可降解光交联聚（醚—酐）凝胶用于药物增溶的研究
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摘要
一些水难溶性药物因其溶解性差导致生物利用度低,吸收不完全,严重的影响了其临床应用,成为制剂领域面临的一大难题。国内外很多学者致力于难溶性药物增溶的研究并取得了一定成果,如制成固体分散体、环糊精包合物、可溶性药物前体等,但均在不同程度上存在着缺陷,如贮存不稳定等。为解决这一难题,本文提出了一种通过用生物可降解三维光交联网络凝胶来包载难溶性药物并达到药物增溶和贮存稳定性的思想。
本文选用美国FDA批准用于人体的生物相容性材料聚乙二醇PEG、癸二酸SA等作为组成凝胶网络的骨架,将亲水性PEG引入到聚酸酐的链段中,使两种材料的优势得以充分体现。将PEG衍生物和癸二酸均通过双键封端后,通过生物相容性引发剂2,2-二甲氧基-2-苯基苯乙酮的引发,在紫外光的照射下发生自由基聚合反应,形成生物可降解聚(醚-酐)三维光交联网络凝胶,用FTIR和1H NMR进行产物结构表征并进行溶胀性和降解性能测定。用原位法和后包合两种方法将水难溶性模型药物吲哚美辛包载于凝胶中,以满足不同的用药目的。通过X-ray和DSC测定药物存在形态及贮存稳定性,两种方法制成的载药凝胶中吲哚美辛均以无定型或分子状态分布,且在贮存8个月后仍能保持原有形态,无任何晶体析出;药物体外溶出实验表明,包载于聚(醚-酐)网络中的药物有较结晶原料药更快的溶出速率和累积溶出量,且通过调节亲、疏水性大分子单体比例可延缓药物释放。聚(醚-酐)凝胶网络中,聚乙二醇的引入可有效增加难溶性药物的表面润湿性,无定型或分子形态的分布状态能够增加药物与介质接触的表面积,三维网络可有效抑制药物结晶,此法有望解决水难溶性药物溶解度和溶出速率低及制剂中药物物理形态不稳定、易析晶老化等难题,为难溶性药物增溶提出了一种新思路,对药物制剂领域的整体发展具有一定的指导意义。
The poor solubility of hydrophobic drugs in water and their low dissolution rate in the body fluids often leads to insufficient bioavailability and is one of the most difficult and non-dissolved problems in pharmaceutical industry. Over the years, various solid dosage formulation techniques including solid dispersion,β-cyclodextrin inclusion complex, water-soluble prodrug et al., which enhance the dissolution of poorly soluble substances, have been successfully introduced to some extent. However, some of the formulated drug systems become instable and will recrystallize when they are stored for a period of time. The aim of this work was to explore a method that the hydrophobic drugs were entrapped into the biodegradable poly(ether-anhydride) photocrosslinked gels to increase the dissolution rate and enhance the stability of these drugs .
Polyethylene glycol (PEG) and sebacic acid (SA) were chosen as the candidates to construct the matrix of the poly (ether-anhydride) gels due to their excellent properties such as biocompatibility, non-toxicity and non-immunogenicity, which are proved by FDA for widely use in the field of biomedical science. By introducing hydrophilic PEG chain to polyanhydride structures, PEG-based macromers containing anhydride bonds were synthesized and photopolymerized to form degradable gels under UV irradiation. The structures were characterized by FTIR and 1H NMR. Indomethacin (IMC) as a model of poorly water-soluble drug was embedded in the degradable poly (ether-anhydride) photocrosslinked network by two different methods: in situ and post-fabrication. The drug was proved to be distributed with amorphous or molecular state in the crosslinked network and the physical morphology of the drug remained stable after at least 8 months storage by employing X-ray diffraction and differential scanning calorimetery (DSC). Dissolution tests showed that the drug in the network displayed better dissolution rate and more cumulative drug release than the crystal raw indomethacin. This method could increase the dissolution rate, inhibit recrystallization and enhance the stability of indomethacin in the degradable poly (ether-anhydride) networks, which provides a novel method and can be extended to other hydrophobic drugs.
本文选用美国FDA批准用于人体的生物相容性材料聚乙二醇PEG、癸二酸SA等作为组成凝胶网络的骨架,将亲水性PEG引入到聚酸酐的链段中,使两种材料的优势得以充分体现。将PEG衍生物和癸二酸均通过双键封端后,通过生物相容性引发剂2,2-二甲氧基-2-苯基苯乙酮的引发,在紫外光的照射下发生自由基聚合反应,形成生物可降解聚(醚-酐)三维光交联网络凝胶,用FTIR和1H NMR进行产物结构表征并进行溶胀性和降解性能测定。用原位法和后包合两种方法将水难溶性模型药物吲哚美辛包载于凝胶中,以满足不同的用药目的。通过X-ray和DSC测定药物存在形态及贮存稳定性,两种方法制成的载药凝胶中吲哚美辛均以无定型或分子状态分布,且在贮存8个月后仍能保持原有形态,无任何晶体析出;药物体外溶出实验表明,包载于聚(醚-酐)网络中的药物有较结晶原料药更快的溶出速率和累积溶出量,且通过调节亲、疏水性大分子单体比例可延缓药物释放。聚(醚-酐)凝胶网络中,聚乙二醇的引入可有效增加难溶性药物的表面润湿性,无定型或分子形态的分布状态能够增加药物与介质接触的表面积,三维网络可有效抑制药物结晶,此法有望解决水难溶性药物溶解度和溶出速率低及制剂中药物物理形态不稳定、易析晶老化等难题,为难溶性药物增溶提出了一种新思路,对药物制剂领域的整体发展具有一定的指导意义。
The poor solubility of hydrophobic drugs in water and their low dissolution rate in the body fluids often leads to insufficient bioavailability and is one of the most difficult and non-dissolved problems in pharmaceutical industry. Over the years, various solid dosage formulation techniques including solid dispersion,β-cyclodextrin inclusion complex, water-soluble prodrug et al., which enhance the dissolution of poorly soluble substances, have been successfully introduced to some extent. However, some of the formulated drug systems become instable and will recrystallize when they are stored for a period of time. The aim of this work was to explore a method that the hydrophobic drugs were entrapped into the biodegradable poly(ether-anhydride) photocrosslinked gels to increase the dissolution rate and enhance the stability of these drugs .
Polyethylene glycol (PEG) and sebacic acid (SA) were chosen as the candidates to construct the matrix of the poly (ether-anhydride) gels due to their excellent properties such as biocompatibility, non-toxicity and non-immunogenicity, which are proved by FDA for widely use in the field of biomedical science. By introducing hydrophilic PEG chain to polyanhydride structures, PEG-based macromers containing anhydride bonds were synthesized and photopolymerized to form degradable gels under UV irradiation. The structures were characterized by FTIR and 1H NMR. Indomethacin (IMC) as a model of poorly water-soluble drug was embedded in the degradable poly (ether-anhydride) photocrosslinked network by two different methods: in situ and post-fabrication. The drug was proved to be distributed with amorphous or molecular state in the crosslinked network and the physical morphology of the drug remained stable after at least 8 months storage by employing X-ray diffraction and differential scanning calorimetery (DSC). Dissolution tests showed that the drug in the network displayed better dissolution rate and more cumulative drug release than the crystal raw indomethacin. This method could increase the dissolution rate, inhibit recrystallization and enhance the stability of indomethacin in the degradable poly (ether-anhydride) networks, which provides a novel method and can be extended to other hydrophobic drugs.
引文
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