缓释辛伐他汀明胶软膏促进牙槽骨再生的研究
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摘要
牙槽骨丧失影响颌骨的稳定、功能、容貌及身心健康,严重危害病人的生活质量。他汀类药物能够诱导骨形成蛋白的表达而促进成骨,直接、大量应用辛伐他汀虽可促进牙槽骨再生,却会导致毒、副作用,浪费药物,造成生物利用度过低。
本研究拟选择可生物降解性聚合物PLGA、明胶作为载体制备载辛伐他汀缓释制剂,促进牙槽骨再生修复,减少用药次数、降低用药总量、降低乃至消除辛伐他汀的毒、副作用,提高生物利用度。
本研究首先制备了载辛伐他汀缓释微球体系(已获国家发明专利,专利号:ZL200810050306.2)。表征显示,微球为圆形、表面光滑、粒径及药物释放速率可通过制备环节来调控、在PBS中可缓释辛伐他汀。分别以辛伐他汀和载辛伐他汀微球为主要功能成分制备可注射性缓释辛伐他汀明胶软膏,体外质量检测,性能稳定,可缓释辛伐他汀;动物体内研究证实,两类缓释软膏均可促进牙槽骨再生修复。
本研究的创新点在于首次制备了PLGA载辛伐他汀缓释微球体系,并获国家发明专利;分别将载辛伐他汀微球和辛伐他汀药物与药用辅料复合制备可注射性缓释辛伐他汀软膏;体内、外的系列表征证实两类缓释软膏均具有生物相容性,可促进牙槽骨再生修复;本研究为难溶性药物的剂型选择及应用提供了新的可行性方案。
Alveolar bone repair or regeneration is a common and complicated clinical problem in orthopaedic surgery.Every year, millions of people are suffering from bone defects arising from trauma, tumor or bone diseases and of course several are dying due to insufficient of ideal bone substitute. There is a long history of using autogenic and allogenic bones in the treatment of bone defects. Even though autogenic bone performs better functions in terms of biocompatibility and other factors, it needs secondary surgery to procure donor bone from the patient’s own body. Allogenic bone bears risk of infections and immune responses, which may even intricate other health problems and thus affecting quality of life. As an alternative, synthetic biomaterials have been developed and clinically tested. However, some of those materials implanted into bone defects are often encapsulated by a fibrous tissue and do not adhere to bone due to lack of bioactivity, thus be isolated from the surrounding bone and remains as a foreign body.
Sustained release delivery of drugs via PLGA polymers as implants, microspheres, and nanoparticles has gained wide acceptance. Availability of a variety of PLGA polymers makes it easy for pharmaceutical scientists to custom-develop a sustained release formulation based on the disease state and the drug indicated. An ideal sustained release formulation should release the entrapped drugs in a slower and continuous manner over desired time periods. Drug release occurs from PLGA microspheres because of drug diffusion from both the intact and degrading microsphere matrix. However, the extent of drug release during each phase and time lag between the two phases could vary considerably among the PLGA polymers possibly because of differences in their lactide/glycolide ratios and molecular weights. PLGA polymers with different molecular weights and lactide/glycolide ratio had been studied for modifying drug release. PLGA is a biocompatible polymer and can degrad finally into CO2 and H2O in physiological envirenments.
Gelatin is a natural polymer that is derived from collagen, and is commonly used for pharmaceutical and medical applications due to its biodegradability,biocompatibility and relatively lower antigenicity in physiological envirenments. Gelatin contains a large number of glycine, proline and 4-hydroxyproline residues. These characteristics have contributed to gelatin's safety as a component in drug formulations or as a sealant for vascular prostheses. Due to its promising properties, safety and mainly to the possibility of polyion complexation, gelatin is been used in drug delivery for tissue engineering applications targeting several tissues. There are several commercially available gelatin based carriers for drug delivery that are being applied in tissue engineering applications. The properties of gelatin as a typical rigid-chain high molecular weight compound are in many issues analogous to those of rigid-chain synthetic polymers. Gelatin exhibits essentially the same common properties typical of polymeric substances. Thus, in a similar way to linear-chain synthetic polymers, in aqueous solutions gelatin macromolecules assume, at elevated temperatures, the conformation of a statistical coil. Under specific conditions, such as temperature, solvent or pH, gelatin macromolecules present sufficient flexibility to realize a variety of conformations. This makes it possible to vary also all the gelatin characteristics dependent on its molecular structure. Besides, gelatin shows a rather wide molecular weight distribution. Structural diversity of gelatin chain units determines the specific features of gelatin properties. Most synthetic polymers show no such features that are typical of most biopolymers, such as the presence of both acidic and basic functional groups in the gelatin macromolecules. Its easy processability and gelation properties, lead to gelatin be manufactured in a range of shapes including sponges and injectable hydrogels, but the most used carriers are gelatin microspheres which normally are incorporated in a second scaffold such as a hydrogel. The results from these systemic trials show the efficacy and safety of using gelatin based microparticles as carriers for tissue engineering applications.
Simvastatin (Sim), a member of the statin family of drugs known for primary and secondary prevention of cardiovascular disease that effectively reduce cholesterol by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and consequently improve morbidity and mortality. It also has been reported to stimulate bone formation and influence bone activity. Sim induces expression of bone morphogenetic protein 2(BMP-2) in osteoblast and human osteosarcoma cells. The incubation of cultured bone cells with statins enhanced the expression of BMP-2 gene expression. It has also been demonstrated that relatively low doses of Sim induce osteoblast differentiation and increase mineralization in osteoblastic cells. Statins exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. Statins are now recognized as atypical anti-inflammatory agents possessing a variety of immunomodulating effects in addition to their conventional lipid-lowering properties. A number of large studies with statins have noted greater reductions in levels of circulating C-reactive protein (CRP). Investigators demonstrated that Sim reduced inflammation and resorption of bone through suppressing of matrix metalloproteinase 9 (MMP-9) expressions and the inhibitory effect of Sim on the generation of osteoclast was dose and time dependent. Several recent studies indicate a beneficial effect of statins on bone quality as measured by a reduction in hip fracture risk and an increase in hip bone mineral density. Sim has been shown in experimental models to stimulate bone acting growth factors and enhance bone formation. It has been reported that pharmacological doses of statins such as Sim stimulated in vivo bone formation in rodents and increased new bone volume in calvarial cultures in vitro. Some researchers demonstrated that Sim improved fracture healing in mice as judged by histologic and biomechanical analysis. Anothers found that Sim significantly increased serum levels of osteocalcin (OC) but not of bone alkaline phosphatase (ALP). Thus, in the study to improve repair and regeneration of alveolar bone utilizing Sim as a functional drug.
The aim of this project is to study about injectable gelatin paste for sustained release of Sim manufactured from microspheres loaded-Sim or neat Sim powder with helpful materials for drug, respectively, and then utilize it for repair and regeneration of alveolar bone defect after systemic examinations of pastes quality. The paste could be injected through a 7-gauge soft needle. Microspheres system is prepared from bioresobable composite materials PLGA using a modified oil-in-water emulsion system, and this preparation technology of systemic microspheres in various size ranges is our state invention patent (No:ZL200810050306.2). An initial phase (phase I) consists of drug release from microspheres because of diffusion from surface bound and poorly encapsulated drug. A relatively slower releasing second phase (phase II) is generally attributed to binding of drug molecules to the polymer in case of peptides. Rapid drug release during the third phase is commonly attributed to the faster drug diffusion from the eroding matrix. All three phases are usually not evident for lipophilic drugs, as these molecules can diffuse efficiently across the intact polymer resulting in the loss of phase II. Sim is a hydrophobic molecule and its release manner is not evident three phases. Release-modifying agents such as ethylene glycols, Spans and Tweens have been incorporated into microspheres to induce constant release of drug.
Drug-release of microspheres and paste studies have been performed, and data were fitted to better understanding of various mechanisms involved in Sim release from PLGA microspheres in a controlled and sustained manner and gelatin paste over extended periods of time.The two types of gelatin paste loaded-Sim for sustained release were prepared by mixing neat Sim or PLGA microspheres loaded-Sim with gelatin, glycerin, EDTA and water for injection, respectively, in 37℃bath. In vitro physiological stability of pastes was performed in phosphate buffered saline under physiological condition. Their quality is stable for 5 weeks at least. The release rate of Sim from gelatin pastes could be effectively controlled by altering the loading content of Sim in the microspheres and (or) paste, delivery material quality and its concentration. In vitro/In vivo examinations of paste quality demonstrated that gelatin paste with neat Sim or microspheres loaded-Sim all can in slower controlled manner release the drug up to 14 weeks at least and effectively improve regeneration of alveolar bone in Rats,mandibles as judged by mandible length mearement,soft X ray and histologic analysis. For these pastes, time to start release drug and release rate are different, and effect of drug released from paste on repair and regeneration of alveolar bone defect is different, too. At a local lower concentration of Sim to inhibit resorption of primary bone and at a higher concentration of Sim to active formation, deposition and mineralization of bone matrix newly formed.
In conclusion, injectable gelatin paste loaded-Sim for sustained release containing neat Sim or PLGA microspheres loaded-Sim has been thoroughly investigated. Two types of paste can improve regeneration of alveolar bone, but effect on repair and regeneration of alveolar bone defect was dose or concentration of Sim in local tissue and release time dependent. Overall, gelatin paste loaded-Sim can be utilized to custom-prepare drug delivery systems meeting specific patient and tissue needs.
本研究拟选择可生物降解性聚合物PLGA、明胶作为载体制备载辛伐他汀缓释制剂,促进牙槽骨再生修复,减少用药次数、降低用药总量、降低乃至消除辛伐他汀的毒、副作用,提高生物利用度。
本研究首先制备了载辛伐他汀缓释微球体系(已获国家发明专利,专利号:ZL200810050306.2)。表征显示,微球为圆形、表面光滑、粒径及药物释放速率可通过制备环节来调控、在PBS中可缓释辛伐他汀。分别以辛伐他汀和载辛伐他汀微球为主要功能成分制备可注射性缓释辛伐他汀明胶软膏,体外质量检测,性能稳定,可缓释辛伐他汀;动物体内研究证实,两类缓释软膏均可促进牙槽骨再生修复。
本研究的创新点在于首次制备了PLGA载辛伐他汀缓释微球体系,并获国家发明专利;分别将载辛伐他汀微球和辛伐他汀药物与药用辅料复合制备可注射性缓释辛伐他汀软膏;体内、外的系列表征证实两类缓释软膏均具有生物相容性,可促进牙槽骨再生修复;本研究为难溶性药物的剂型选择及应用提供了新的可行性方案。
Alveolar bone repair or regeneration is a common and complicated clinical problem in orthopaedic surgery.Every year, millions of people are suffering from bone defects arising from trauma, tumor or bone diseases and of course several are dying due to insufficient of ideal bone substitute. There is a long history of using autogenic and allogenic bones in the treatment of bone defects. Even though autogenic bone performs better functions in terms of biocompatibility and other factors, it needs secondary surgery to procure donor bone from the patient’s own body. Allogenic bone bears risk of infections and immune responses, which may even intricate other health problems and thus affecting quality of life. As an alternative, synthetic biomaterials have been developed and clinically tested. However, some of those materials implanted into bone defects are often encapsulated by a fibrous tissue and do not adhere to bone due to lack of bioactivity, thus be isolated from the surrounding bone and remains as a foreign body.
Sustained release delivery of drugs via PLGA polymers as implants, microspheres, and nanoparticles has gained wide acceptance. Availability of a variety of PLGA polymers makes it easy for pharmaceutical scientists to custom-develop a sustained release formulation based on the disease state and the drug indicated. An ideal sustained release formulation should release the entrapped drugs in a slower and continuous manner over desired time periods. Drug release occurs from PLGA microspheres because of drug diffusion from both the intact and degrading microsphere matrix. However, the extent of drug release during each phase and time lag between the two phases could vary considerably among the PLGA polymers possibly because of differences in their lactide/glycolide ratios and molecular weights. PLGA polymers with different molecular weights and lactide/glycolide ratio had been studied for modifying drug release. PLGA is a biocompatible polymer and can degrad finally into CO2 and H2O in physiological envirenments.
Gelatin is a natural polymer that is derived from collagen, and is commonly used for pharmaceutical and medical applications due to its biodegradability,biocompatibility and relatively lower antigenicity in physiological envirenments. Gelatin contains a large number of glycine, proline and 4-hydroxyproline residues. These characteristics have contributed to gelatin's safety as a component in drug formulations or as a sealant for vascular prostheses. Due to its promising properties, safety and mainly to the possibility of polyion complexation, gelatin is been used in drug delivery for tissue engineering applications targeting several tissues. There are several commercially available gelatin based carriers for drug delivery that are being applied in tissue engineering applications. The properties of gelatin as a typical rigid-chain high molecular weight compound are in many issues analogous to those of rigid-chain synthetic polymers. Gelatin exhibits essentially the same common properties typical of polymeric substances. Thus, in a similar way to linear-chain synthetic polymers, in aqueous solutions gelatin macromolecules assume, at elevated temperatures, the conformation of a statistical coil. Under specific conditions, such as temperature, solvent or pH, gelatin macromolecules present sufficient flexibility to realize a variety of conformations. This makes it possible to vary also all the gelatin characteristics dependent on its molecular structure. Besides, gelatin shows a rather wide molecular weight distribution. Structural diversity of gelatin chain units determines the specific features of gelatin properties. Most synthetic polymers show no such features that are typical of most biopolymers, such as the presence of both acidic and basic functional groups in the gelatin macromolecules. Its easy processability and gelation properties, lead to gelatin be manufactured in a range of shapes including sponges and injectable hydrogels, but the most used carriers are gelatin microspheres which normally are incorporated in a second scaffold such as a hydrogel. The results from these systemic trials show the efficacy and safety of using gelatin based microparticles as carriers for tissue engineering applications.
Simvastatin (Sim), a member of the statin family of drugs known for primary and secondary prevention of cardiovascular disease that effectively reduce cholesterol by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and consequently improve morbidity and mortality. It also has been reported to stimulate bone formation and influence bone activity. Sim induces expression of bone morphogenetic protein 2(BMP-2) in osteoblast and human osteosarcoma cells. The incubation of cultured bone cells with statins enhanced the expression of BMP-2 gene expression. It has also been demonstrated that relatively low doses of Sim induce osteoblast differentiation and increase mineralization in osteoblastic cells. Statins exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. Statins are now recognized as atypical anti-inflammatory agents possessing a variety of immunomodulating effects in addition to their conventional lipid-lowering properties. A number of large studies with statins have noted greater reductions in levels of circulating C-reactive protein (CRP). Investigators demonstrated that Sim reduced inflammation and resorption of bone through suppressing of matrix metalloproteinase 9 (MMP-9) expressions and the inhibitory effect of Sim on the generation of osteoclast was dose and time dependent. Several recent studies indicate a beneficial effect of statins on bone quality as measured by a reduction in hip fracture risk and an increase in hip bone mineral density. Sim has been shown in experimental models to stimulate bone acting growth factors and enhance bone formation. It has been reported that pharmacological doses of statins such as Sim stimulated in vivo bone formation in rodents and increased new bone volume in calvarial cultures in vitro. Some researchers demonstrated that Sim improved fracture healing in mice as judged by histologic and biomechanical analysis. Anothers found that Sim significantly increased serum levels of osteocalcin (OC) but not of bone alkaline phosphatase (ALP). Thus, in the study to improve repair and regeneration of alveolar bone utilizing Sim as a functional drug.
The aim of this project is to study about injectable gelatin paste for sustained release of Sim manufactured from microspheres loaded-Sim or neat Sim powder with helpful materials for drug, respectively, and then utilize it for repair and regeneration of alveolar bone defect after systemic examinations of pastes quality. The paste could be injected through a 7-gauge soft needle. Microspheres system is prepared from bioresobable composite materials PLGA using a modified oil-in-water emulsion system, and this preparation technology of systemic microspheres in various size ranges is our state invention patent (No:ZL200810050306.2). An initial phase (phase I) consists of drug release from microspheres because of diffusion from surface bound and poorly encapsulated drug. A relatively slower releasing second phase (phase II) is generally attributed to binding of drug molecules to the polymer in case of peptides. Rapid drug release during the third phase is commonly attributed to the faster drug diffusion from the eroding matrix. All three phases are usually not evident for lipophilic drugs, as these molecules can diffuse efficiently across the intact polymer resulting in the loss of phase II. Sim is a hydrophobic molecule and its release manner is not evident three phases. Release-modifying agents such as ethylene glycols, Spans and Tweens have been incorporated into microspheres to induce constant release of drug.
Drug-release of microspheres and paste studies have been performed, and data were fitted to better understanding of various mechanisms involved in Sim release from PLGA microspheres in a controlled and sustained manner and gelatin paste over extended periods of time.The two types of gelatin paste loaded-Sim for sustained release were prepared by mixing neat Sim or PLGA microspheres loaded-Sim with gelatin, glycerin, EDTA and water for injection, respectively, in 37℃bath. In vitro physiological stability of pastes was performed in phosphate buffered saline under physiological condition. Their quality is stable for 5 weeks at least. The release rate of Sim from gelatin pastes could be effectively controlled by altering the loading content of Sim in the microspheres and (or) paste, delivery material quality and its concentration. In vitro/In vivo examinations of paste quality demonstrated that gelatin paste with neat Sim or microspheres loaded-Sim all can in slower controlled manner release the drug up to 14 weeks at least and effectively improve regeneration of alveolar bone in Rats,mandibles as judged by mandible length mearement,soft X ray and histologic analysis. For these pastes, time to start release drug and release rate are different, and effect of drug released from paste on repair and regeneration of alveolar bone defect is different, too. At a local lower concentration of Sim to inhibit resorption of primary bone and at a higher concentration of Sim to active formation, deposition and mineralization of bone matrix newly formed.
In conclusion, injectable gelatin paste loaded-Sim for sustained release containing neat Sim or PLGA microspheres loaded-Sim has been thoroughly investigated. Two types of paste can improve regeneration of alveolar bone, but effect on repair and regeneration of alveolar bone defect was dose or concentration of Sim in local tissue and release time dependent. Overall, gelatin paste loaded-Sim can be utilized to custom-prepare drug delivery systems meeting specific patient and tissue needs.
引文
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