201200471 四、指定代表圖： ㈠本案指定代表圖為：第（5 )圖。 (二)本代表圖之元件符號簡單說明： 圖5.顯示氟化_灰石複合不囉件製 譜儀檢測結果，分別具備(a) 0H和0H.F氫鍵；或㈤ΛΗ、轉換紅外光201200471 IV. Designated representative map: (1) The representative representative of the case is: (5). (2) A brief description of the symbol of the representative figure: Figure 5. shows the results of the spectrometer detection of the fluorinated ash-stone composite, with (a) 0H and 0H.F hydrogen bonds, respectively; or (5) ΛΗ, converted infrared light
oh" " ：：· ^5 ^ ^ C 五、本綠有化學鱗’請齡最能齡發明槪的化 氟化經碟灰石複合物由於敗化程度的不同形成不同的氣化工^ 合物，ε^(ρ〇4)6(〇υ (X氟化程度，x =1 〇氣碟灰石，χ= 石，〇<χ<1敦化氫氧鱗灰石）。 嶙次 六、發明說明： 【發明所屬之技術領域】 本發明涉及一種氟化羥磷灰石複合物製備及其用途，特別是涉及幾種 同時具備不同官能基團的活化氟化經填灰石複合物製備及其用途。 【先前技術】 一般習知氟化羥磷灰石複合物的製備方法可以歸納爲兩種途徑：一、直 接合成法，是指合成填灰石時直接將氟離子引入從而形成氟化經填灰石複 合物的方法。典型代表爲固相反應法、熱分解法、共沈澱法、熱合成法和 溶膠-凝膠法;二、分步置換法’是指合成磷灰石時不直接將氟離子引入， 而是在形成羥磷灰石後將氟離子引入取代羥基而形成氟化羥磷灰石複合物 的方法(L.M. Rodriguez-Lorenzo，etal. 4; 3777-3785，2003.)。 在先前技術中所提供作爲製備氟化羥磷灰石複合物的方法，需經由多 *. ·*-* 種化合物水溶液製備而成。在TW 253936號專利案揭示一種氟磷灰石的簡 便製備方法，該製備方法無法製備同時具有羥基與羥基氟離子氫鍵或同時 具有羥基與不同羥基氟離子氫鍵等各種不同官能基團表現者。因此，本發 明的目的係在提供一種同時具有羥基與羥基氟離子氫鍵或同時具有羥基與 201200471 不同細基氣離子氫鍵等各種不同官能基團表現，且具生物活性的氣化經碟 灰石複合物者。 【發明内容】 本發明的目的，是提供一種具有生物相容性的氟化羥磷灰石複合物。 複σ物在傅立葉轉換紅外線光譜儀檢測下同時具有經基團與經基氟離子氫 鍵或同時具有羥基與不同羥基氟離子氫鍵特徵的各種氟化羥磷灰石複合 物。 先前技術作爲製備氟化羥磷灰石複合物的方法，需經由多種化合物水 / 谷液製備或無法製備在傅立葉轉換紅外線光譜儀檢測下同時具有經基與經 • 基氟離子氫鍵或同時具有羥基與不同羥基氟離子氫鍵等各種不同官能基表 現者。 本發明的目的係透過改變煆燒溫度、時間與改變氟化鈣、羥磷灰石混 合比例的條件下製造具生物活性的氟化羥磷灰石複合物。本發明之氟化羥 磷灰石複合物或其與其他化合物之組成物適用做爲生物醫學材料，其可以 促進骨細胞之再生與修復。又，本發明之組成物可進一步包含有一種或多 種骨再生與修復的醫藥組成物’以使該醫藥組成物被植入動物體内進一步 有助於體内骨組織再生與修復。 本發明具有如下特點： • L不同比例的氟化鈣與羥磷灰石，未藉助其他需進一步工藝程序排除 的化合物水溶液下’所燒結形成的氟化經填灰石複合物，在不同的製備條 件下展現不同分子特性。 2. 藉助氟化鈣和其與羥磷灰石反應產物氫氧化鈣爲共晶易熔物，使得 燒結氟化羥磷灰石複合物所需的溫度遠低於羥磷灰石本身燒结所需的溫 度》 3, 當氟化辑的力口入< 1 wt%，燒结後氟化羥磷灰石複合物於小角度(3〇〇) 繞射峰的X光晶體繞射分析觀察到主要羥填灰石晶相與較少的氟化羥磷灰 石的結晶相’伴隨傅立葉轉換紅外光譜檢測下的0H基團與0H.F氫鍵波峰。 4·當氟化鈣的加入=1的％，燒結後羥磷灰石複合物於小角度(300)繞 射峰的X光晶體繞射分析^ι察到主要經填灰石晶相與較少的氟化羥磷灰石 201200471 的結晶相，伴隨傅立葉轉換红外光譜檢測下的OH基團，OH. F氫鍵與〇H. F. HO 氫鍵波峰。 5. 當氟化鈣的加入=5 wt%，燒結後羥磷灰石複合物於小角度(300)繞 射峰的X光晶體繞射分析觀察到主要氟化羥磷灰石晶相，伴隨傅立葉轉換紅 外光譜檢測下的OH. F氫鍵與OH. F. H0氫鍵波峰。 6. 當氟化鈣的加入2 25 wt% ’燒結後羥磷灰石複合物於小角度(3〇〇)繞 射峰的X光晶體繞射分析觀察到主要氟化鈣晶相、次要氟化羥碟灰石與氟填 灰石晶相，伴隨傅立葉轉換紅外光譜檢測下的0H.F氫鍵與0H.F.H0氫鍵波 峰。 7. 骨細胞(hFOB 1.19)於不同分子特性的氟化經碟灰石複合物培養下， φ 在骨形態蛋白的表現不同。傅立葉轉換紅外光譜檢測下同時具備〇H基團， 0H.F氫鍵分子特性的氟化羥磷灰石複合物，具備骨誘導之能力。 【實施方式】 將不同重量百分比的氟化約（重量百分比2 50 wt%)與經璃灰石（重量 百分比2 50 wt%)在去離子水下’滚球滾動混合二十四小時。混合後取出 乾燥，將乾燥後的混合物在不同攝氏溫度、時間下煆燒。將瑕燒後的混合 物’以球研磨器研磨成粉狀後再乾燥。燒結後所得氟化羥磷灰石複合物具 備氟化羥磷灰石晶相。傅立葉轉換紅外線光譜儀檢測下，分別可獲得同時 φ 具有羥基團（0H)與羥基氟離子氫鍵(0H.F)或同時具有羥基團（〇H)與不同經 基氟離子氫鍵(0H.F，OH. F.H0)等各種不同官能基表現者，上述具生物活性 的複合物在造骨細胞(hFOB 1· 19)培養實驗下顯示具有良好的生物相容性。 【圖式簡單說明】 圖1.顯示氟化羥磷灰石複合生醫材料密度測試。 圖2.顧不不同溫度下氟化#5與經鱗灰石燒結所得氟化經璃灰石複备物在傳 統X光晶體繞射(20-65°)分析的結果。 圖3·顯示氟化羥磷灰石複合物在傳統X光晶體繞射（1〇_8〇。)分析的結果。氟 化鈣在未燒結氟化羥磷灰石複合物的重量百分比分別為：（A)〇 〇 1(B) 〇·〇5,（C) 1，(D) 5, (E) 25,（F) 50,（G)0. 201200471 圖4.顯不氣化_灰石複合物小角度繞射(32· 5_33. 5。)的χ射線(獨繞射 分析’顯示具備氟化輔灰石晶相。t*化飼在未燒結氣化鋪灰石複 2的重量百分比分別為：⑷ 〇.〇1，(B) 0.G5,（C) 1，(D) 5, (E) 25, (F) 50, 圖5.員不傅立葉轉換紅外線光譜儀檢測結果顯示，氣化賴灰石複合物於 不同條件製備下’分別具備(a) 〇H和〇〇氫鍵；或⑹〇H，〇〇 和0H.F.H0氯鍵；或（c) OH F^〇H F H〇氫鍵，各種不同官能基團表 現者°氟化#5在未燒結氟她做石複合物的重量百姐分別為：（A) 〇.〇1，(B) 0.05,（C) 1，(D) 5, (E) 25, (F) 50, (G)0. (*，0H鍵；+，OH. F 鍵. #，〇H. F· H0 鍵） ’ 圖6·月細胞(hFOB 1.19)在不同分子特性的氣化經填灰石複合物試片與同一 種培養液培養下’骨形祕自呈現不同表現。氟簡在未燒結氣化經 磷灰石複合物的重量百分比分別為：（A)〇〇1，⑻〇〇5，(c)1(d 25, (F) 50,⑹〇. ’ 【主要元件符號說明】Oh"" ::· ^5 ^ ^ C V. This green has chemical scales. The fluorinated disc-grey stone composites of the age-old inventions are different in terms of the degree of disintegration. ε^(ρ〇4)6(〇υ (X degree of fluorination, x =1 〇 碟 碟 χ χ χ χ 石 石 石 石 石 石 石 χ χ 1 1 1 1 1 1 1 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 敦 氢 氢 氢[Description of the Invention] [Technical Field] The present invention relates to the preparation of a fluorinated hydroxyapatite composite and its use, in particular to the preparation of activated fluorinated ore-filled composites having simultaneously different functional groups [Previous technique] Generally, the preparation method of the fluorinated hydroxyapatite composite can be summarized into two ways: First, the direct synthesis method refers to direct introduction of fluoride ions into the fluoridation when forming the ash-filled stone. The method of filling the stone composite. The typical representative is solid phase reaction method, thermal decomposition method, coprecipitation method, thermal synthesis method and sol-gel method; second, step replacement method refers to the synthesis of apatite Introducing fluoride ions directly, but introducing fluorine ions into the substituted hydroxyl groups after forming hydroxyapatite Method for forming a fluorinated hydroxyapatite composite (LM Rodriguez-Lorenzo, et al. 4; 3777-3785, 2003.) The method provided in the prior art for preparing a fluorinated hydroxyapatite composite is via A method for preparing a fluoroapatite is disclosed in the TW 253936 patent. The preparation method cannot simultaneously prepare a hydrogen bond with a hydroxyl group and a hydroxyl fluoride ion or a hydroxyl group at the same time. Different kinds of different functional groups such as different hydroxyl fluoride hydrogen bonds are expressed. Therefore, the object of the present invention is to provide a hydrogen bond having a hydroxyl group and a hydroxyl fluoride ion or a hydroxyl group at the same time and a hydrogen ion bond of a different fine group at 201200471. A functional group exhibits a biologically active gasified discite composition. SUMMARY OF THE INVENTION It is an object of the present invention to provide a biocompatible fluorinated hydroxyapatite composite. Under the detection of Fourier transform infrared spectrometer, there are various kinds of fluorinated hydroxyphosphorus which are characterized by a hydrogen bond between a group and a radical fluoride ion or a hydrogen bond with a hydroxyl group and a different hydroxyl group. Stone composite. The prior art as a method for preparing a fluorinated hydroxyapatite composite needs to be prepared by a plurality of compounds of water/gluten solution or cannot be prepared by a Fourier transform infrared spectrometer with both a base group and a radical ion bond. Or at the same time having various functional groups such as hydroxyl groups and different hydroxyl fluoride hydrogen bonds. The object of the present invention is to produce biological activity by changing the temperature and time of calcination and changing the mixing ratio of calcium fluoride and hydroxyapatite. Fluorinated hydroxyapatite composite. The fluorinated hydroxyapatite composite of the present invention or a composition thereof and other compounds are suitable as biomedical materials, which can promote regeneration and repair of bone cells. The composition may further comprise one or more medicinal compositions for bone regeneration and repair 'to enable the medicinal composition to be implanted into the animal to further aid in the regeneration and repair of bone tissue in the body. The invention has the following characteristics: • L different proportions of calcium fluoride and hydroxyapatite, which are formed by different aqueous solutions of the fluorinated ore formed by the aqueous solution of the compound which is excluded by further process procedures. Different molecular properties are exhibited under conditions. 2. By using calcium fluoride and its hydroxyapatite reaction product calcium hydroxide as a eutectic fusible, the temperature required for sintering the fluorinated hydroxyapatite composite is much lower than that of hydroxyapatite itself. The required temperature" 3, when the fluorination of the force into the < 1 wt%, after sintering, the fluorinated hydroxyapatite composite at a small angle (3 〇〇) diffraction peak X-ray crystal diffraction analysis The crystal phase of the main hydroxyapatite crystal phase with less fluorinated hydroxyapatite is accompanied by the HF group and the 0H.F hydrogen bond peak detected by Fourier transform infrared spectroscopy. 4. When the addition of calcium fluoride is =1%, the X-ray crystal diffraction analysis of the hydroxyapatite composite after sintering at a small angle (300) diffraction peak is observed by the main intercalated crystal phase and The crystalline phase of less fluorinated hydroxyapatite 201200471, accompanied by Fourier transform infrared spectroscopy detection of OH groups, OH. F hydrogen bonds and 〇HF HO hydrogen bond peaks. 5. When the addition of calcium fluoride = 5 wt%, the main fluorinated hydroxyapatite crystal phase is observed by the X-ray crystal diffraction analysis of the hydroxyapatite composite at a small angle (300). OH. F hydrogen bond and OH. F. H0 hydrogen bond peak under Fourier transform infrared spectroscopy. 6. When calcium fluoride is added to 2 25 wt% 'sintered hydroxyapatite composites at a small angle (3 〇〇) diffraction peak X-ray crystal diffraction analysis observed the main calcium fluoride crystal phase, secondary Fluorinated hydroxyapatite and fluorine-filled naphtha crystal phase, accompanied by Fourier transform infrared spectroscopy detection of 0H.F hydrogen bond and 0H.F.H0 hydrogen bond peak. 7. Bone cells (hFOB 1.19) are different in the expression of bone morphogenetic proteins under the fluorination of different molecular properties by the disc ash-stone complex. The fluorinated hydroxyapatite composite with 〇H group and 0H.F hydrogen bond molecular characteristics under the Fourier transform infrared spectroscopy has the ability of osteoinduction. [Embodiment] Different weight percentages of fluorination (weight 2 50 wt%) were mixed with pulverite (weight 2 50 wt%) under deionized water's balls for twenty-four hours. After mixing, it was taken out and dried, and the dried mixture was calcined at different temperatures and temperatures. The mixture after the simmering was ground into a powder by a ball mill and then dried. The fluorinated hydroxyapatite composite obtained after sintering has a fluorinated hydroxyapatite crystal phase. Under the detection of Fourier transform infrared spectrometer, it can be obtained that φ has hydroxyl group (0H) and hydroxyl fluoride hydrogen bond (0H.F) or both hydroxyl group (〇H) and different radical fluoride ion hydrogen bond (0H.F , OH. F. H0) and other different functional groups, the above bioactive complex showed good biocompatibility under osteoblast (hFOB 1 · 19) culture experiments. [Simple description of the diagram] Figure 1. shows the density test of fluorinated hydroxyapatite composite biomedical materials. Figure 2. Results of analysis of conventional X-ray crystal diffraction (20-65°) of fluorinated glaze-recycled fluorinated #5 and titaned sinter. Figure 3 shows the results of analysis of a fluorinated hydroxyapatite composite in a conventional X-ray crystal diffraction (1 〇 _8 〇.). The weight percentages of calcium fluoride in the unsintered fluorinated hydroxyapatite composite are: (A) 〇〇 1 (B) 〇 · 〇 5, (C) 1, (D) 5, (E) 25, ( F) 50,(G)0. 201200471 Figure 4. Xenon ray (double diffraction analysis) showing fluorinated auxiliary limestone with small angle diffraction (32·5_33. 5) The crystal phase. The weight percentage of t* feed in the unsintered gasified limestone complex 2 is: (4) 〇.〇1, (B) 0.G5, (C) 1, (D) 5, (E) 25 , (F) 50, Figure 5. The results of the non-Fourier transform infrared spectrometer show that the gasified limestone composites have (a) 〇H and 〇〇 hydrogen bonds respectively under different conditions; or (6) 〇H, 〇〇 and 0H.F.H0 chlorine bond; or (c) OH F^〇HFH〇 hydrogen bond, various functional groups expressed by ° °#5 in the unsintered fluorine she made stone compound weight It is: (A) 〇.〇1, (B) 0.05, (C) 1, (D) 5, (E) 25, (F) 50, (G)0. (*, 0H bond; +, OH. F key. #,〇H. F· H0 key) ' Figure 6. Moon cells (hFOB 1.19) in the gasification of different molecular properties through the ascites composite test piece and the same culture medium culture The performance is different. The weight percentage of fluorine in the unsintered gasified apatite composite is: (A) 〇〇 1, (8) 〇〇 5, (c) 1 (d 25, (F) 50, (6) 〇 . ' [Main component symbol description]