preferably in the range of 30% by weight.
このような濃厚水溶液の調製は、ＰＶＡを加熱溶解させ
ることにより行なわれる。Such a concentrated aqueous solution is prepared by heating and dissolving PVA.
ＰＶＡ水溶液は室温まで冷却したのち、直ちに氷点以下
で凍結させる。凍結温度はＰＶＡ水溶液が充分に凍結し
さえすればよく、−５℃以下が好ましいが、充分に凍結
するのに要する時間の点から、とくに−２０℃で行なう
のが好ましい。After the PVA aqueous solution is cooled to room temperature, it is immediately frozen below the freezing point. The freezing temperature should be as long as the PVA aqueous solution is sufficiently frozen, and is preferably -5°C or lower, but from the viewpoint of the time required for sufficient freezing, it is particularly preferable to carry out the freezing at -20°C.
また凍結時間は５時間以上、通常は１０〜２４時間であ
る。この凍結操作により水が氷結し、ＰＶＡの高分子相
が分離して相分離構造体かえられる。Further, the freezing time is 5 hours or more, usually 10 to 24 hours. This freezing operation freezes water, separates the PVA polymer phase, and changes the phase-separated structure.
その際、薬理活性物質は高分子相、氷相または高分子相
の表面に存在していると考えられる。In this case, the pharmacologically active substance is considered to be present on the surface of the polymer phase, ice phase, or polymer phase.
ついで凍結相分離構造体を０〜１０℃に放置し、ＰＶＡ
をざらに結晶化させて最終ゲルをうるのであるが、放置
時間は１０時間以上が好ましい。放置時間が１０時間よ
り短すぎるばあいには結晶化が不充分であり、高強度の
ゲルはえられない。The frozen phase-separated structure was then left at 0 to 10°C, and the PVA
The final gel is obtained by coarsely crystallizing the gel, and the standing time is preferably 10 hours or more. If the standing time is shorter than 10 hours, crystallization will be insufficient and a gel with high strength will not be obtained.
薬理活性物質としてはヒトまたは動物の治療または疾病
の予防に用いられる化合物であればよく、とくに限定さ
れない。また水溶性であっても非水溶性であってもよく
、液状でも粉末状、粒状でもよい。The pharmacologically active substance is not particularly limited as long as it is a compound used for treatment or disease prevention in humans or animals. Moreover, it may be water-soluble or water-insoluble, and may be in liquid, powder, or granular form.
薬理活性物質の配合量は任意に選択でき、投与目的、剤
形、徐放性などにより適宜選定すればよいが、通常ＰＶ
Ａ１００部（重量部、以下同様）に対して０．０１〜５
００部、好ましくは１０〜５０部である。The amount of the pharmacologically active substance can be selected arbitrarily depending on the purpose of administration, dosage form, sustained release properties, etc., but usually PV
0.01 to 5 per 100 parts (parts by weight, same hereinafter) of A
00 parts, preferably 10 to 50 parts.
本発明の製剤における徐放性は、ＰＶＡの濃度ヤ薬理活
性物質の量などを調節することにより、任意に制御でき
る。The sustained release properties of the formulation of the present invention can be controlled arbitrarily by adjusting the concentration of PVA, the amount of pharmacologically active substance, etc.
本発明の徐放性製剤は、徐放性が要求される種々の剤形
にすることができ、たとえば坐剤、経皮投与剤、舌下剤
、経口投与剤などにすることができる。The sustained release preparation of the present invention can be made into various dosage forms that require sustained release properties, such as suppositories, transdermal preparations, sublingual preparations, and oral preparations.
つぎに参考例および実施例をあげて本発明の徐放性製剤
を説明するが、本発明はかかる実施例のみに限定される
ものではない。Next, the sustained release preparation of the present invention will be explained with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.
参考例
（ＰＶＡ多孔質ハイドロゲルの製造と分析）ＰＶＡ
（■ユニチカ製、ケン化度９９．５モル％、平均重合度
１ 、７００ ＞に第１表の濃度となるように水を加え
、オートクレーブ中で１１０℃にて２時間加熱して完全
に溶解させたのち、室温にまで冷却し、ＰＶＡ水溶液を
調製した。Reference example (manufacture and analysis of PVA porous hydrogel) PVA
(■ Manufactured by Unitika, degree of saponification 99.5 mol%, average degree of polymerization 1.700) Add water to the concentration shown in Table 1 and heat in an autoclave at 110°C for 2 hours to completely dissolve. After that, the mixture was cooled to room temperature to prepare a PVA aqueous solution.
ついで各ＰＶＡ水溶液を一２０℃のフリーザ中に入れ、
２４時間かけて凍結させた。えられた凍結物を第１表に
示す条件にて解凍し、ＰＶＡハイドロゲル１〜５をえた
。Next, each PVA aqueous solution was placed in a freezer at -20°C.
It was frozen for 24 hours. The obtained frozen product was thawed under the conditions shown in Table 1 to obtain PVA hydrogels 1 to 5.
［以下余白］
第１表
（水中膨潤度および収縮度試験）
ゲル１および３ならびに比較ゲル１〜３の試料的６ｇを
蒸留水５０ｄ中に浸漬し、３７℃の恒温槽中で１日毎に
ゲル試料の重量を秤量することにより膨潤度と収縮度を
測定した。ここで膨潤度および収縮度は３７℃の水中に
おける重量変化から次式により求めた。[Left below] Table 1 (Underwater swelling and shrinkage test) A sample of 6 g of Gels 1 and 3 and Comparative Gels 1 to 3 was immersed in 50 d of distilled water, and the gel was tested in a constant temperature bath at 37°C every day. The degree of swelling and shrinkage was determined by weighing the sample. Here, the degree of swelling and degree of shrinkage were determined from the weight change in water at 37° C. using the following formula.
Ｗ−Ｗ。W-W.
膨潤度（％）または収縮度（％） ＝−Ｘ １００Ｗｏ
−膨潤前のゲル重量
Ｗ−膨潤後のゲル重量
ゲル１および３の本発明の試料、比較ゲル１および２の
急速解凍試料および比較ゲル３の高温体解凍試料の３７
℃における水中膨潤度および収縮度の経時変化を測定し
た結果を第１図に示す。Swelling degree (%) or shrinkage degree (%) =-X 100Wo
- Gel weight before swelling W - Gel weight after swelling 37 of samples of the present invention of Gels 1 and 3, rapid thawing samples of Comparative Gels 1 and 2, and high temperature body thawing samples of Comparative Gel 3
Figure 1 shows the results of measuring changes over time in the degree of swelling and shrinkage in water at °C.
第１図から明らかなように、比較ゲル１および２の急速
解凍試料では各Ｐｖ＾濃度とも時間経過と共に膨潤度が
増大し、約４日後には一定値に達する。また膨潤度はＰ
ＶＡ ９度に依存しており、濃度が高い程膨潤度は大き
い。一方、比較ゲル３の高温体解凍試料では初期に若干
膨潤し、４日後には収縮減少を示す。これに反し、ゲル
１および３の本発明の試料では膨潤現象はまったく認め
られず、逆に収縮現象が認められる。As is clear from FIG. 1, in the rapidly thawed samples of Comparative Gels 1 and 2, the degree of swelling increases with time for each Pv^ concentration and reaches a constant value after about 4 days. Also, the degree of swelling is P
It depends on VA 9 degrees, and the higher the concentration, the greater the degree of swelling. On the other hand, the high-temperature thawed sample of Comparative Gel 3 swells slightly at the initial stage and shows a decrease in shrinkage after 4 days. On the contrary, in the samples of the present invention, Gels 1 and 3, no swelling phenomenon is observed at all, but on the contrary, a shrinkage phenomenon is observed.
このばあいも４日程度までは徐々に収縮し、それ以降は
一定値に達する。また、膨潤度と同じく収縮変化にもＰ
ＶＡ濃度依存性が認められ、ゲル１の方がゲル３に比べ
て収縮度は大きい。ゲル１および２の急速解凍試料にお
いて認められる膨潤現象は、ゲルが不安定で３７℃にお
いて微結晶の部分溶解が起こるためであり、一方、ゲル
１および３の本発明の試料に認められる収縮現象は、ア
ニーリング効果によって非晶部の一部がざらに結晶化す
るためと考えられる。In this case, it also gradually shrinks until about 4 days, and then reaches a certain value. Also, as with the degree of swelling, P
VA concentration dependence was observed, and the degree of shrinkage was greater in Gel 1 than in Gel 3. The swelling phenomenon observed in the rapidly thawed samples of Gels 1 and 2 is due to the instability of the gels and partial dissolution of microcrystals at 37°C, while the shrinkage phenomenon observed in the samples of the present invention of Gels 1 and 3. It is thought that this is because a part of the amorphous portion is roughly crystallized due to the annealing effect.
これらの実験結果は、凍結後の解凍温度、換言すれば、
ゲルの結晶化条件が強固なゲルの生成に大きく影響して
いることを示すものである。These experimental results indicate that the thawing temperature after freezing, in other words,
This shows that the gel crystallization conditions greatly influence the formation of a strong gel.
（力学的性質）
■東洋ボールドウィン製、Ｔｅｎ５ ｉ Ｉ Ｏｎ／
ＵＴＭ−４−１００を用いて引張速度１００ＩＲ１１ｔ
／ｍｉｎ 、 温度２０℃、相対湿度６５％でゲル１〜
５および比較ゲル３〜６の力学特性を測定した。なお、
ゲル試料は２履厚でダンベル型引張試験片に打扱いて測
定に供し、破断引張強度と伸度を求めた。(Mechanical properties) ■Ten5 i I On/manufactured by Toyo Baldwin
Tensile speed 100IR11t using UTM-4-100
/min, temperature 20℃, relative humidity 65% gel 1 ~
The mechanical properties of Gels 5 and Comparative Gels 3 to 6 were measured. In addition,
The gel sample had a thickness of two shoes and was subjected to measurement by being shaped into a dumbbell-shaped tensile test piece, and the tensile strength and elongation at break were determined.
ゲル１．３および５の本発明の試料の応力−ひすみ曲線
は第２図に示す通りであった。この応力−ひずみ曲線は
一般のプラスチック、繊維、エラストマーなどの曲線と
は異なり、むしろ生体組織の力学特性に類似している。The stress-strain curves of the inventive samples of Gels 1.3 and 5 were as shown in FIG. This stress-strain curve is different from the curves of general plastics, fibers, elastomers, etc., and is rather similar to the mechanical properties of living tissue.
ゲル１〜５の本発明の試料および比較ゲル３〜６の高温
体解凍試料の引張強度と伸度を測定した結果を第３図お
よび第４図に示す。比較ゲル１および２の急速解凍試料
は軟弱なため測定は不可能であった。第３図および第４
図には、明らかに、凍結後の結晶化条件がゲルの機械的
強度に大きく影響していることが示されている。The results of measuring the tensile strength and elongation of the samples of the present invention, Gels 1 to 5, and the high temperature thawed samples of Comparative Gels 3 to 6 are shown in FIGS. 3 and 4. The rapidly thawed samples of comparative gels 1 and 2 were too soft to measure. Figures 3 and 4
The figure clearly shows that the crystallization conditions after freezing greatly influence the mechanical strength of the gel.
一般に、架橋剤や放射線によって架橋したばあい、架橋
密度の増大に伴って強度は増大するが、逆に伸度は減少
する。しかしながら、本発明に用いるゲルは第２〜４図
からも明らかなように、強度が増大する程、伸度も増大
している。このことは、低温結晶化によってえられるゲ
ルの構造は、一般の化学的架橋によってえられるゲルと
は本質的に異なることを示唆している。Generally, when crosslinking is performed using a crosslinking agent or radiation, the strength increases as the crosslink density increases, but the elongation decreases. However, as is clear from FIGS. 2 to 4, as the strength of the gel used in the present invention increases, the elongation also increases. This suggests that the structure of gels obtained by low-temperature crystallization is essentially different from gels obtained by general chemical crosslinking.
（電子顕微鏡観察）
日立−明石製８３）ｆ−９型走査型電子顕微鏡を用い、
臨界点乾燥したゲル試料の形態を観察した。(Electron microscopy observation) Using a Hitachi-Akashi 83) F-9 scanning electron microscope,
The morphology of the critical point dried gel samples was observed.
ゲル試料をそのまま凍結乾燥すると大きな体積収縮が起
こり、ゲルの構造が破壊されてしまうため、生体組織の
電顕観察用の試料作製と同様に、臨界点乾燥法により試
料を作製した。ゲル１．３および５の本発明の試料を走
査型電顕観察した結果、いずれの試料にも多孔質構造が
認められ、その孔径はゲル試料のＰＶＡ濃度に大きく依
存していることがわかった。ゲル１は平均的５μｍ、ゲ
ル３は平均約２〜３μｍ１ゲル５は平均的１μｍの孔径
を有していた。If a gel sample is freeze-dried as it is, a large volumetric contraction will occur and the gel structure will be destroyed, so the sample was prepared using the critical point drying method, similar to the preparation of samples for electron microscopy of biological tissues. As a result of scanning electron microscopy observation of the samples of the present invention, Gels 1.3 and 5, it was found that both samples had a porous structure, and the pore size was found to be largely dependent on the PVA concentration of the gel sample. . Gel 1 had an average pore size of 5 μm, Gel 3 had an average pore size of about 2-3 μm, and Gel 5 had an average pore size of 1 μm.
実施例１〜７
ＰＶＡ ｌユニチカ製、ケン化度９９．５モル％、平
均重合度１７００ ）に第２表の濃度となるように水を
加え、オートクレーブ中で１１０℃にて２時間加熱して
完全に溶解させたのち、室温にまで冷却してそれぞれＰ
ＶＡ水溶液を調製した。Examples 1 to 7 Water was added to PVA (manufactured by Unitika, saponification degree 99.5 mol%, average polymerization degree 1700) to the concentration shown in Table 2, and heated in an autoclave at 110°C for 2 hours. After completely dissolving, cool to room temperature and dissolve each P.
A VA aqueous solution was prepared.
ついで各ＰＶＡ水溶液に、薬理活性物質として抗悪性腫
瘍剤である水溶性のアドリアマイシン（協和発酵工業■
製、以下ＡＤＨという）を第２表に示す量加えて溶解さ
せたのち、５ＩｒＩ！ｎφの試験管に入れた。Next, water-soluble adriamycin (Kyowa Hakko Kogyo Co., Ltd.), an anti-malignant tumor agent, was added to each PVA aqueous solution as a pharmacologically active substance.
After adding and dissolving 5IrI! (hereinafter referred to as ADH) shown in Table 2, It was placed in an nφ test tube.
各試験管を一２０℃のフリーザ中に入れ、約１０時間か
けて水溶液を凍結させた。ついでえられた凍結体を５℃
の恒温槽中で約１０時間かけて解凍し、長ざ１α、直径
５＃ｌｌ１１のロッド状の本発明の徐放性製剤をえた。Each test tube was placed in a freezer at -20°C, and the aqueous solution was frozen for about 10 hours. The resulting frozen body was then incubated at 5°C.
The mixture was thawed in a constant temperature bath for about 10 hours to obtain a rod-shaped sustained release preparation of the present invention with a length of 1α and a diameter of 5#ll11.
［以下余白］
第２表
（八〇Ｈの溶出試験）
日本薬局方の規格に準拠した溶出試験機（ＮＴＲ−ＶＳ
３ 、富山産業１１１１）を用いて、所定時間毎にサン
プリングした。測定は４８２止のｕｖ吸収により行なっ
た。結果を第５〜７図に示す。[Left below] Table 2 (80H dissolution test) Dissolution tester (NTR-VS
3, Toyama Sangyo 1111), sampling was performed at predetermined time intervals. Measurements were made using UV absorption at 482 degrees. The results are shown in Figures 5-7.
第５図はＡｌ濃度が１．２５１！ｔｇ／ｄＰＶＡ水溶液
のばあいで、ＰＶＡ濃度を変化させたときの放出率（重
量％）の経時変化を示すグラフ、第６図はへ〇Ｈ濃度が
２．５η／ ｄ ＰＶＡ水溶液のばあいで、ＰＶＡ濃度
を変化させたときの放出率（重量％）の経時変化を示す
グラフ、第７図はＰＶＡ水溶液のＰＶＡ濃度を一定（１
０％）とし、八〇）ｌ濃度を変化させたときの放出率（
重量％）の経時変化を示すグラフである。In Figure 5, the Al concentration is 1.251! Figure 6 is a graph showing the change in release rate (wt%) over time when the PVA concentration is changed in the case of a PVA aqueous solution with a H concentration of 2.5η/d. , a graph showing the change in release rate (wt%) over time when the PVA concentration is changed.
0%), and 80) The release rate when changing the l concentration (
It is a graph showing a change over time in weight %).
第５図に示すごとく、各試料とも溶出初期の溶出速度は
大きいが、ＰＶＡ濃度が高い程、溶出しにくい傾向にあ
る。１０％濃度のゲル試料（実施例１）は３０分間です
でに約５０％ものＡＤＨを放出し、約４時間で放出が完
結している。２０％濃度のゲル試料（実施例４）は、３
０分間で約４０％の放出を示し、放出完結は約８時間で
ある。これらに対して３０％濃度のゲル試料（実施例６
）は、初期の放出は約２０％と低く、６時間で約７０％
の放出を示すが、その後の放出はきわめて遅く、１３時
間でも約７５％しか放出していない。このようにＰＶＡ
濃度を変化させることにより八〇Ｈの放出時間を調節で
きる。 ＡＤＨの濃度を２．５ｆｆｉｆｆ／ｄＰＶＡ水
溶液としたばあいも、第６図に示すごとく第５図と同様
の傾向が認られ、しかも放出時間を大幅に延長すること
ができる。As shown in FIG. 5, the elution rate at the initial stage of elution is high for each sample, but the higher the PVA concentration, the harder it is to elute. The 10% concentration gel sample (Example 1) already released about 50% of ADH in 30 minutes, and the release was completed in about 4 hours. The 20% concentration gel sample (Example 4) was
It shows about 40% release in 0 minutes and the release is completed in about 8 hours. Gel samples at 30% concentration (Example 6)
), the initial release is low at about 20% and about 70% after 6 hours.
However, the subsequent release was extremely slow, with only about 75% released even after 13 hours. In this way PVA
By changing the concentration, the release time of 80H can be adjusted. When the concentration of ADH is 2.5 ffiff/dPVA aqueous solution, the same tendency as shown in FIG. 5 is observed as shown in FIG. 6, and the release time can be significantly extended.
ＡＤＨ濃度と放出速度との関係は、第７図に示すごとく
、ＡＤＨ濃度の増大に伴って放出速度が低下する傾向に
ある。As shown in FIG. 7, the relationship between ADH concentration and release rate is such that the release rate tends to decrease as the ADH concentration increases.
実施例８〜１１
ＰＶＡ （（ｅｌユニチカ製、ケン化度９９．５モル
％、平均重合度１，７００）に第３表の濃度となるよう
に水を加え、オートクレーブ中で１１０℃にて２時間加
熱してＰＶＡを溶解させたのち、室温にまで冷却してＰ
ＶＡ水溶液を調製した。Examples 8 to 11 Water was added to PVA (manufactured by El Unitika, degree of saponification 99.5 mol%, average degree of polymerization 1,700) to the concentration shown in Table 3, and the mixture was heated in an autoclave at 110°C for 2 hours. After heating for a period of time to dissolve the PVA, the PVA is cooled to room temperature.
A VA aqueous solution was prepared.
ついで各ＰＶＡ水溶液に、血小板凝集抑制剤である非水
溶性のプロスタグランジンエコ類似体（小野薬品工業■
製、以下ＰＧＩ２−Ａという）を第３表に示す量加えて
分散させたのち、５Ｍφの試験管に入れた。Next, a water-insoluble prostaglandin eco analog (Ono Pharmaceutical Co., Ltd.), which is a platelet aggregation inhibitor, was added to each PVA aqueous solution.
(hereinafter referred to as PGI2-A) was added and dispersed in the amount shown in Table 3, and then placed in a 5Mφ test tube.
各試験管を一２０℃のフリーザ中に入れ、約１０時間か
けて水溶液を凍結させた。ついでえられた凍結体を５℃
の恒温槽中で約１０時間かけて解凍し、長ざ１ ｃｒｔ
ｔ、直径５ｍｍのロッド状の本発明の徐放性製剤をえた
。Each test tube was placed in a freezer at -20°C, and the aqueous solution was frozen for about 10 hours. The resulting frozen body was then incubated at 5°C.
Thaw in a thermostatic oven for about 10 hours, and cut into 1 crt.
A rod-shaped sustained release preparation of the present invention with a diameter of 5 mm was obtained.
第３表
（ＰＧＩ２−＾の溶出試験）
実施例１で使用した溶出試験機を用いて、所定時間毎に
サンプリングした。測定は高速液体クロマトグラフィー
（カラム：ステンレス１゜４Ｘ ２００７１１１．波長
：２１０止）を用いて定量した。結果を第８〜９図に示
す。第８図および第９図は、それぞれＰＶＡ水溶液のＰ
ＶＡ濃度を１０％および１５％と一定にし、ＰＧＩ２−
Ａ濃度を変えたばあいの放出率（重量％）の経時変化を
示すグラフである。Table 3 (Elution test of PGI2-^) Using the elution tester used in Example 1, samples were taken at predetermined time intervals. The measurement was carried out quantitatively using high performance liquid chromatography (column: stainless steel 1°4X 2007111. Wavelength: 210 stops). The results are shown in Figures 8-9. Figures 8 and 9 show the P of the PVA aqueous solution, respectively.
The VA concentration was kept constant at 10% and 15%, and PGI2-
It is a graph showing the change in release rate (wt%) over time when the A concentration is changed.
第８図に示すごとく、ＰＧＩ２−Ａ濃度が０．５ｑ／１
ｅＰＶ＾水溶液のばあい（実施例８）、３０分後１７．
９４Ｑ％放出し、約４時間後には放出が停止する（約６
５％）。しかしＰＧＩ２−＾濃度が２．０１１１１／ｒ
１１１ＰＶＡ水溶液のばあい（実施例９）は約６時間後
には１００％放出される。また、ＰＶＡ濃度が１５％の
ばあいく第９図）でも同様の傾向があるが、ＰＧＩ２−
Ａの放出は遅延されている。As shown in Figure 8, the PGI2-A concentration is 0.5q/1
In the case of ePV^ aqueous solution (Example 8), 17. after 30 minutes.
It releases 94Q%, and the release stops after about 4 hours (about 6
5%). However, the PGI2-^ concentration is 2.01111/r
In the case of the 111PVA aqueous solution (Example 9), 100% release was achieved after about 6 hours. Also, when the PVA concentration is 15% (Fig. 9), there is a similar tendency, but PGI2-
The release of A is delayed.
以上の実施例の結果から、本発明の徐放性製剤は有効な
徐放性を示し、かつＰＶＡ １度および（または）薬理
活性物質の濃度を適当に組合せることにより、徐放時間
や傾向を制御することができることが明らかである。From the results of the above examples, it is clear that the sustained-release preparation of the present invention exhibits effective sustained-release properties, and that by appropriately combining the PVA concentration and/or the concentration of the pharmacologically active substance, the sustained-release time and tendency can be improved. It is clear that it is possible to control
［発明の効果］
本発明の徐放性製剤は、ＰＶＡのゲル化に際して化学的
架橋剤や触媒などは一切使用していないうえ、加熱もし
ないので、薬理活性物質の活性の低下や変性が生起する
ことはない。したがって、きわめて安定に薬理活性物質
をゲル内に包含させることができると同時に、生体に対
してまったく刺激を与えない。[Effects of the Invention] The sustained-release preparation of the present invention does not use any chemical crosslinking agent or catalyst when gelling PVA, and also does not heat, so there is no reduction in the activity or denaturation of the pharmacologically active substance. There's nothing to do. Therefore, the pharmacologically active substance can be incorporated into the gel in an extremely stable manner, and at the same time, it does not cause any irritation to living organisms.
ざらに、薬理活性物質の性状や形状に無関係に均一にＰ
Ｖ＾ゲル内に薬理活性物質を包含させることかできるの
みならず、ＰＶＡ濃度や薬理活性物質含有量を変化させ
ることにより、徐放性を制御することもできる。Generally, P is uniformly applied regardless of the properties and shape of the pharmacologically active substance.
Not only can a pharmacologically active substance be incorporated into the V^gel, but the sustained release properties can also be controlled by changing the PVA concentration and the pharmacologically active substance content.
第１図は本発明に用いるＰＶＡハイドロゲルおよび比較
用ゲルの水中膨潤度および収縮度の経時変化を示すグラ
フ、第２図は本発明に用いるＰＶＡハイドロゲルの応力
−ひすみ曲線を示すグラフ、第３図は本発明に用いるＰ
ＶＡハイドロゲルおよび比較用ゲルの引張強度とＰＶＡ
濃度の関係を示すグラフ、第４図は本発明に用いるＰＶ
Ａハイドロゲルおよび比較用ゲルの伸度とＰＶＡ濃度の
関係を示すグラフ、第５図はＡＤＨ濃度１．２５１ｆｔ
ｇ／ｄＰＶＡ水溶液の本発明の徐放性製剤のＰＶＡ濃度
を変えたばあいの放出率の経時変化を示すグラフ、第６
図はＡＤＨ濃度２．５７１ｔ！？／ｌ’ＰＶＡ水溶液の
本発明の徐放性製剤のＰＶＡ １１度を変えたばあいの
放出率の経時変化を示すグラフ、第７図は本発明の徐放
性製剤のＰＶＡ濃度を一定（１０％）としＡＤＨ濃度を
変化させたときの放出率の経時変化を示すグラフ、第８
図および第９図はそれぞれ本発明のＰＧＩ２−Ａを含む
徐放性製剤のＰＶＡ濃度を１０％および１５％としてＰ
ＧＩ２−＾濃度を変えたばあいの放出率の経時変化を示
すグラフである。
特許出願人 株式会社バイオマテリアル・ユニバー
ス
代理人弁理士 朝 日 奈宗 太 ほか１名才１ 図
時 間（ｈｒ）
、？２図
ひずみ（％） ・
濃 度 （％〕
濃 度 （％）
蝙ミーｆ７（承）
蝙 ＝ 千（承）
蝙 ミー１Ｆ−（承 ）FIG. 1 is a graph showing changes over time in the degree of swelling and shrinkage in water of the PVA hydrogel used in the present invention and the comparative gel, and FIG. 2 is a graph showing the stress-strain curve of the PVA hydrogel used in the present invention. Figure 3 shows P used in the present invention.
Tensile strength of VA hydrogel and comparison gel versus PVA
A graph showing the relationship between concentrations, Figure 4 shows the PV used in the present invention.
Graph showing the relationship between elongation and PVA concentration of A hydrogel and comparative gel, Figure 5 shows ADH concentration of 1.251 ft.
Graph showing the change in release rate over time when the PVA concentration of the sustained release preparation of the present invention of g/d PVA aqueous solution is changed, No. 6
The figure shows ADH concentration of 2.571t! ? Figure 7 is a graph showing the change in release rate over time when the PVA concentration of the sustained release preparation of the present invention in a PVA aqueous solution is changed by 11 degrees. ), a graph showing the change in release rate over time when changing the ADH concentration, No. 8
Figures 9 and 9 show PVA concentrations of 10% and 15%, respectively, of sustained-release preparations containing PGI2-A of the present invention.
It is a graph showing the change in release rate over time when the GI2-^ concentration is changed. Patent applicant Biomaterial Universe Co., Ltd. Patent attorney Asahi Nasota and 1 other person Figure Time (hr) ? Figure 2 Strain (%) / Concentration (%) Concentration (%) F7 (accepted) Fau = 1,000 (accepted) Fami 1F- (accepted)
Claims (1)
氷点以下の温度にて凍結させて氷相と高分子相に分離し
たのち、０〜１０℃の低温にて高分子相を結晶化させて
えられる多孔質徐放性製剤。1 A porous material obtained by freezing an aqueous polyvinyl alcohol solution containing a pharmacologically active substance at a temperature below the freezing point to separate it into an ice phase and a polymer phase, and then crystallizing the polymer phase at a low temperature of 0 to 10°C. Sustained release formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3233085A JPS61191609A (en) | 1985-02-20 | 1985-02-20 | Slow-releasing medicinal preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3233085A JPS61191609A (en) | 1985-02-20 | 1985-02-20 | Slow-releasing medicinal preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61191609A true JPS61191609A (en) | 1986-08-26 |
| JPH0511091B2 JPH0511091B2 (en) | 1993-02-12 |
Family
ID=12355928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3233085A Granted JPS61191609A (en) | 1985-02-20 | 1985-02-20 | Slow-releasing medicinal preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61191609A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5346935A (en) * | 1991-05-28 | 1994-09-13 | Takeda Chemical Industries, Ltd. | Hydrogel |
| US6447701B1 (en) | 1997-11-19 | 2002-09-10 | Ingo Heschel | Method for producing porous structures |
| JP2006523613A (en) * | 2002-12-20 | 2006-10-19 | エスティ．ジェイムス アソシエイト エルエルシー／フェイバー リサーチ シリーズ | Coated particles for sustained release pharmaceutical administration |
| CN111606630A (en) * | 2020-06-15 | 2020-09-01 | 陕西金磊混凝土有限公司 | Steam-curing-free high-fluidity concrete and preparation method thereof |
| WO2021205886A1 (en) * | 2020-04-10 | 2021-10-14 | 日本酢ビ・ポバール株式会社 | Binder |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5956446A (en) * | 1982-09-24 | 1984-03-31 | Nippon Oil Co Ltd | Method for lowering flexibility of frozen polyvinyl alcohol gel |
-
1985
- 1985-02-20 JP JP3233085A patent/JPS61191609A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5956446A (en) * | 1982-09-24 | 1984-03-31 | Nippon Oil Co Ltd | Method for lowering flexibility of frozen polyvinyl alcohol gel |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5346935A (en) * | 1991-05-28 | 1994-09-13 | Takeda Chemical Industries, Ltd. | Hydrogel |
| US6447701B1 (en) | 1997-11-19 | 2002-09-10 | Ingo Heschel | Method for producing porous structures |
| JP2006523613A (en) * | 2002-12-20 | 2006-10-19 | エスティ．ジェイムス アソシエイト エルエルシー／フェイバー リサーチ シリーズ | Coated particles for sustained release pharmaceutical administration |
| JP2012072197A (en) * | 2002-12-20 | 2012-04-12 | St James Associates Llc Faber Research Series | Coated particle for sustained-release pharmaceutical administration |
| WO2021205886A1 (en) * | 2020-04-10 | 2021-10-14 | 日本酢ビ・ポバール株式会社 | Binder |
| CN111606630A (en) * | 2020-06-15 | 2020-09-01 | 陕西金磊混凝土有限公司 | Steam-curing-free high-fluidity concrete and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0511091B2 (en) | 1993-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5346935A (en) | Hydrogel | |
| JP3134935B2 (en) | Branched polyanhydride | |
| Yoshida et al. | A new temperature-sensitive hydrogel with α-amino acid group as side chain of polymer | |
| US4164560A (en) | Systems for the controlled release of macromolecules | |
| US8734834B2 (en) | Acrylic hydrogels with deprotonated amine groups that undergo volumetric expansion in response to changes in environmental pH | |
| US6030634A (en) | Polymer gel composition and uses therefor | |
| EP1592405B1 (en) | Composition for chemoembolotherapy of solid tumors | |
| US20050271727A1 (en) | Biodegradable and biocompatible crosslinked polymer hydrogel prepared from PVA and/or PEG macromer mixtures | |
| EP3393537B1 (en) | High strength biomedical materials | |
| JPH11510160A (en) | Polymeric drug formulations | |
| Mongia et al. | Mucoadhesive poly (vinyl alcohol) hydrogels produced by freezing/thawing processes: applications in the development of wound healing systems | |
| JP2006523733A5 (en) | ||
| WO1998028364A1 (en) | Novel polymer gel composition and uses therefor | |
| JP3296579B2 (en) | Compounds with controlled component release | |
| JPS61191609A (en) | Slow-releasing medicinal preparation | |
| Bagri et al. | Evaluation of starch based cryogels as potential biomaterials for controlled release of antibiotic drugs | |
| US4781926A (en) | Transdermal therapeutic composition | |
| Villar-Padilla et al. | Development of a xanthan gum film for the possible treatment of vaginal infections | |
| KR20090017310A (en) | Poly(n-isopropylacrylamide)-immobilized monoolein cubic phase and the method for production of the said monoolein cubic phase | |
| Taşkın Çakıcı | Nano TiO2-doped sodium alginate/hydroxypropyl methylcellulose synthesis of bionanocomposite membrane and its use in controlled release of anti-cancer drug 5-fluorouracil | |
| Shi et al. | Sustained release of alginate hydrogel containing antimicrobial peptide Chol-37 (F34-R) in vitro and its effect on wound healing in murine model of Pseudomonas aeruginosa infection | |
| US6238688B1 (en) | Method for repairing blood vessel system | |
| KR101274608B1 (en) | Anti-adhesion agent comprising curdlan and gellan gum, and process for producing the same | |
| JPS60177066A (en) | Gel formation by low-temperature crystallization of concentrated pva aqueous solution | |
| SK1795A3 (en) | Drug delivery device and method of this production |