201200172 四、 指定代表圖： (一) 本案指定代表圖為：第（2 )圖。 (二) 本代表圖之元件符號簡單說明： 圖5.顯示氟化羥磷灰石複合物於不同條件製備下，傅立葉轉換紅外光 譜儀檢測結果，分別具備(a) 0H和0H.F氫鍵；或（b) 〇H，〇H.F和 0H.F.H0氩鍵’各種不同官能基表現者。（*，〇11鍵；+，〇H F鍵.# 〇Η ρ H〇 鍵） ’ ’ · · 五、 本案若有化學式時，請揭示最能顯示發明特徵的化學式： 氧化經碟灰石複合物由於氟化程度的不同形成不同的氟化羥磷灰石複 着合物，CaieCPOiXOHVdzx (X氟化程度，x =1. 〇氟填灰石，χ=〇經礎灰 石，〇〈χ<1氟化氮氧碌灰石）。 六、 發明說明： 【發明所屬之技術領域】 本發明涉及一種活化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構灰石複合物製備及其用途。 【先前技術】 在先前技術中所提供作爲製備氟化羥碟灰石複合物的方法，需經由多 _ 種化合物水溶液製備而成(L.M. Rodriguez-Lorenzo, etal. 4; 3777-3785, 2003·)。在TW 253936號專利案揭示一種氟填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經 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 一種氟化羥磷灰石複合物經傅立葉轉換红外線光譜儀檢測同時具有羥基團 (OH)與經基氟離子氫鐽(OH.F)或同時具有經基團(OH)與不同經基氟離子氩 鍵(OH.F和OH.F.HO)等各種不同官能基表現，且具有提昇人類造骨細胞生 物活性作闬之氱化經填灰石複合物，其製備方法及包含這些複合物之醫藥 組成。 【發明内容】 201200172 本發明的目的’是提供一種具有生物相容性、骨傳導性外更具有骨誘導性 的氟化羥構灰石複合物。上述複合物在傅立葉轉換紅外線光譜儀檢測下同 時具有羥基團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 溶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羥基與經 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。 本發明係關於某些新穎的氟化羥磷灰石複合物，其製備方法及包含這 些複合物之醫藥組成物及此類複合物與組成物的醫藥用途。我們進一步從 鲁TW 253936號專利案發現一種新穎的複合物，其對於哺乳類的造骨細胞特別 是人類的造骨細胞’可選擇性的提昇其骨誘導性(osteoinducti〇r〇。 製造具骨誘導性的氟化羥碟灰石複合物。本發明之氟化經碟灰石複合 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： 1. 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 φ的化合物水溶液下，所燒結形成的氟化羥磷灰石複合物，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經麟灰石本身燒结所需的溫 度。 3. 當氟化鈣的加入< 1 wt% ’燒結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磷灰石晶相與較少的氟化經填灰 石的結晶相’伴隨傅立葉轉換紅外光譜檢測下的0H基團與〇H F氫鍵波峰。 4. 當氟化鈣的加入=1 wt%，燒結後經鱗灰石複合物於小角度(3〇〇)繞 射聲的X光晶體繞射分析觀察到主要輕破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〇{1基圏，〇H F氩鍵舆〇H F H〇 201200172 說鍵波锋。 5. 當氟化妈的加入=5 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羥磷灰石晶相，伴隨傅立葉轉換紅 外光譜檢測下的〇H. F氫鍵與OH. F. H0氫鍵波峰。 6. 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， 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好（重量百分比^ 5 wt%)與羥磷灰石（重量 φ 百分比2 95 wt%)在去離子水下，滾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、時間下假燒。將煆燒後的混合 物，以球研磨器研磨成粉狀後再乾燥。燒結後所得氟化經碟灰石複合物具 備氟化羥鱗灰石晶相。傅立葉轉換紅外線光譜儀檢測下，分別可獲得同時 具有經基團（01〇與經基氟離子氫鍵(〇H. F)或同時具有經基團（〇H)與不同經 基氟離子虱鍵(OH· F，0H_ 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骨誘導性。 【圖式簡單說明】 圖1.顯示氟化羥磷灰石複合物小角度繞射(32. 5-33. 5。)的X射線(300)繞射 分析’顯示具備氟化經填灰石晶相。氟化約在未燒結氟化經鱗灰石複 合物的重量百分比分別為：（A) 0.01，(B) 〇.〇5,（〇 1，(D)5, (E)0. 圖2.顯示傅立葉轉換紅外線光譜儀檢測結果顯示，氟化羥磷灰石複合物於 不同條件製備下，分別具備(a) 0H和0H.F氫鍵；或（b) 0H，0H.F 和OH. F. H0氫鍵等不同官能基團表現者。氟化角在未燒結氟化經碟灰 石複合物的重量百分比分別為：（A) 0.01，(B) 0.05,（C) 1, (D)5, (E)0.(木， 0H鍵；+，0H.F 鍵；#，0H.F.H0 鍵） 圖3.骨細胞(hFOB 1.19)在不同分子特性的氟化經填灰石複合物試片與同一 種培養液培養下，骨形態蛋白呈現不同表現。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) 0.01, (B) 0.05,（C)1,(D)5， 201200172 (E)〇. 【主要元件符號說明】201200172 IV. Designated representative map: (1) The representative representative of the case is: (2). (2) A brief description of the symbol of the representative figure: Figure 5. shows the results of Fourier transform infrared spectroscopy with the fluorinated hydroxyapatite composite prepared under different conditions, with (a) 0H and 0H.F hydrogen bonds, respectively; Or (b) 〇H, 〇HF and 0H.F.H0 argon bonds' various functional groups. (*, 〇11 key; +, 〇HF key. # 〇Η ρ H〇 key) ' ' · · V. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Oxidation via a disc stone complex Due to the different degree of fluorination, different fluorinated hydroxyapatite complexes were formed, CaieCPOiXOHVdzx (X degree of fluorination, x =1. 〇Fluorine filled with ash, χ=〇 by basis ash, 〇<χ<1 Fluorinated nitrogen oxide limestone). VI. Description of the Invention: [Technical Field] The present invention relates to the preparation and use of an activated fluorinated hydroxyapatite composite, in particular to an activated fluorinated structured limestone composite having simultaneously different functional groups. Preparation and use thereof. [Prior Art] The method for preparing a fluorinated hydroxy-washstone complex provided in the prior art is prepared by using an aqueous solution of a plurality of compounds (LM Rodriguez-Lorenzo, et al. 4; 3777-3785, 2003) . A simple preparation method of a fluorine-filled limestone is disclosed in the TW 253936 patent, which cannot produce a hydrogen functional bond having a hydroxyl group and a hydroxyl fluoride ion or a different functional group such as a hydroxyl group and a different hydronium ion bond. By. Accordingly, it is an object of the present invention to provide a fluorinated hydroxyapatite composite which is detected by a Fourier transform infrared spectrometer having both a hydroxyl group (OH) and a transfluoroindoline (OH.F) or a via group ( OH) is represented by various different functional groups such as different transatomic fluoride ion argon bonds (OH.F and OH.F.HO), and has an antimony-filled ore-filled composite which enhances the biological activity of human osteoblasts. Preparation methods and pharmaceutical compositions comprising these complexes. SUMMARY OF THE INVENTION 201200172 The object of the present invention is to provide a fluorinated hydroxy-ashstone composite having osteoinductivity in addition to biocompatibility and osteoconductivity. The above composites have various fluorinated hydroxyapatite composites having a hydroxyl group and a hydroxyl fluoride ion bond or a hydroxyl group and a different hydroxyl group hydrogen ion bond characteristic as detected by a Fourier transform infrared spectrometer. The prior art as a method for preparing a fluorinated hydroxyapatite composite needs to be prepared through an aqueous solution of a plurality of compounds or cannot be prepared by a Fourier transform infrared spectrometer to simultaneously have a hydrogen bond with a hydroxyl group and a transfluorinated ion or a hydroxyl group with a different hydroxyl fluoride ion. A variety of different functional groups such as hydrogen bonds. This invention relates to certain novel fluorinated hydroxyapatite composites, to processes for their preparation, to pharmaceutical compositions comprising such complexes, and to pharmaceutical uses of such complexes and compositions. Further, we have discovered a novel complex from the TW 253936 patent, which selectively enhances osteoinductivity (osteoinducti〇r〇) for mammalian osteoblasts, especially human osteoblasts. A fluorinated hydroxy-washstone composite. The fluorinated ore-ash 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 of the invention may further comprise one or more pharmaceutical compositions for bone regeneration and repair, such that the pharmaceutical composition is implanted into the animal body to further contribute to bone tissue regeneration and repair in vivo. The present invention has the following characteristics: 1. Different proportions of calcium fluoride and hydroxyapatite, the fluorinated hydroxyapatite composite formed by sintering without any other aqueous solution requiring further process to eliminate φ, exhibit different molecules under different preparation conditions. Characteristics>> 2. Calcium fluoride and its reaction with the hydroxyapatite reaction product calcium hydroxide as a eutectic fusible, required for sintering fluorinated hydroxyapatite composite The temperature is much lower than the temperature required for the sintering of the sulphate itself. 3. When the calcium fluoride is added < 1 wt% 'sintered fluorinated hydroxyapatite composite at a small angle (3 〇〇) diffraction The X-ray crystal diffraction analysis of the peak observed that the main hydroxyapatite crystal phase and the crystal phase of the less fluorinated ore-filled stone were accompanied by Fourier transform infrared spectroscopy to detect the 0H group and the 〇HF hydrogen bond peak. When the addition of calcium fluoride is =1 wt%, the main light-crushed crystal phase is observed by diffraction analysis of the X-ray crystal of the small-angle (3 〇〇) diffraction sound through the phenolite composite after sintering. The crystalline phase of fluorinated hydroxyapatite, accompanied by Fourier transform infrared spectroscopy, 〇{1 圏, 〇HF argon bond 舆〇HFH〇201200172 said bond wave front. 5. When fluorided parent added =5 wt The main fluorinated hydroxyapatite crystal phase was observed by X-ray crystal diffraction analysis of the hydroxyapatite composite after sintering at a small angle (3〇〇), accompanied by Fourier transform infrared spectroscopy. F hydrogen bond and OH. F. H0 hydrogen bond peak. 6. Bone cell (hFOB 1.19) in different molecular properties of fluorinated by discite complex, in bone The expression of the state protein is different. The fluorinated hydroxyapatite complex with the 〇H group and the 0H.F hydrogen bond molecular property under the Fourier transform infrared spectroscopy has the ability to induce bone. [Embodiment] Different weight percentages Good fluorination (% by weight ^ 5 wt%) and hydroxyapatite (weight φ percentage 2 95 wt%) under deionized water, rolling ball rolling for twenty-four hours. After mixing, take out the drying, after drying The mixture is simmered at different temperatures and times of Celsius. The simmered mixture is ground into a powder by a ball mill and then dried. The fluorinated fluorite-containing ash-stone composite obtained after sintering has a fluorinated hydroxyapatite crystal phase. Under the detection of Fourier transform infrared spectrometer, it is possible to obtain both a via group (01〇 and a transfluoro ion bond (〇H. F) or a via group (〇H) and a different radical via a fluoride ion). The various bioactive complexes, such as (OH·F, 0H_F. H0), showed good osteoinductivity under the culture experiment of osteoblasts (hFOB 1.19). [Simple diagram of the diagram] Figure 1. X-ray (300) diffraction analysis showing the fluorinated hydroxyapatite composite with small angle diffraction (32. 5-33. 5) Crystal phase. The weight percentages of fluorinated about the unsintered fluorinated titanite composite are: (A) 0.01, (B) 〇.〇5, (〇1, (D)5, (E)0. Figure 2. The results of the Fourier transform infrared spectrometer show that the fluorinated hydroxyapatite composite has (a) 0H and 0H.F hydrogen bonds under different conditions; or (b) 0H, 0H.F and OH. The different functional groups such as H0 hydrogen bond are represented. The weight percentage of the fluorinated angle in the unsintered fluorinated discite composition is: (A) 0.01, (B) 0.05, (C) 1, (D) 5 (E)0.(Wood, 0H key; +,0H.F key; #,0H.F.H0 key) Figure 3. Fluoride-filled ash-filled composite of bone cells (hFOB 1.19) with different molecular properties Bone morphological proteins showed different performances in the test piece and the same culture medium. The weight percentage of calcium fluoride in the unsintered fluorinated hydroxyapatite composite was: (A) 0.01, (B) 0.05, (C) 1, (D) 5, 201200172 (E) 〇. [Main component symbol description]