JP5463504B2 - 非球形微粒子および非球形微粒子の製造方法 - Google Patents
非球形微粒子および非球形微粒子の製造方法 Download PDFInfo
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- JP5463504B2 JP5463504B2 JP2009082705A JP2009082705A JP5463504B2 JP 5463504 B2 JP5463504 B2 JP 5463504B2 JP 2009082705 A JP2009082705 A JP 2009082705A JP 2009082705 A JP2009082705 A JP 2009082705A JP 5463504 B2 JP5463504 B2 JP 5463504B2
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- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Materials For Medical Uses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Medicinal Preparation (AREA)
Description
PS=RL/RS ・・・・・(1)
(RLは、上記非球形微粒子を内部に含む最小の球の半径であり、RSは、上記非球形微粒子の内部に含まれる最大の球の半径である)。
本実施の形態の非球形微粒子は、ポリエステルまたは極性基末端を構成成分として含む重合体によって形成された支持体の表面上に、カルシウム塩によって形成されたナノ粒子が固定化されている。なお、本明細書における「非球形」には、球形ではない全ての形状(例えば、円板状、偏平状など)が含まれる。
PS=RL/RS ・・・・・(1)
(RLは、上記非球形微粒子を内部に含む最小の球の半径であり、RSは、上記非球形微粒子の内部に含まれる最大の球の半径である)。
本実施の形態の非球形微粒子の製造方法は、疎水性の溶媒中に、ポリエステルまたは極性基末端を構成成分として含む重合体が溶解された疎水性溶液と、親水性の溶媒中に、カルシウム塩によって形成されたナノ粒子が懸濁された親水性溶液と、を混合して混合溶液を作製する工程(第1工程と呼ぶ);および、上記混合溶液から、上記疎水性の溶媒を揮発させる工程(第2工程と呼ぶ)を含む。また、上記疎水性溶液における上記重合体の濃度は、5.0重量%よりも低い。
第1工程では、疎水性の溶媒中に、ポリエステルまたは極性基末端を構成成分として含む重合体が溶解された疎水性溶液と、親水性の溶媒中に、カルシウム塩によって形成されたナノ粒子が懸濁された親水性溶液と、が混合されて混合溶液が作製される。
第2工程では、第1工程にて作製された混合溶液から疎水性の溶媒を揮発させる。
ここで「一次粒子」とは、焼結工程の前に、ハイドロキシアパタイト(HAp)によって形成された粒子のことを意味する。すなわち、ハイドロキシアパタイト粒子の製造工程において、初めて形成された粒子のことを意味する。また狭義には単結晶粒子のことを意味する。なお本明細書において「一次粒子」とは、非晶質(アモルファス)の状態のもの、およびその後に焼結を行った焼結体の状態のものをも含む。
混合工程は、一次粒子と融着防止剤とを混合する工程である。つまり、上記一次粒子生成工程によって得られた一次粒子群の粒子間に、あらかじめ融着防止剤を介在させておくことによって、その後の焼結工程における一次粒子同士の融着を防止するための工程である。なお本当該混合工程によって得られた一次粒子と融着防止剤との混合物を「混合粒子」と呼ぶこととする。
焼結工程は、上記混合工程によって得られた混合粒子を焼結温度に曝して、当該混合粒子に含まれる混合粒子をセラミック粒子(焼結体粒子)にする工程である。このとき、混合粒子の粒子間には融着防止剤が介在しているので、焼結工程における高温条件に曝されても、ハイドロキシアパタイト一次粒子同士の融着を防止することができる。
除去工程は、焼結工程によって得られた焼結体粒子の粒子間に混在する融着防止剤を取り除く工程である。
<1−1>一次粒子生成工程
球状のリン酸カルシウムナノ粒子を、湿式法にて合成した。
後述する焼結工程におけるリン酸カルシウムナノ粒子同士の融着を防止するために、一次粒子生成工程にて得られた球状のリン酸カルシウムナノ粒子と融着防止剤とを混合した。なお、当該実施例では、融着防止剤としてポリアクリル酸カルシウムを用いた。
上記混合粒子をルツボに入れ、800℃にて1時間の焼結を行った。この際、ポリアクリル酸カルシウムは、熱分解して酸化カルシウム〔CaO〕となった。また、焼結工程終了後の酸化カルシウム〔CaO〕の残存率は、25%以上であった。なお、酸化カルシウム〔CaO〕の残存率は、セイコーインスツルメンツ株式会社製のTG/DTA6300を用いて、700℃付近における重量減少量に基いて計算した。
上記融着防止剤の水への溶解性を上げるために、50mmol/Lの硝酸アンモニウム〔NH4NO3〕水溶液を調製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.25gを50mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.25gを50mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.25gを50mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
<5−1>末端にカルボキシル基を有するポリスチレン
末端にカルボキシル基を有するポリスチレンを溶液重合によって調製した。
末端にカルボキシル基を有さないポリスチレンを溶液重合により調製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.125gを25mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.125gを25mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
上述した〔1.リン酸カルシウム粒子の調製〕にて得られた焼結体粒子0.125gおよびドデシルベンゼンスルホン酸ナトリウム(東京化成工業株式会社製)0.125gを25mLの水に加え、当該水溶液に対して超音波を15分間照射することによって、水性分散体(親水性溶液)を作製した。
Claims (11)
- ポリエステルまたは極性基末端を構成成分として含む重合体によって形成された支持体の表面上に、カルシウム塩によって形成されたナノ粒子が固定化されている非球形微粒子であって、
下記式(1)にて規定される上記非球形微粒子の異形化度PSが、1.1以上であり、
上記重合体が、乳酸、ε−カプロラクトン、グリコール酸、ジオキサノンおよびメチレンカーボネートからなる群より選択される少なくとも一つ以上の単量体を含み、
上記重合体の末端が、カルボキシル基、硫酸基、スルホン酸基、アミノ基、または水酸基であることを特徴とする非球形微粒子。
PS=RL/RS ・・・・・(1)
(RLは、上記非球形微粒子を内部に含む最小の球の半径であり、RSは、上記非球形微粒子の内部に含まれる最大の球の半径である) - 上記カルシウム塩が、ハイドロキシアパタイト、β−リン酸三カルシウム、α−リン酸三カルシウム、バイオガラス、または炭酸カルシウムであることを特徴とする請求項1に記載の非球形微粒子。
- 上記RLが、1μm〜1000μmであることを特徴とする請求項1または2に記載の非球形微粒子。
- 上記ナノ粒子の粒子径が、10nm〜1000nmであることを特徴とする請求項1〜3の何れか1項に記載の非球形微粒子。
- 上記支持体が、上記重合体以外に生体吸収性高分子を含むことを特徴とする請求項1〜4の何れか1項に記載の非球形微粒子。
- 請求項1〜5の何れか1項に記載の非球形微粒子からなることを特徴とする担体。
- 請求項1〜5の何れか1項に記載の非球形微粒子の表面上に、細胞または生理活性物質が接着していることを特徴とする薬学的組成物。
- 疎水性の溶媒中に、ポリエステルまたは極性基末端を構成成分として含む重合体が溶解された疎水性溶液と、親水性の溶媒中に、カルシウム塩によって形成されたナノ粒子が懸濁された親水性溶液と、を混合して混合溶液を作製する工程;および
上記混合溶液から、上記疎水性の溶媒を揮発させる工程、を含み、
上記疎水性溶液における上記重合体の濃度は、5.0重量%よりも低く、
上記重合体の末端が、カルボキシル基、硫酸基、スルホン酸基、アミノ基、または水酸基であることを特徴とする非球形微粒子の製造方法。 - 上記重合体が、乳酸、ε−カプロラクトン、グリコール酸、ジオキサノンおよびメチレンカーボネートからなる群より選択される少なくとも一つ以上の単量体を含むことを特徴とする請求項8に記載の非球形微粒子の製造方法。
- 上記カルシウム塩が、ハイドロキシアパタイト、β−リン酸三カルシウム、α−リン酸三カルシウム、バイオガラス、または炭酸カルシウムであることを特徴とする請求項8または9に記載の非球形微粒子の製造方法。
- 上記疎水性の溶媒は、ジクロロメタン、クロロホルムまたはトルエンであることを特徴とする請求項8〜10の何れか1項に記載の非球形微粒子の製造方法。
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