1299995 玖、發明說明： 【發明所屬之^技術領域】 發明領域 本發明關於一種呈固體狀物形式的組成物及其製造方 5法。特別地，本發明關於一種可供作為骨骼填充物之固體狀物 形式的組成物及其製法，該組成物具有含鈣化合物且位於該組 成物之至少一部分外表面當中所含有的含鈣化合物係呈水合 狀態。 【先前技術3 10 發明背景 在骨移植（bone graft)的臨床應用上，自體骨移植 (autograft)、同種異體骨移植(allograft)、異種骨移植(xen〇graft) 以及骨移植取代物質（bone graft substitute materials)，在骨外科 手術與整形外科上扮演著重要角色（Thoms W. Bauer，and 15 Georage F. Muschler， CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, No. 37lf pp.10^27) 〇 進行骨移植時，適合做為骨骼填充物的生物材料 (Bio-materials)有很多，例如，可以選用高分子材料、無機材料 以及複合材料等。以使用無機材料的硫酸鈣鹽為例，當該材料 20 被移植入需進行骨組織修復或再生治療之個體的骨骼内一段 時間之後可被生物體吸收代謝，故此類型的材料具有良好的生 物可相容性，且不會造成不良的發炎反應（Chih-Hong Chen et al·，J. Orthop Surg ROC 19:28-31，2002)。 另外，動物骨骼是主要的礦物質儲存處，含有大約包含99% 1299995 的體鈣(body calcium)以及88%的體磷(body phosphate)。無機的 骨基質（inorganic bone matrix)，主要是由平板狀或紡鐘狀的經 基磷灰石（Ca1(}(P04)6(0H)2)所構成。目前已知，將商業上開發 出來的含礙酸妈鹽骨移植材料（Fracture Grout; Norian， 5 Cupertini，California)注入於受損的動物骨骼内，可有助於受損 骨組織的再生（E. P. FRANKENBURG et al·，The Journal of Bone And Joint，80-A，Νο·8, ρρ· 1112-1123, Aug. 1998)。 一般習知製備骨絡填充物的方法，大抵是將用來做骨路填 充物之材料以適當的溶液(水或食鹽水)混合，進而形成具黏滯 10 性且呈糊膏狀的混合物。而後，再將該混合物注入需要治療的 動物體内。例如，US 5,281，265即揭示一種供用於骨科或是牙 科手術之綴補物，其係包含黏固成份（cementing components)、填充物（fillers)以及固化成份（setting components)，雖該綴補物之黏固成份可包含有硫酸鈣鹽，例如 15 無水硫酸鈣、硫酸鈣二水合物以及硫酸鈣半水合物，但該專利 案揭示，構成該綴補物之成份必須先行與水或食鹽水相混合以 形成膏狀物，而後才應用於骨科或是牙科手術中。 又，為了操作上的方便，習知亦有將含有嚷酸鈣鹽的骨骼 .....一 填充物製成錠劑的形式，以供以直接置入於需進行骨組織重建 20或是骨移植的動物體内。例如，Gabriele Pec〇ra等人即利用一 種商業上可取得之含有硫酸鈣鹽的醫藥級滅菌錠劑（u· s. Gypsum，Medical Division，Chicag0, min〇is )移植入大白鼠之 骨骼受測處，以了解骨骼受測處骨組織的再生情形。該篇文獻 也有揭示，所使用的鍵劑可藉由下述方式製得··將硫酸触滅 1299995 菌的食鹽水相混合後，再注入一直徑9 mm，高度2mm的鑄 模，繼之被滅菌於一乾熱的烘箱中（325T，歷時9〇分鐘）。 在US 5,614,206與US 5,807,567皆揭示一種可供作為骨路 填充物的組合物，該組成物可以被製備成糊膏狀或是錠劑等形 气US 5,614,206係則疋將α -硫酸#5半水合物以及点_硫酸|弓 半水合物之粉末與食鹽水混合，因而得到一供骨移植用之呈糊 膏狀的混合物。 一般來說，在治療受損的骨骼或是接受骨移植治療過程 中，骨組織的再生時間很長，短則數天，長則可能需數星期之 1〇久，甚或在骨骼產生病變或是受傷嚴重時，則可能需要更久時 間才能使骨組織再生或使骨骼受傷處癒合。由於具有硫酸鈣的 這一類骨骼填充物會被吸收，有效地控制骨骼填充物中的硫酸 鈣溶解速率以持續地維持骨再生對於骨移植臨床應用是重要 的。 15 在1^ 6,030,636專利案中發展一種可做為骨骼填充物且具 有可控制溶解速率的錠劑，但該錠劑仍必須藉由將α _硫酸鈣半 水合物粉末（平均顆粒大小大約為12 μιη至75 μιη)或是冷_ 硫酸鈣半水合物粉末先行溶解於一含有水或是食鹽水的溶液 中，以形成一混合物，繼而藉由鑄模或是施加壓力之方式，使 20 該混合物形成一鍵劑。 在先前技術中所提供用作為骨骼填充物之組成物都是需 要事先與水或是-含水的溶液相混合，之後才進行錠劑之壓鍵 處理。以硫酸舞做為主要成份的骨絡填充物中，雖揭示所選用 的骨質填充物之材料可選用呈粉末狀物質，但當進行旋劑製備 7 1299995 時，適合使用的無機鹽、高分子材料或是其他添加物等，都是 要與適當的溶液(水或食鹽水）互相混合後，以先行形成具黏滯 14糊貧狀的混合物之後，再經由後續的壓錠處理或是鑄模處理 後，才能製備出可直接被用以骨移植使用的錠劑。 5 為了將水或是一含水的溶液在錠劑製造時之干擾因素降 至最低，巾請人經多方試驗與悉錢證㈣致本發明。本發明 所提供之體狀物形式的組成物以及其製備方法係適用 於骨絡填充物之製備。又，本發明方法不用在製旋前須事先必 須與水或是-含水的溶液相混合，而可利用乾燥混合處理直接 10製得該固體狀物形式的組成物。 L· 發明概要 因此，本發明之目的係在提供係一種生物可吸收且長效型 之為骨骼填充物及其製備方法。 15 本發明係提供-種呈固體狀物形式的組成物，其包含有— 具有下列組份之混合物： (a) 40%〜100%的硫酸鈣半水合物；以及 ⑼0〜祕之至少-種選自於下列群組中的含触合物^水 硫_、硫水合物、硫酸每二水合物、碳_、磷 姜弓化合物，以及此等之一組合；1299995 玖, INSTRUCTION DESCRIPTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a composition in the form of a solid and a method for producing the same. In particular, the present invention relates to a composition for use as a solid form of a bone filler having a calcium-containing compound and a calcium-containing compound contained in at least a portion of an outer surface of the composition. It is hydrated. [Prior Art 3 10 BACKGROUND OF THE INVENTION In the clinical application of bone graft, autograft, allograft, xen〇graft, and bone graft replacement substances (bone) Graft substitute materials) plays an important role in orthopedic surgery and orthopedic surgery (Thoms W. Bauer, and 15 Georage F. Muschler, CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, No. 37lf pp.10^27) There are many bio-materials suitable for bone filling, and for example, polymer materials, inorganic materials, and composite materials can be used. Taking a calcium sulfate salt using an inorganic material as an example, when the material 20 is transplanted into the bone of an individual in need of bone tissue repair or regeneration treatment, it can be absorbed and metabolized by the living body for a period of time, so that the material of this type has good biocompatibility. Compatibility and does not cause undesirable inflammatory reactions (Chih-Hong Chen et al., J. Orthop Surg ROC 19:28-31, 2002). In addition, animal bones are the main mineral deposits containing approximately 99% 1299995 of body calcium and 88% of body phosphate. The inorganic bone matrix is mainly composed of a plate-like or spin-shaped base-based apatite (Ca1(}(P04)6(0H)2). It is known to be commercially developed. The Fracture Grout (Norian, 5 Cupertini, California) is injected into the bones of damaged animals to aid in the regeneration of damaged bone tissue (EP FRANKENBURG et al., The Journal of Bone) And Joint, 80-A, Νο·8, ρρ· 1112-1123, Aug. 1998). It is generally known that the method of preparing the bone filling is generally to use a suitable solution for the material used for the bone filling. The water or saline is mixed to form a viscous, paste-like mixture which is then injected into the animal in need of treatment. For example, US 5,281,265 discloses one for orthopedics or Dental surgery patch, which includes cementing components, fillers, and setting components, although the adhesive component of the patch may contain calcium sulfate, such as 15 anhydrous Calcium sulfate, calcium sulfate dihydrate And calcium sulphate hemihydrate, but the patent discloses that the ingredients constituting the suffix must first be mixed with water or saline to form a paste, and then applied to orthopedics or dental surgery. For the convenience of operation, it is also known to have a bone containing calcium citrate salt in the form of a tablet for direct implantation in bone tissue reconstruction 20 or bone grafting. In vivo, for example, Gabriele Pec〇ra et al. used a commercially available pharmaceutical grade sterilized tablet containing calcium sulphate (u·s. Gypsum, Medical Division, Chicag0, min〇is) to transplant into large animals. The bones of the white rat are tested to understand the regeneration of the bone tissue at the bone. The literature also reveals that the key used can be obtained by the following method: · Touching sulfuric acid to the salt water phase of 1299999 After mixing, a mold having a diameter of 9 mm and a height of 2 mm is injected, and then sterilized in a dry heat oven (325 T, which lasts for 9 minutes). Both US Pat. No. 5,614,206 and US Pat. Composition, the The composition can be prepared into a paste or a tablet or the like. US 5,614,206 is a mixture of α-sulfate #5 hemihydrate and a point-sulfate|bow hemihydrate powder mixed with saline, thereby obtaining a supply. A paste-like mixture for bone grafting. In general, bone tissue regeneration takes a long time in the treatment of damaged bones or bone graft treatment. It can take several days, and it can take several weeks for a long time, or even a bone lesion. When the injury is severe, it may take longer to regenerate the bone tissue or heal the wound. Since this type of bone filler with calcium sulfate is absorbed, effectively controlling the dissolution rate of calcium sulfate in the bone filler to continuously maintain bone regeneration is important for clinical application of bone grafts. 15 In the 1^6,030,636 patent, a lozenge which can be used as a bone filler and has a controlled dissolution rate is developed, but the tablet must still have a powder of α-calcium sulfate hemihydrate (average particle size of about 12) Ιιη至75 μιη) or cold _ calcium sulphate hemihydrate powder is first dissolved in a solution containing water or brine to form a mixture, which is then formed by molding or applying pressure to form 20 A key agent. The composition used in the prior art as a bone filler is required to be mixed with water or an aqueous solution before the press of the tablet. In the bone filling with sulfuric acid as the main component, although the material of the bone filler selected for use may be selected as a powdery substance, when the preparation of the spinner is 7 1299995, the inorganic salt or polymer material suitable for use is used. Or other additives, etc., are mixed with a suitable solution (water or saline) to form a mixture with a viscous 14 paste, and then subjected to subsequent ingot treatment or mold treatment. Tablets that can be used directly for bone grafting can be prepared. 5 In order to minimize the interference factor of water or an aqueous solution in the manufacture of tablets, the person in charge of the invention is subjected to a multi-party test and a certificate (4). The composition in the form of a body provided by the present invention and a method for producing the same are suitable for the preparation of a bone filling. Further, the method of the present invention does not have to be previously mixed with water or an aqueous solution before spinning, and the composition in the form of the solid can be obtained by direct mixing treatment. L. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a bioabsorbable and long-acting type of bone filler and a method of preparing the same. 15 The present invention provides a composition in the form of a solid comprising - a mixture of the following components: (a) 40% to 100% calcium sulphate hemihydrate; and (9) 0 to at least one species a combination comprising: a hydrated sulfur _, a sulfur hydrate, a sulfuric acid per dihydrate, a carbon _, a phosphorus ginger compound, and a combination thereof;
其中該呈固體狀物形式的組成物的至少—部分外表面曾鱼 -水性溶液賴過，岐得㈣_狀細式的組成物的駐 少-部分外表面當中所含有的含_合物Mu L 本發明之組成物適用作為骨路填充劑，㈣以促料 20 1299995 之再生與修復。 本發明之組成物係適用做為長效型骨骼填充物，當其被置 入一需要做骨治療的動物體内，該組成物之溶解速率亦可受到 控制並且可以長效地發揮效用，而有助於持續地使骨細胞完全 再生。又，本發明之組成物可進一步包含有一種或多種助於骨 組織再生與修復的藥物，以使該藥物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。 另外，本發明係有關於一種用以製備一適用作為骨骼填充 物之呈固體狀物形式的組成物之方法，其包含下列步驟： (1)形成一包含有下列組份(a)與組份(b)的混合物： (a) 40%〜1〇〇%的硫酸鈣半水合物；以及 (b) 〇〜60%之至少一種選自於下列群組中的含鈣化合 物：無水硫酸鈣、硫酸鈣一水合物、硫酸鈣二水 合物、碳酸#5、填#5化合物，以及此等之一組合； (ϋ)將步驟⑴所形成的混合物壓製成一固體狀物，藉此而 形成一具有一外表面之被壓製的組成物； (出）令得自於步驟（ii)之被壓製的組成物之至少一部分的 外表面與-水性溶液接觸，藉此，該被塵製的組成物 之與該水性溶液接觸的該至少一部分的外表面當中所 含有的含#5化合物被水合；以及 (1V)將得自步驟(iii)的產物乾燥。 本發明之上述以及其他目的、特徵與優點在參照以下之詳 細說明與較佳實施例後會變為明顯可知。 圖式簡單說明 1299995 第1圖顯不依據本發明之具有無水硫酸舞，硫酸舞二水合 物奴目文妈以及硫自文舞一水合物之組成物在溶解測試實驗中隨 著時間改變之組成物殘餘重量； 第2圖顯不依據本發明之具有無水硫酸辦，硫酸舞半水合 物之組成物在溶解測試實驗中隨著時間改變之組成物殘餘重 量； 第3圖顯不依據本發明之具有無水硫酸鈣，硫酸鈣二水合 物、碳酸鈣，硫酸鈣二水合物與含磷鈣成分之玻璃體之組成物 在溶解測試實驗中隨著時間改變之組成物殘餘重量； 10 第4圖顯不依據本發明之具有無水硫酸鈣，硫酸鈣半水合 物、碳酸鈣，硫酸鈣二水合物以及羥基磷灰石之組成物在溶 解測试實驗中隨著時間改變之組成物殘餘重量； 第5圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣半水合 物、碳酸鈣，硫酸鈣二水合物以及一抗生素之組成物在溶解 15測試實驗中隨著時間改變之組成物殘餘重量； 第6圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣半水合 物、碳酸鈣’硫酸鈣二水合物以及抗生素之組成物在溶解測 試實驗中隨著時間改變之組成物殘餘重量； 第7圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣半水合 20物、碳酸鈣，硫酸鈣二水合物、生物可分解之聚合物以及抗 生素之組成物在溶解測試實驗中隨著時間改變之組成物殘餘 重量； 第8圖顯示依據本發明之具有硫酸鈣半水合物之組成物在 溶解測試實驗中隨著時間改變之組成物殘餘重量； 1299995 第9圖顯示適用做為骨骼填充物之依據本發明的組成物被 用於進行動物試驗四周後之組織學結果；以及 第圖顯示適用做為骨骼填充物之依據本發明的組成物 被用於進行動物試驗八週後之組織學結果。 5 【實施方式】 發明的詳細說明 本發明組成物中所使用的含鈣化合物，較佳地，係為一種 選自於下列群組··無水硫酸鈣、硫酸鈣一水合物、硫酸鈣二水 合物、碳酸鈣、含磷鈣化合物，以及此等之一組合。 10 本發明組成物所使用之含磷鈣化合物係可選自於一由下 列所構成之群組： 含磷鈣成分之玻璃體、含磷鈣成分之陶瓷體、羥基磷灰石 (hydroxylapatite)、氟礙灰石（fluorapatite)、含磷酸氫#5之玻璃 體、含填酸氫#5之陶竟體、罐酸三辦(tricalcium phosphate)、填 15 酸單約一水合物(monocalcium phosphate monohydrate)、無水填 酸二 #5 (dicalcium phosphate anhydrous)、鱗酸二 #5 二水合物 (dicalcium phosphate dihydrate)、磷酸八鈣（octacalcium phosphate)、α-填酸三姜弓(alpha-tricalcium phosphate)、石_填酸 三妈(beta-tricalcium phosphate)、含構酸鹽之玻璃體、含鱗酸鹽 20 之陶竟體、一氧鱗酸四#5(tetra-calcium phosphate monoxide)、 含磷化合物之玻璃體、含磷化合物之陶瓷體。 本發明之含磷鈣成分化合物較佳是為該等符合諸如 IS013485、ISO10993或與之同等規定之物質。在一較佳具體例 中，該磷鈣化合物係為羥基磷灰石。另一較佳具體例中，該磷 1299995 I弓化合物係為含填妈成分之玻璃體。 在一較佳的具體例中，本發明之呈固體狀物形式的組成物 包含100%的硫酸鈣半水合物。又，在另一較佳具體例中的該 組成物包含有50%的硫酸#5半水合物以及50%的無水硫酸I弓。 5 在一較佳的具體例中，本發明之呈固體狀物形式的組成物 包含有： (a) 50%的硫酸鈣半水合物；以及 (b) 20%的無水硫酸鈣、15%的硫酸鈣二水合物以及15%的 碳酸鈣。 10 在另一較佳的具體例中，本發明之呈固體狀物形式的組成 物包含有： (a) 40%的硫酸鈣半水合物；以及 (b) 20%的無水硫酸鈣、15%的硫酸鈣二水合物、15%的礙 酸#5以及10%的碌酸舞化合物。 15 本發明組成物更佳是包含有10%的含磷鈣成分之玻璃體或 10%的經基碟灰石。 又，本發明之呈固體狀物形式的組成物，係可被製造成雙 劑的形式或者丸粒的形式。 另外，本發明並提供一種用以製備上述之適用作為骨骼填 20充物之呈固體狀物形式的組成物之方法，其包含下列步驟： (1)形成一具有下列組份(a)與組份(b)的混合物： (a) 40%〜1〇〇%的硫酸鈣半水合物；以及 ⑻0〜60%之至少一種選自於下列群組中的含鈣化合 物：無水硫酸鈣、硫酸鈣一水合物、硫酸鈣二水 12 1299995 合物、碳酸鈣、磷鈣化合物，以及此等之一組合； (ii) 將步驟⑴所形成的混合物壓製成一固體狀物，藉此而 形成一具有一外表面之被壓製的組成物； (iii) 令得自於步驟(ii)之被壓製的組成物之至少一部分的外 5 表面與一水性溶液接觸，藉此，該被壓製的組成物之 與該水性溶液接觸的該至少一部分的外表面當中所含 有的含#5化合物被水合；以及 (iv) 將得自步驟(iii)的產物乾燥。 在本發明之製備方法中，被使用於形成步驟⑴中的組份(a) 10 與組份(b)二者本身是呈粉末的形式。較佳的是，該組份(a)與組 份(b)進行壓製步驟之前有先經研磨處理，較佳是經過乾式研磨 例如，經球磨處理，以獲得適當大小的粉末。 在本發明之製備方法中所述之壓製步驟(iii)，該被壓製的 組成物的至少一部分的外表面與該水性溶液之接觸，係藉由一 15 選自下列群組中的方式來進行：喷霧處理（spray)、蒸氣處理 (vaporing)、浸泡處理(dipping)，以及此等之一組合。 較佳的是，使用於步驟(iii)中的該水性溶液係為水，且該 被壓製的組成物之至少一部分的外表面係經由蒸氣處理與一 熱水蒸氣相接觸。如此可使得該被壓製的組成物之至少一部分 20 的外表面當中所含有的含鈣化合物與該水性溶液接觸而被水 合。 更佳的是，使用於步驟(iii)中的該水性溶液除了包含水之 外，還包含有一或多種添加劑，且該被壓製的組成物之至少一 部分的外表面係藉由在該水性溶液中之浸泡處理，而使得該水 13 1299995 至該被壓製的組成物之與該 性溶液内所含有的添加劑被附著 水性溶液接觸的外表面上。 在另一具體實施例中，該 於該被壓製的組成物之至少一 液内所含有的添加缝附著至該漏製的組絲之與該水性 該包含有添加劑之水性溶液被喷灑 一部分的外表面，俾使得該水性溶 溶液相接觸的外表面上。 又在一具體實施例中，該被壓製的組成物之至少一部分的 外表面係被浸泡於該包含有添加劑之水性溶液中，俾使得該水 f /合液内所3有的添加劑被附著至該被壓製的組成物之與該 10 水性溶液相接觸的外表面上。 本發明之添加劑係可為一種或多種選自於下列群中之物 質·抗生素、生物可分解之聚合物，以及此等之一組合。其中 該抗生素較佳是選自於下列群組中的抗生素：四環素氯化氫 (tetracycline hydrochloride)、萬古黴素(vancomycin)、頭孢菌素 15 (cePhal〇sporins)、奎諾抗生素（qUinolone)與胺基糖苔抗菌素 (aminoglycocides)、見大黴素(gentamycin)，以及此等之一組合。 該生物可分解的聚合物較佳係選自於下列群中：多羥族、聚乙 二醇酸（polyglycolic acid)、聚對二氧雜環己烷酮 (poly-paradioxanone)、曱基纖維素(methyl cellulose)、乙基纖 20 維素(ethyl cellulose)、經乙基纖維素(hydroxyethyl cellulose)， 以及此等之一組合。該生物可分解的聚合物係以甲基纖維素或 羥乙基纖維素為最佳。 又，本發明之添加劑亦可為習知可使用於骨治療或修復的 各種藥物或化學品，較佳是該等可符合藥典規範之藥物或化學 I299995 物ο 該方法中之乾燥步驟較佳是以風乾乾燥或者烘乾乾燥方 式進行。該烘乾乾燥較佳是在40°C下處理30分鐘。 在本發明中所使用之該含磷鈣成分之玻璃體係先經研磨 處理，較佳的是乾式研磨處理，例如，以球磨處理，而形成適 當大小之粉末，再進行該壓製步驟(ii)。 又，本發明組成物之含磷鈣成分之玻璃體係屬熟悉該項技 術所熟知。較佳的是，該含磷鈣成分之玻璃體是經由下列步驟 製得： (I) 將一磷酸鈣粉末混合以一磷酸溶液，以得到一混合溶 液； (II) 令該步驟(I)所得之混合溶液在一 lioot至1300〇c範圍 内之溫度進行溶融處理，俾以得到一磷舞溶融體； (III) 冷卻該步驟(Π)之該磷鈣熔融體，以得到該含碟辦成分 之玻璃體。 在一較佳具體例中，混合步驟(I)所得到之混合溶液可進— 步混合以一擇自由下列群組所構成之物質··矽、鈇、含欽化風 物、鋇、含鋇化學物、其他供以骨科植入物之物質以及此等之 —組合0 20 在一較佳具體例中，其中該熔融處理步驟(11)，係在 °c之溫度來對得自該步驟⑴之混合溶液進行該熔融處理。 將得自 以供用於其後所 之成型處理係 在一較佳具體例中，該冷卻步驟(III)進—步包含— 該步驟(II)之磷鈣熔融體降溫至7〇〇°c之步驟， 為之一成型處理。較佳地，所得到的碟I弓炫融體 15 1299995 藉由將該經冷卻之熔融體倒入一適當的模具中，以得到一具有 所欲形狀之含填鈣成份之玻璃體。較佳地，該具有所欲形狀之 含磷鈣成份之玻璃體係可直接做為一骨骼填充物(bone filler)或 骨科植入物，而可廣泛地應用於骨科。如此製得的含填舞成份 5 之玻璃體亦可以經適當的粉碎及/或研磨處理，並與其它成份 相組合，以供骨科技藝之應用。 在一較佳具體例中，該混合步驟(I)與融熔步驟(π)之間進一 步包含一將該混合溶液在400 C處理2小時而後在9〇〇。0處理4 小時之預處理步驟。 又，本發明的製備方法之接觸步驟(iii)係依所使用之不同 的水性溶液而採用不同的處理方式。因此，在一較佳具體例， 接觸步驟⑼係可利用喷霧處理(spray)、蒸氣處理(vap〇麵)以 及浸泡處理(dipping)，㈣得雜紐健觀製敝成物之 外表面相接觸。 15 20 此外，由本發明的組成物所製備出的錠劑在被移植入活體 動物之受測骨路時，鍵劑之溶解速率可以受到控制，並且可幫 助骨細胞的再纽及«的重建。所以可使人預_本發明的 、且成物所製備出錠劑，可以做為骨路填充物使用，並且會是一 細胞生長與幫助於受損骨路重建的良好藥物。又，鍵 =本身具有㈣龍雜、生射分躲錢 劑在活體内是可=且!發明的組成物所製得輯 ，，不_進行;：:::劑故當錠劑被置 16 1299995 再者，本發明組成物更可含有其它有助於骨再生與修復之 其它藥物，例如，抗生素或纖維素，所以當本發明之組成物被 植入動物體之骨組織時，外層的抗生素可與骨組織接觸，可先 將骨骼發炎或病變的部位予以治療。又，本發明的組成物中所 5 含有的物質可以幫助骨基質的形成。因此本發明的組成物可以 發揮治療骨骼發炎與骨病變以及幫助骨骼生長之雙重功效。 本發明將參照下面的實施例來作更詳細的說明，該等實施 例被提供是為達例示說明之目的，而不意欲用來限制本發明之 範圍。 10 較佳實施例之詳細說明 用於本發明中之對照組，是使用一商業上可得的骨骼填充 物製備套組(OSTEOSETBVFKit)，其係含有硫酸鈣半水合物， 5亥對照組之製備方法是依據該套組内所示步驟進行。 洛解速率測定方法 15 有關錠劑溶解速率的測定是依據US 6,030,636專利中關於 錠劑的溶解速率測定方法來進行測定。 實施例1 :製偁具有無水硫酸鈣，硫酸鈣半水合物、瓖酸鈣， 硫酸鈣二水合物之觝成物 製馕方法 20 取無水硫酸鈣1〇0 g，硫酸鈣半水合物250 g，碳酸鈣75 g，硫酸鈣二水合物75 g，所構成之總重為5〇〇g的粉末倒入球 磨機中’以對其進行研磨混合24小時。之後，使用一具有内 直徑為2cm之球形模具以及一壓錠機來對所形成的混合物進 行一壓錄:處理，俾得到做為實驗組使用的鍵劑，每一個錠劑工 17 1299995 的直徑大小約為2 cm χ 2 cm，且呈球型。 啟動蒸氣製造機（佳時達實業公司出品，型號p-l003),將 水（100 ml)經由注水口注入蒸氣製造機内，約μ至30分鐘後， 俾以產生水蒸氣。使該蒸氣製造機内部的蒸氣壓穩定地控制於 5 90°C，一大氣壓之條件。 將藉由壓錠處理而得到的那些做為實驗組使用之錠劑置 入一不銹鋼盤中，繼而將盛有錠劑的不銹鋼盤置入充滿水蒸氣 的蒸氣製造機的氣室中，以使錠劑的表面與水蒸氣相接觸，歷 0^*3分姜里。之後’取出不錄鋼盤’並將其置於4〇°c供箱中，進 10 行烘乾30分鐘。 溶解速率比較 取出由實施例1所製得之5個錠劑做為實驗組之測試樣 品，使用前述商業來源之錠劑（Osteo SetBVF Kit)做為對照組， 並依據前述之溶解速率測定方法來對實驗組與對照組分別進行 15錠劑溶解速率測定。分別紀錄實驗組與對照組所得到的平均結 果。 溶解速率測定的比較結果顯示於第1圖。如該圖所示，對 照組在31天左右，其殘餘重量已接近零。相較於對照組，本實 施例之組合物在37。(：水中被溶解的時間多出數天，且其殘餘重 20量直至約40天左右才接近零。 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，相較於對照組，本實施例之組成物提供骨組織更佳的 生長環境與時間。 實施例2 :製備具有無水硫酸鈣，硫酸鈣半水合物之組成物 18 1299995 本實施例除使用無水硫酸鈣250 g，硫酸轉二水合物25〇 g(總重為500g)做為製備錠劑的材料以外，是依照實施例1所述 方法之步驟來製備錠劑並進行溶解速率測試。 溶解速率測定的比較結果顯示於第2圖。如該圖所示，對 5照組在31天左右，其殘餘重量已接近零。相較於對照組，本實 施例之組合物在37°C水中被溶解的時間多出數天，且其殘餘重 量在直至約37天左右才接近零。 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，相較於對照組，本實施例之組成物提供骨組織更佳的 10生長環境與時間。 實施例3 :製儀具有無水硫酸鈣，硫酸鈣二水合物、碳酸每， 硫酸鈣二水合物舆含磷鈣成分玻璃Λ之組成物 製僑方法 含磷鈣成分玻璃體的製備 15 將嶙酸鈣粉末（50〇幻均勻混合以磷酸溶液(200 ml，85%， 產品編號100563，MERCK)，繼而將所形成的均勻混合液倒入 究掛麵内。接者，將盛有該均勻混合液的陶竟掛銷置入溫度 南達4〇〇 c之兩溫爐中’並在4〇〇。0下歷時2小時。接著，將 高溫爐的溫度提升至9〇(rc，並在9〇(rc下歷時4小時，再進 20 一步將高溫爐的溫度提升至1100°C度，並在該溫度歷時2小 時以使鱗酸#5呈一炼融態。 將壚溫降至700°C後，取出陶瓷坩鍋，並將陶瓷坩鍋内的 s液岣勻倒在一石墨板上。當溶融液冷卻，其係呈玻璃狀 . $溶融液溫度降至室溫，即獲得一含鱗#5成分之破璃 19 1299995 體。將所得到的玻璃體敲碎後並以球磨機研磨’以供下述步驟 使用。 取研磨過的含磷鈣成分之玻璃體50 g混合以由無水硫酸 鈣100 g、硫酸鈣半水合物200 g、碳酸鈣75 g與硫酸鈣二水 5 合物75 g所構成之總重為500g的粉末，並將之倒入球磨機 中，進行研磨混合24小時。再依照實施例1所述方法之步驟 製備錠劑並進行溶解速率測試。 溶解速率測定的比較結果顯示於第3圖。如該圖所示，對 照組在31天左右，其殘餘重量已接近零。相較於對照組，本實 10施例之組合物在37°C水中被溶解的時間多出數天，且其殘餘重 量約在34天以後維持在一個定值，這可能是因含填#5成分之玻 璃體殘留所致。 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，且相較於對照組本實施例之組成物提供骨組織更佳的 15生長環境與時間。 實施例4 :製僑具有無水硫酸鈣，硫酸鈣半水合物、碳酸鈣， 硫酸鈣二水合物以及羥基磷灰石之级成物 本實施例除使用無水硫酸鈣100 g、硫酸鈣半水合物200 g、碳酸鈣75 g，硫酸鈣二水合物250 g以及醫藥級羥基磷灰石 20 50 g(總重為5〇〇g)做為製備錠劑的材料外，是依照實施例1所 述方法之步驟來製備錠劑並進行溶解速率測試。 溶解速率測定的比較結果顯示於第4圖。如該圖所示，對 照組的錠劑在31天左右，其殘餘重量已接近零。相較於對照組， 本實施例之組成物在37t水中被溶解的時間多出數天且在約34 20 1299995 天左右，其殘餘重量達到一定值，此可能是因羥基磷灰石殘留 所致。 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，相較於對照組，本實施例之組成物提供骨組織更佳的 5生長環境與時間。 貧施例5 :製俤具有無水硫酸鈣，硫酸鈣半水合物、碳酸鈣、 硫酸鈣二水合物以及抗生素之组成物 本實施例是使用無水硫酸妈100 g、硫酸妈半水合物250 g、碳酸鈣75 g，硫酸鈣二水合物75 g(總重為500g)做為製備 1〇 鍵劑的材料並以下列的抗生素溶液取代水在利用下述條件進 行蒸氣處理與烘乾處理，其餘步驟皆是依照實施例1所述之步 驟來製備錠劑並進行溶解速率測試。 將1〇 g萬古黴素(Vancomycin)粉末溶解於90g水中，以用 於注入蒸氣製造機之注水口，並在蒸氣製造機運作約7分鐘 15 後’蒸氣製造機的器室即充滿含有抗生素混合於其内的水蒸 氣’並且將氣室的溫度控制於攝氏55度中。 將藉由壓錠處理所得到的那些做為實驗組使用之錠劑置 入一不銹鋼盤中，繼而將盛有錠劑的不銹鋼盤置入充滿含有抗 生素混合於其内的水蒸氣環境中，以使錠劑的表面與水蒸氣相 20 接觸，歷時3分鐘。之後，取出不銹鋼盤，並將其置於40°C烘 箱中’進行烘乾30分鐘。 溶解速率測定的比較結果顯示於第5圖。如該圖所示，對 照組在31天左右，其殘餘重量已接近零。相較於對照組，本實 施例之組合物在37°C水中被溶解的時間多出數天，且其殘餘重 21 1299995 量直至約40天左右才接近零。 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，且相較於對照組本實施例之組成物提供骨組織更佳的 生長環境與時間。 5 又’當本實施例之組成物被植入動物體之骨組織時，外層 的萬古黴素會先與骨組織接觸，所以可先將骨骼發炎或病變的 部位予以治療，一當發炎或病變情形獲得改善後，本實施例之 組成物的其他成分可再用以幫助骨骼生長，以發揮出治療骨發 炎或病變與幫助骨再生雙重功效。 10 實施例6 :製僙具有無水碴致角、硫酸好半水合物、碳酸角、 硫酸鈣二水合物以及抗生素之组成物 在本實施例中使用另一種種抗生素，以用於進行該蒸氣處 理。本實施例除了使用見大黴素(gentamicin) 5g取代實施例5中 所使用之萬古黴素之外，製備本實施例之錠劑及實施步驟皆與 15實施例5相同。 溶解速率測定的比較結果顯示於第6圖。如該圖所示，對 照組在31天左右，其殘餘重量已接近零。相較於對照組，本實 施例之組成物在37°C水中被溶解的時間多出數天，且其殘餘重 量直至約40天左右才接近零。 20 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間，且相較於對照組本實施例之組成物提供骨組織更佳的 生長環境與時間。 又，當本實施例之組成物被植入動物體之骨組織時，外層 的見大黴素會先與骨組織接觸，所以可先將骨骼發炎或病變的 22 1299995 部位予以治療，一當發炎或病變情形獲得改善後，本實施例之 組成物的其他成分可再用以幫助骨骼生長，以發揮出治療骨發 炎或病變與幫助骨再生雙重功效。 實施例7 ··製備具有無水硫酸鈣，硫酸鈣半水合物、碳酸鈣， 5 硫酸鈣二水合物、生物可分解之聚合物以及抗生素 之组成物 本實施例是以無水硫酸舞100 g、硫酸約半水合物250 g、碳酸鈣75 g，硫酸鈣二水合物75 g(總重為500g)做為製備 錠劑的材料，並以下列的具有生物可分解之聚合物以及抗生素 10的溶液來取代實施例1所使用的水，並以下述的浸泡處理取代 以該蒸氣處理。在本實施例中，其餘步驟皆是依照實施例i所 述之步驟來製備錠劑並進行溶解速率測試。 本實施例之具有該生物可分解之聚合物與該抗生素的水 性溶液是以下列方法製得。 15 將甲基纖維素(5 g)、羥乙基纖維素(5g )以及水（100g)相混 合，並加熱所形成的混合溶液，攪拌至沸騰。待混合溶液冷卻 至約4〇<：時’將萬古黴素（10 g)以及見大黴素(5 g)粉末添加至 該混合溶液中並將抗生素溶解於其中來得到該水性溶液。 將將前述所製得之錠劑浸泡於含有該生物可分解之聚合 20物與該抗生素的水性溶液巾10分鐘。之後，取出經過浸泡的 錠劑，並將其置於4〇°C烘箱中，進行烘乾30分鐘來對錠劑進 行乾燥處理’俾得到一種外表面附著有可分解的聚合物與抗生 素之錠劑。 /谷解速率測定的比較結果顯示於第7圖 。如該圖所示，對 23 1299995 照組在31天左右’其殘餘重夏已接近零。相較於對日夸組，本實 施例之組成物在37°C水中被溶解的時間多出數天，且其殘餘重 量直至約40天左右才接近零。 由此可推之，本實施例之組合物在動物體内有較長的被溶 5 解時間。當本實施例之組合物植入動物體之受測骨組織時，甲 基纖維素與羥乙基纖維素及水的組成物可有效的控制萬古徽 素與見大黴素的藥理作用時間，且附著於組成物外層的見大徽 素會先與骨組織接觸，所以可先將骨骼發炎或病變的部位予以 治療，一當發炎或病變情形獲得妥善治療與改善後，本實施例 10 之組成物的其他成分可再用以幫助骨骼生長，以發揮出骨發炎 或病變之治療與骨再生雙重功效。 實施例8 :製偁具有碴酸鈣半水合物之艇成物 本實施例除了使用硫酸鈣半水合物200 g做為製備錠劑的 材料以及是以50 ml之生理食鹽水進行溶劑速率測定外，其它是 I5依照實施例1所述方法之步驟來製備錠劑並進行溶解速率測定。 溶解速率測定的比較結果顯示於第8圖。如該圖所示，對 照組的錠劑在15天左右，其殘餘重量已接近零。相較於對照組 本實施例之組成物在37°C水中被溶解的時間多出數天，且其殘 餘重量直至約20天左右才接近零。 20 由此可推之，本實施例之組合物在動物體内有較長的被溶 解時間。再者，本實施例與對照組二者雖皆含有硫酸鈣半水合 物，但由於存在於由本發明組成物所至得的錠劑之外表面上的 含鈣化合物係預先經水合作用，因而本實施例之組成物的溶解 時間較對照組為長。 24 1299995 動物試驗 _發鳶勿··年齡約6個月大之雄性紐西蘭大白兔(2.3公斤-2.6公 斤重），測試數量5隻。 屬韓之翁齋··依據實施例1之組成比例，製備錠劑。錠劑（直徑 5 3 mm X厚度2mm)置入褐色玻璃瓶後，予以珈瑪 射線（r-ray)滅菌後，以用於進行動物試驗。 +術流程： 所有試驗動物係被挑選過，以確保他們是在健全的生理狀 況下。將若夢2% (Rompun solution，拜耳製藥廠）以容積比1 ·· 10 1的比例與Ketalar injection 50 mg/ml (永信製藥廠)混合，因此 而得的混合液被用於手術麻醉。以5毫升混合液之劑量予以肌 肉内地注射至被測試的白兔大鼠的體内，接著以電動刺刀去除 欲進行手術之部位的兔毛，再對該部位予以75%酒精消毒。 每一隻兔子之接近脛骨内側中央韌帶附著點MCL (medial 15 collateral ligament)的一部分被施以一局部鑽孔手術，孔徑3mm 大小。將得自實施例1之錠劑予以置入至試驗動物鑽孔處。 縫合傷口，並使用抗生素藥膏塗抹於傷口上。以凯復寧 (Keflin，禮來製藥廠)3.0 ml之劑量予以經肌肉内注射至試驗動 物體内以避免感染。 20 動物犧牲： 咼劑量的若夢2% (Rompun solution，拜耳製藥薇）以容積 比1 : 1混合Ketalar injection 50 mg/ml (永信製藥廠），以形 成一混和液，繼而將該混合液肌肉内地注射至試驗動物體内， 進行動物犧牲。 25 1299995 以上的活體内（/n wVo)的試驗，係可依據國際標準組織 10993 (International Organization for Standardization 10993) 第六章節：植入後對局部的影響測試（part 6 ·· tests for local effects after implantation)所設計的測試來進行。 5 組織切片之製備 組織病理學切片研究·· H&E染色。切片的範圍需包括植入 的部位及正常的組織。每一種樣本經固定、脫鈣、包埋、切片 後，染以H&E染色。 所得到的切片樣本被用以進行新生骨生成之觀察及以組織 病理研究，檢視的項目包括：（1)纖維化或纖維變性及發炎反 應，（2)組織型態的退化情形；（3)與發炎反應相關的細胞，如： 巨核球，淋巴球，漿細胞，嗜酸性球，巨噬細胞，多核細胞之 數量觀察(4)當組織壞死時，細胞核碎片及微血管壁破損之情 15 : 材料碎片、脂肪液滲透、肉芽腫之變化；以及(6)觀察 骨組織與植入物的界面。 結果 〜第9與1〇圖分別顯示適用做為骨料充物之本發明的鍵劑 進行動物試驗四週與八週後所顯示之組織切片結果。在圖式中 扣成骨細胞(()Ste〇blast ce_以B表示、歸細胞(。敝㈣cdi) r、乂 c表不、新生約化骨係以N表示、骨細胞㈣⑽y㈣係以 0表示’所植入之錠劑係以T表示。 以實施例1所製得之鍵劑植入動物體，不論四週還是八週 谈，皆可發現在錠劑（圖式中標示為τ之位置）周圍有骨組織 生成。此可由殘留的錠劑的表面附近之成骨細胞（見圖式中標 26 1299995 不為B之位置）與蝕骨細胞（見圖式中標示為c之位置）之分 佈情況可以得知。再者，也觀察到骨組織間存在有新生鈣化骨 (見圖式中標示為N之位置）。在新生鈣化骨的周圍處亦可明 顯看到成骨細胞分佈，此為顯示該處正進行骨組織修復再生。 5 此修復再生作用可能是由於本發明之組成物在體内會被存 在於植入部分之組織液（或血液）溶解，致使剩餘組成物與骨組 織之間的空隙會被隨之而來之組織液（或血液)填補，經由在此 體液中所含有成骨細胞、蝕骨細胞與骨細胞作用，產生新生骨 組織之活動，即骨組織修復或再生現象。又，本發明之組成物 1〇可提供諸如成骨細胞、蝕骨細胞與骨細胞等生物相容性良好且 無細胞毒性之生存環境。 再者，第9圖與第10圖中所示之結果亦顯示，在受測動 物的骨骼中並沒有組織纖維化或纖維變性等現象。縱使本發明 的組成物在植入受測動物體内八週後，骨骼的型態並無改變， 15 且無骨骼退化情形。 同樣地，本發明之組成物在四週及八週的組織切片中，未 存在有任何發炎反應細胞，故無移植後的發炎現象產生。 此外，由該組織切片亦顯示，該等植入部位並沒有細胞核 碎片及微血管壁破損之情形。附帶一提，從組織切片結果顯 20示，本發明錠劑在四週與八週的組織中皆未出現肉芽腫組織， 此可能是因為肉芽組織一般是在在硬骨修復的早期出現，而根 據成兔的代謝率換算，第四週應該已經進入硬骨生成期，故在 四週及八週的切片中無法觀察到肉芽組織。 由以上的組織切片結果與上述内容可顯示，依據本發明之 27 1299995 錠劑在供做為骨胳填充物使用而被移植人受測動物體内時，。 展現出極佳的生物可降解性及生物相容性。 可 綜合以上的實施例以及動物試驗結果，申請人所製備 適用做為㈣填充物之組成物，在有較長的溶解速率，且^ 移植中展現不’段性的徐緩溶解，以有利於骨細胞再生之優 異效用。 於本說明書中被引述之所有專利和文獻以其整體被併入 本案作為參考資料。若有所衝突時，本案詳細說明（包含界定在 内）將佔上風。 雖然本發明已參考上述特定的具體例被描述，明顯地在不 背離本發明之範圍和精神之下可作出很多的修改和變化。因此 意欲的^，本發明僅受如隨文檢附之帽專利範目所示者之限 制0 【圖式簡皁規明迴 15 第1圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣二水合 物、彼酸飼以及硫酸4弓二水合物之組成物在溶解測試實驗中隨 著時間改變之組成物殘餘重量； 第2圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣半水合 物之組成物在溶解測試實驗中隨著時間改變之組成物殘餘重 20 量； 第3圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣二水合 物、碳酸鈣，硫酸鈣二水合物與含磷鈣成分之玻璃體之組成物 在溶解測試實驗中隨著時間改變之組成物殘餘重量； 第4圖顯示依據本發明之具有無水硫酸鈣，硫酸|弓半水合 28 1299995 炭酉文鈣，硫酸鈣二水合物以及羥基磷灰石之組成物在溶 解’則4實驗中隨著時間改變之組成物殘餘重量； 第5圖顯不依據本發明之具有無水硫酸鈣，硫酸鈣半水合 物蚊酸鈣，硫酸鈣二水合物以及一抗生素之組成物在溶解 ^武實驗中隨著時間改變之組成物殘餘重量； 第6圖顯示依據本發明之具有無水硫酸鈣，硫酸鈣半水 、灭硫自文舞二水合物以及抗生素之組成物在溶解測 試實驗中隨著時間改變之組成物殘餘重量； 10Wherein at least a part of the outer surface of the composition in the form of a solid is subjected to a fish-aqueous solution, and the content of the compound-containing compound contained in the outer surface of the composition of the (four)_fine composition is obtained. L The composition of the present invention is suitable for use as a bone filling agent, and (4) to promote regeneration and repair of 20 1299995. The composition of the present invention is suitable for use as a long-acting bone filler, and when it is placed in an animal requiring bone treatment, the dissolution rate of the composition can be controlled and can be effective for a long time. Helps to continuously regenerate bone cells. Further, the composition of the present invention may further comprise one or more drugs which aid in the regeneration and repair of bone tissue, so that the drug composition is implanted into the animal body to further contribute to bone tissue regeneration and repair in the body. Further, the present invention relates to a method for preparing a composition in the form of a solid as a bone filler, comprising the steps of: (1) forming a composition comprising the following components (a) and components a mixture of (b): (a) 40% to 1% by weight of calcium sulfate hemihydrate; and (b) at least one of 〇~60% of a calcium-containing compound selected from the group consisting of anhydrous calcium sulfate, Calcium sulfate monohydrate, calcium sulfate dihydrate, carbonic acid #5, filling #5 compound, and a combination thereof; (ϋ) pressing the mixture formed in the step (1) into a solid, thereby forming a a pressed composition of an outer surface; (out) contacting an outer surface of at least a portion of the pressed composition obtained in step (ii) with an aqueous solution, whereby the dust-containing composition is The #5-containing compound contained in the outer surface of the at least one portion in contact with the aqueous solution is hydrated; and (1V) the product obtained from the step (iii) is dried. The above and other objects, features and advantages of the present invention will become apparent from Brief Description of the Drawings 1299999 Figure 1 shows the composition of an anhydrous sulfuric acid dance, a composition of sulfuric acid dance dihydrate, and a composition of sulfur self-culture dance monohydrate in a dissolution test experiment according to the present invention. Residual weight of the material; Figure 2 shows the residual weight of the composition of the composition of the sulfuric acid dance hemihydrate in the dissolution test experiment with time according to the present invention; Figure 3 is not according to the present invention. The residual weight of the composition having the composition of the anhydrous calcium sulfate, calcium sulfate dihydrate, calcium carbonate, calcium sulfate dihydrate and the phosphorus-containing calcium component in the dissolution test test over time; 10 Figure 4 shows The residual weight of the composition according to the present invention having the composition of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate, calcium sulfate dihydrate and hydroxyapatite changed over time in a dissolution test experiment; The composition according to the present invention having anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate, calcium sulfate dihydrate and an antibiotic is shown in the dissolution test The residual weight of the composition changed with time; Figure 6 shows the composition of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate 'calcium sulfate dihydrate and antibiotic according to the present invention in the dissolution test experiment Time-varying composition residual weight; Figure 7 shows the composition of anhydrous calcium sulfate, calcium sulfate hemihydrate 20, calcium carbonate, calcium sulfate dihydrate, biodegradable polymer and antibiotic in accordance with the present invention. The residual weight of the composition changed over time in the test experiment; Figure 8 shows the residual weight of the composition with the calcium sulfate hemihydrate composition according to the present invention as a function of time in the dissolution test; 1299995 Figure 9 shows The composition according to the invention, which is suitable for use as a bone filler, is used for histological results after four weeks of animal testing; and the figure shows that the composition according to the invention, which is suitable for use as a bone filler, is used for animal testing. Histological results after the week. [Embodiment] DETAILED DESCRIPTION OF THE INVENTION The calcium-containing compound used in the composition of the present invention is preferably one selected from the group consisting of anhydrous calcium sulfate, calcium sulfate monohydrate, and calcium sulfate dihydrate. , calcium carbonate, phosphorus-containing calcium compounds, and a combination of these. The phosphorus-containing calcium compound used in the composition of the present invention may be selected from the group consisting of a glass body containing a phosphorus-calcium component, a ceramic body containing a phosphorus-calcium component, hydroxyapatite, and fluorine. Fluorpatite, glass body containing hydrogen phosphate #5, pottery body containing acid hydrogen #5, tricalcium phosphate, monocalcium phosphate monohydrate, anhydrous Dicalcium phosphate anhydrous, dicalcium phosphate dihydrate, octacalcium phosphate, alpha-tricalcium phosphate, stone_fill Beta-tricalcium phosphate, vitate-containing vitreous, sulphate-containing sulphate 20, tetra-calcium phosphate monoxide, phosphorous-containing vitreous, phosphorus Ceramic body of the compound. The phosphorus-containing calcium component compound of the present invention is preferably one which conforms to such requirements as IS013485, ISO10993 or the like. In a preferred embodiment, the phosphorus calcium compound is hydroxyapatite. In another preferred embodiment, the phosphorus 1299995 I bow compound is a vitreous body containing a parent ingredient. In a preferred embodiment, the composition of the present invention in the form of a solid comprises 100% calcium sulfate hemihydrate. Further, in another preferred embodiment, the composition comprises 50% sulfuric acid #5 hemihydrate and 50% anhydrous sulfuric acid I bow. 5 In a preferred embodiment, the composition of the present invention in the form of a solid comprises: (a) 50% calcium sulfate hemihydrate; and (b) 20% anhydrous calcium sulfate, 15% Calcium sulfate dihydrate and 15% calcium carbonate. In another preferred embodiment, the composition of the present invention in the form of a solid comprises: (a) 40% calcium sulfate hemihydrate; and (b) 20% anhydrous calcium sulfate, 15% Calcium sulfate dihydrate, 15% acidity #5 and 10% acid dance compound. More preferably, the composition of the present invention comprises a glass body containing 10% of a phosphorus-containing calcium component or 10% of a base-glass limestone. Further, the composition of the present invention in the form of a solid can be produced in the form of a double dose or in the form of pellets. Further, the present invention provides a method for preparing the above-described composition in the form of a solid as a bone filling, which comprises the following steps: (1) forming a composition having the following components (a) and groups a mixture of parts (b): (a) 40% to 1% by weight of calcium sulfate hemihydrate; and (8) 0 to 60% of at least one calcium-containing compound selected from the group consisting of anhydrous calcium sulfate and calcium sulfate a monohydrate, calcium sulfate dihydrate 12 1299995 compound, calcium carbonate, a calcium phosphate compound, and a combination thereof; (ii) pressing the mixture formed in the step (1) into a solid, thereby forming a a pressed composition of the outer surface; (iii) contacting the outer 5 surface of at least a portion of the pressed composition from step (ii) with an aqueous solution whereby the composition of the pressed composition The #5 compound contained in the outer surface of the at least one portion of the aqueous solution contact is hydrated; and (iv) the product from step (iii) is dried. In the production method of the present invention, both of the components (a) 10 and (b) used in the formation of the step (1) are themselves in the form of a powder. Preferably, the component (a) and the component (b) are subjected to a grinding treatment prior to the pressing step, preferably by dry milling, for example, by ball milling to obtain a powder of an appropriate size. In the pressing step (iii) described in the production method of the present invention, the contact of the outer surface of at least a portion of the pressed composition with the aqueous solution is carried out by a method selected from the group consisting of 15 : spray, vapor, dipping, and a combination of these. Preferably, the aqueous solution used in step (iii) is water and the outer surface of at least a portion of the pressed composition is contacted with a hot water vapor via steam treatment. Thus, the calcium-containing compound contained in the outer surface of at least a portion 20 of the pressed composition is brought into contact with the aqueous solution to be hydrated. More preferably, the aqueous solution used in step (iii) comprises, in addition to water, one or more additives, and the outer surface of at least a portion of the pressed composition is in the aqueous solution. The soaking treatment causes the water 13 1299995 to the outer surface of the pressed composition to be contacted with the aqueous solution by the additive contained in the solution. In another embodiment, the additive slit contained in at least one of the liquids of the pressed composition is attached to the leaked filament and the aqueous solution containing the additive is sprayed with a portion of the aqueous solution. The outer surface, 俾, causes the aqueous solution to contact the outer surface. In still another embodiment, the outer surface of at least a portion of the pressed composition is immersed in the aqueous solution containing the additive such that the additive contained in the water f/liquid is adhered to The pressed composition is on the outer surface in contact with the 10 aqueous solution. The additive of the present invention may be one or more selected from the group consisting of antibiotics, biodegradable polymers, and a combination thereof. Wherein the antibiotic is preferably an antibiotic selected from the group consisting of tetracycline hydrochloride, vancomycin, cePhal〇sporins, qUinolone and amino sugars. Amino antibiotic (aminoglycocides), gentamycin, and a combination of these. The biodegradable polymer is preferably selected from the group consisting of polyhydroxy, polyglycolic acid, poly-paradioxanone, sulfhydryl cellulose. (methyl cellulose), ethyl cellulose, ethyl cellulose, and a combination of these. The biodegradable polymer is preferably methylcellulose or hydroxyethylcellulose. Further, the additive of the present invention may also be a variety of drugs or chemicals which are conventionally used for bone treatment or repair, preferably such drugs or chemical I299995 which conform to the Pharmacopoeia specifications. The drying step in the method is preferably It is dried by air drying or drying. The drying and drying is preferably carried out at 40 ° C for 30 minutes. The glass system containing the phosphorus-calcium component used in the present invention is first subjected to a grinding treatment, preferably a dry grinding treatment, for example, by ball milling to form a powder of a suitable size, and the pressing step (ii) is carried out. Further, the glass system of the phosphorus-containing calcium component of the composition of the present invention is well known in the art. Preferably, the phosphorous-containing calcium component is obtained by the following steps: (I) mixing the calcium monophosphate powder with a monophosphoric acid solution to obtain a mixed solution; (II) obtaining the step (I) The mixed solution is subjected to a melt treatment at a temperature ranging from lioot to 1300 〇c to obtain a phosphorus dance melt; (III) cooling the phosphorus calcium melt of the step (Π) to obtain the disk-containing composition Vitreous body. In a preferred embodiment, the mixed solution obtained in the mixing step (I) can be further mixed to select a substance consisting of the following groups: 矽, 鈇, containing chin, 钡, 钡 钡 chemistry , other materials for orthopedic implants, and the like - a combination 0 20 In a preferred embodiment, wherein the melting treatment step (11) is at a temperature of °c from the step (1) The mixed solution is subjected to the melting treatment. The molding process to be used for subsequent use is in a preferred embodiment, and the cooling step (III) further comprises - cooling the phosphorus calcium melt of the step (II) to 7 〇〇 °c Step, for one molding process. Preferably, the resulting disc I melt fused body 15 1299995 is obtained by pouring the cooled melt into a suitable mold to obtain a glass body containing a calcium-containing component having a desired shape. Preferably, the glass system containing the phosphorus-calcium component of the desired shape can be directly used as a bone filler or an orthopedic implant, and can be widely applied to orthopedics. The glass body containing the dance composition 5 thus obtained can also be appropriately pulverized and/or ground and combined with other ingredients for use in the application of the bone technology. In a preferred embodiment, the mixing step (I) and the melting step (π) further comprise treating the mixed solution at 400 C for 2 hours and then at 9 Torr. 0 Process 4 hours pretreatment step. Further, the contacting step (iii) of the production method of the present invention employs different treatment methods depending on the different aqueous solutions used. Therefore, in a preferred embodiment, the contacting step (9) can utilize spray, vapor treatment (vap kneading) and dipping (dipping), and (4) obtaining the surface contact of the ruthenium . Further, in the case where the tablet prepared by the composition of the present invention is transplanted into the bone path of the living animal, the dissolution rate of the bond can be controlled, and it can help the reconstruction of the bone cells and the reconstruction of the bone cells. Therefore, it is possible to prepare a lozenge which can be used as a bone filling material, and which is a good medicine for cell growth and for assisting reconstruction of damaged bone. In addition, the key = itself has (4) dragon miscellaneous, the raw shots are in the living body can be = and! The composition of the invention is made, not _ carry out;:::: agent, when the lozenge is set 16 1299995 Furthermore, the composition of the present invention may further contain other drugs which are useful for bone regeneration and repair, such as antibiotics or cellulose, so when the composition of the present invention is implanted into the bone tissue of an animal body, the outer layer of antibiotics It can be in contact with bone tissue, and the area of inflammation or lesions of the bone can be treated first. Further, the substance contained in the composition of the present invention 5 can contribute to the formation of a bone matrix. Therefore, the composition of the present invention can exert the dual effects of treating bone inflammation and bone lesions as well as helping bone growth. The invention will be described in more detail with reference to the following examples, which are intended to be illustrative, and not intended to limit the scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The control group used in the present invention is a kit for preparing a commercially available bone filler (OSTEOSETBVFKit) containing calcium sulfate hemihydrate, 5 The method is based on the steps shown in the kit. The method for determining the rate of dissolution of the tablet 15 is determined by measuring the dissolution rate of the tablet according to the method for measuring the dissolution rate of the tablet in the patent of US 6,030,636. Example 1: Preparation of an anthraquinone having anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium citrate, calcium sulfate dihydrate. Method 20: anhydrous calcium sulfate 1 〇 0 g, calcium sulphate hemihydrate 250 g 75 g of calcium carbonate, 75 g of calcium sulfate dihydrate, and a powder having a total weight of 5 〇〇g was poured into a ball mill 'to grind and mix for 24 hours. Thereafter, a spherical mold having an inner diameter of 2 cm and a tablet press were used to perform an embossing: treatment, and the crucible was used as a key for the experimental group, and the diameter of each of the tablets was 17 1299995. It is about 2 cm χ 2 cm and is spherical. The steam production machine (produced by Jiashida Industrial Co., Ltd., model p-l003) was started, and water (100 ml) was injected into the steam production machine through the water injection port, and after about 5 to 30 minutes, helium was generated to generate water vapor. The vapor pressure inside the steam producing machine was stably controlled at 5 90 ° C under an atmospheric pressure. The tablets obtained by the ingot treatment were placed in a stainless steel pan as the tablet used in the experimental group, and then the stainless steel disk containing the tablet was placed in the air chamber of the steam-filled steam making machine to make the ingot The surface of the agent is in contact with water vapor, and it is 0^*3 minutes. After that, the steel disc was taken out and placed in a box at 4 ° C for 10 minutes in 10 rows. The dissolution rate was compared. The five tablets prepared in Example 1 were taken as test samples of the experimental group, and the above-mentioned commercial source tablet (Osteo Set BVF Kit) was used as a control group, and the dissolution rate measurement method was used according to the above. The dissolution rate of 15 tablets was measured for the experimental group and the control group, respectively. The average results obtained by the experimental group and the control group were recorded separately. The comparison results of the dissolution rate measurement are shown in Fig. 1. As shown in the figure, the control group is around 31 days and its residual weight is close to zero. The composition of this example was at 37 compared to the control group. (The time in which the water is dissolved is several days longer, and the residual weight is 20 times until it is close to zero in about 40 days. It can be inferred that the composition of the present embodiment has a longer dissolution time in the animal body. Compared with the control group, the composition of the present embodiment provides a better growth environment and time for bone tissue. Example 2: Preparation of a composition having anhydrous calcium sulfate, calcium sulfate hemihydrate 18 1299995 This example uses anhydrous water. Calcium sulfate 250 g, sulfuric acid to dihydrate 25 〇g (total weight 500 g) As a material for preparing a tablet, the tablet was prepared in accordance with the procedure of Example 1 and subjected to a dissolution rate test. The comparison result of the measurement is shown in Fig. 2. As shown in the figure, the residual weight of the group 5 was about zero at about 31 days. The composition of the present example was compared in water at 37 ° C compared with the control group. The dissolution time is several days longer, and the residual weight is close to zero until about 37 days. It can be concluded that the composition of the present embodiment has a longer dissolution time in the animal compared to the control. Group, the composition of this embodiment provides Organize a better 10 growth environment and time. Example 3: The instrument has anhydrous calcium sulfate, calcium sulfate dihydrate, carbonic acid, calcium sulfate dihydrate, phosphorus-containing calcium component, glass crucible composition Preparation of Calcium Component Glass Body 15 Calcium citrate powder (50 phantoms were uniformly mixed with a phosphoric acid solution (200 ml, 85%, product number 100563, MERCK), and the resulting homogeneous mixture was poured into the noodles. Put the ceramics containing the uniform mixture into the two furnaces with a temperature of 4 〇〇c and continue for 2 hours at 4 〇〇. 0. Then, raise the temperature of the furnace to 9 〇 (rc, and at 9 〇 (rc for 4 hours, then 20 steps to raise the temperature of the furnace to 1100 ° C degrees, and at this temperature for 2 hours to make squaric acid #5 in a smelt state. After the temperature of the crucible is lowered to 700 ° C, the ceramic crucible is taken out, and the s liquid in the ceramic crucible is poured onto a graphite plate. When the molten solution is cooled, it is in the form of glass. The temperature of the molten solution is lowered. At room temperature, a glass of 19 1299995 containing a scale #5 component is obtained. The obtained glass body is broken and Ball mill grinding 'for the following steps. Take 50 g of the ground phosphorus-containing calcium phosphate mixture to mix 100 g of anhydrous calcium sulfate, 200 g of calcium sulfate hemihydrate, 75 g of calcium carbonate and 5 parts of calcium sulfate dihydrate. 75 g of a powder having a total weight of 500 g was poured into a ball mill and ground for 24 hours. The tablet was prepared according to the procedure of Example 1 and subjected to a dissolution rate test. The comparison results are shown in Fig. 3. As shown in the figure, the control group was about 31 days, and its residual weight was close to zero. Compared with the control group, the composition of the present embodiment was dissolved in 37 ° C water. The time is several days longer and the residual weight is maintained at a constant value after about 34 days, which may be due to the residual vitreous containing the #5 component. Thus, it can be inferred that the composition of the present embodiment has a longer dissolution time in the animal body and provides a better growth environment and time for the bone tissue than the composition of the control group of the control group. Example 4: Manufactured with anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate, calcium sulfate dihydrate and hydroxyapatite. This example except for the use of anhydrous calcium sulfate 100 g, calcium sulfate hemihydrate 200 g, calcium carbonate 75 g, calcium sulfate dihydrate 250 g and pharmaceutical grade hydroxyapatite 20 50 g (total weight 5 〇〇 g) as a material for preparing a tablet, according to the embodiment 1 The procedure of the method is to prepare a tablet and perform a dissolution rate test. The comparison results of the dissolution rate measurement are shown in Fig. 4. As shown in the figure, the tablet of the control group is about 31 days, and its residual weight is close to zero. Compared with the control group, the composition of the present embodiment was dissolved in 37 tons of water for several days and was about 34 20 1299995 days, and the residual weight reached a certain value, which may be caused by residual hydroxyapatite. . Thus, it can be inferred that the composition of the present embodiment has a longer dissolution time in the animal body, and the composition of the present embodiment provides a better growth environment and time for the bone tissue than the control group. Poor Example 5: Composition of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate, calcium sulfate dihydrate and antibiotics in this example is the use of anhydrous sulfuric acid mother 100 g, sulfuric acid mother half-hydrate 250 g, 75 g of calcium carbonate and 75 g of calcium sulfate dihydrate (total weight: 500 g) were used as a material for preparing a bismuth bond and water was replaced by the following antibiotic solution. Steam treatment and drying were carried out under the following conditions, and the remaining steps were carried out. The tablets were prepared in accordance with the procedure described in Example 1 and subjected to a dissolution rate test. 1 〇g vancomycin powder was dissolved in 90 g of water for injection into the steam injection machine, and after the steam generator operated for about 7 minutes 15 'the steam chamber's chamber was filled with antibiotic mixture The water vapor therein is 'and the temperature of the gas chamber is controlled to 55 degrees Celsius. Putting the tablets obtained by the ingot treatment into a stainless steel pan as a tablet used in the experimental group, and then placing the stainless steel plate containing the tablet into a water vapor environment containing the antibiotic mixed therein, so that The surface of the tablet was in contact with the water vapor phase 20 for 3 minutes. Thereafter, the stainless steel pan was taken out and placed in an oven at 40 ° C for drying for 30 minutes. The comparison results of the dissolution rate measurement are shown in Fig. 5. As shown in the figure, the control group is around 31 days and its residual weight is close to zero. Compared to the control group, the composition of this example was dissolved in water at 37 ° C for several days, and its residual weight was 21 1299995 until it was close to zero for about 40 days. It can be inferred that the composition of the present embodiment has a longer dissolution time in the animal body and provides a better growth environment and time for the bone tissue than the composition of the control group of the control group. 5 'When the composition of this embodiment is implanted into the bone tissue of the animal body, the outer vancomycin will first contact the bone tissue, so the bone inflammation or lesion can be treated first, when it is inflamed or diseased. After the situation is improved, the other components of the composition of the present embodiment can be reused to aid bone growth to exert a dual effect of treating bone inflammation or lesions and aiding bone regeneration. 10 Example 6: Composition having an anhydrous sputum angle, a sulfuric acid good hemihydrate, a carbonate horn, a calcium sulphate dihydrate, and an antibiotic. In this example, another antibiotic is used for the steam treatment. . In the present example, in addition to the use of gentamicin 5g instead of vancomycin used in Example 5, the preparation of the tablet of the present embodiment and the steps of the implementation were the same as in the fifth embodiment. The comparison results of the dissolution rate measurement are shown in Fig. 6. As shown in the figure, the control group is around 31 days and its residual weight is close to zero. The composition of this example was dissolved in water at 37 ° C for several days compared to the control group, and its residual weight was close to zero up to about 40 days. Thus, it can be inferred that the composition of the present embodiment has a longer dissolution time in the animal body and provides a better growth environment and time for the bone tissue than the composition of the control group of the control group. Moreover, when the composition of the embodiment is implanted into the bone tissue of the animal body, the outer side of the gentamicin will first contact the bone tissue, so the bone 1220199995 site of the inflammation or lesion may be treated first, and when inflamed After the lesion condition is improved, the other components of the composition of the present embodiment can be reused to aid bone growth to exert a dual effect of treating bone inflammation or lesions and helping bone regeneration. Example 7 · Preparation of a composition having anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium carbonate, calcium sulfate dihydrate, biodegradable polymer and antibiotics This example is a dance of anhydrous sulfuric acid 100 g, sulfuric acid About half of the hemihydrate 250 g, calcium carbonate 75 g, calcium sulfate dihydrate 75 g (total weight 500 g) as a material for preparing the tablet, and the following biodegradable polymer and antibiotic 10 solution The water used in Example 1 was replaced, and the steam treatment was replaced by the following immersion treatment. In the present embodiment, the remaining steps were carried out in accordance with the procedure described in Example i to prepare a tablet and perform a dissolution rate test. The aqueous solution having the biodegradable polymer and the antibiotic of the present embodiment was obtained in the following manner. 15 Methylcellulose (5 g), hydroxyethylcellulose (5 g) and water (100 g) were mixed, and the resulting mixed solution was heated and stirred until boiling. The solution to be mixed is cooled to about 4 〇 <: When' vancomycin (10 g) and gentamicin (5 g) powder were added to the mixed solution and an antibiotic was dissolved therein to obtain the aqueous solution. The above-prepared tablet was soaked in an aqueous solution towel containing the biodegradable polymer 20 and the antibiotic for 10 minutes. After that, the soaked tablet is taken out and placed in an oven at 4 ° C for drying for 30 minutes to dry the tablet. '俾A kind of ingot with a decomposable polymer and antibiotic attached to the outer surface is obtained. Agent. The comparison results of the /glutination rate measurement are shown in Fig. 7. As shown in the figure, the group of 23 1299995 is around 31 days, and its residual heavy summer is close to zero. The composition of this embodiment was dissolved in water at 37 ° C for several days compared to the Japanese group, and its residual weight was near zero until about 40 days. It can be inferred that the composition of the present embodiment has a longer dissolution time in the animal. When the composition of the present embodiment is implanted into the bone tissue of the animal body, the composition of methyl cellulose and hydroxyethyl cellulose and water can effectively control the pharmacological action time of the ancient sulphate and the gentamicin. And attached to the outer layer of the composition, the big Huisu will first contact with the bone tissue, so the bone inflammation or the lesion can be treated first. Once the inflammation or the lesion is properly treated and improved, the composition of the embodiment 10 The other components of the substance can be used to help the bones grow to exert the dual effects of treatment and bone regeneration of bone inflammation or lesions. Example 8: Preparation of a boat having calcium citrate hemihydrate This example was prepared by using 200 g of calcium sulfate hemihydrate as a material for preparing a tablet and a solvent rate of 50 ml of physiological saline. The others were I5 in accordance with the procedure of the method described in Example 1 to prepare a tablet and to determine the dissolution rate. The comparison results of the dissolution rate measurement are shown in Fig. 8. As shown in the figure, the tablet of the control group has a residual weight of approximately zero for about 15 days. Compared to the control group, the composition of this example was dissolved in water at 37 ° C for several days, and its residual weight was near zero until about 20 days. Thus, it can be inferred that the composition of this embodiment has a longer dissolved time in the animal. Further, although both of the present embodiment and the control group contain calcium sulfate hemihydrate, since the calcium-containing compound present on the surface of the tablet obtained from the composition of the present invention is previously subjected to hydration, The dissolution time of the composition of this example was longer than that of the control group. 24 1299995 Animal Test _ 鸢 鸢 · · Male New Zealand white rabbits (about 2.3 kg - 2.6 kg) aged about 6 months, the number of tests is 5. According to the composition ratio of Example 1, a tablet was prepared. The tablet (diameter 5 3 mm X thickness 2 mm) was placed in a brown glass bottle and sterilized by gamma rays (r-ray) for animal testing. + Procedure: All test animals were selected to ensure they were in a healthy condition. The 2% (Rompun solution, Bayer Pharmaceuticals) was mixed with Ketalar injection 50 mg/ml (Yongxin Pharmaceutical Factory) at a volume ratio of 1 ·· 10 1 , and the resulting mixture was used for surgical anesthesia. The muscles were intramuscularly injected into the body of the tested white rabbits at a dose of 5 ml of the mixture, and then the rabbit hairs of the site to be operated were removed with an electric bayonet, and the site was subjected to 75% alcohol sterilization. A portion of each rabbit's proximal medial ligament attachment MCL (medial 15 collateral ligament) was subjected to a partial drilling procedure with a pore size of 3 mm. The tablet obtained in Example 1 was placed in the bore of the test animal. The wound is sutured and applied to the wound with an antibiotic ointment. Intravenous injection into the test object was performed at a dose of 3.0 ml from Keflin (Lilly Pharmaceutical Factory) to avoid infection. 20 Animal Sacrifice: 2% (Rompun solution, Bayer Pharmaceuticals) is mixed with Ketalar injection 50 mg/ml (Yongxin Pharmaceutical Factory) at a volume ratio of 1:1 to form a mixed solution, which is then mixed. The muscles were injected intramuscularly into the test animals for sacrifice. 25 1299995 The above in vivo (/n wVo) test can be organized according to International Standards 10993 (International Organization for Standardization 10993). Section 6: Post-implantation test for local effects (part 6 · tests for local effects After implantation) The test is designed to be carried out. 5 Preparation of tissue sections Histopathological section study··H&E staining. The extent of the slice should include the site of implantation and normal tissue. Each sample was fixed, decalcified, embedded, sliced, and stained with H&E. The obtained slice samples were used for observation of new bone formation and histopathological studies. Items examined included: (1) fibrosis or fibrosis and inflammatory response, and (2) degradation of tissue type; (3) Cells associated with inflammatory reactions, such as: megakaryocytes, lymphocytes, plasma cells, eosinophils, macrophages, multinuclear cells (4) when tissue necrosis, nuclear debris and microvascular wall damage 15 : Materials Fragments, changes in fat fluid penetration, granuloma; and (6) observation of the interface between bone tissue and the implant. Results ~ Figures 9 and 1 respectively show the results of tissue sectioning for the four-week and eight-week animal tests applied to the present invention as a filler for the aggregate. In the figure, osteoblasts are buckled (() Ste〇 blast ce_ is represented by B, homing cells (. 敝 (4) cdi) r, 乂c is not, neonatalized bone is represented by N, bone cells (4) (10) y (four) is represented by 0 'The implanted tablet is indicated by T. The implant obtained in Example 1 is implanted into the animal body, and it can be found in the lozenge (indicated as the position of τ in the figure), whether it is four weeks or eight weeks. There is bone tissue formation around it. This can be attributed to the distribution of osteoblasts near the surface of the residual tablet (see Figure 26 1299995 not where B is located) and osteoclasts (labeled as c in the figure). It can be known that, in addition, new calcified bone is observed between the bone tissues (indicated as N in the figure). The distribution of osteoblasts can also be clearly seen around the newly calcified bone. This site is undergoing bone tissue repair regeneration. 5 This repair regeneration may be due to the fact that the composition of the present invention is dissolved in the body fluid (or blood) present in the implanted part in the body, resulting in a residue between the remaining composition and the bone tissue. The void will be filled with the tissue fluid (or blood) that comes with it. By the action of osteoblasts, osteoblasts and bone cells contained in the body fluid, the activity of the new bone tissue, that is, the repair or regeneration of the bone tissue, is generated. Further, the composition of the present invention can provide osteoblasts such as osteoblasts. Biophysical and non-cytotoxic living environment such as osteoblasts and bone cells. Furthermore, the results shown in Fig. 9 and Fig. 10 also show that there is no tissue fiber in the bones of the tested animals. Even if the composition of the present invention is implanted in the test animal for eight weeks, the shape of the bone does not change, 15 and there is no bone degradation. Similarly, the composition of the present invention is surrounded by In the eight-week tissue section, there was no inflammatory reaction cell, so there was no post-transplant inflammation. In addition, the tissue section showed that there were no nuclear fragments and microvascular wall damage. Incidentally, from the results of tissue sectioning, the lozenge of the present invention showed no granuloma tissue in the tissues of four weeks and eight weeks, which may be because the granulation tissue is generally The early appearance of hard bone repair, and according to the metabolic rate of rabbits, the fourth week should have entered the period of hard bone formation, so granulation tissue could not be observed in the four-week and eight-week sections. The results of the above tissue section and the above can be It is shown that the 27 1299995 lozenge according to the present invention exhibits excellent biodegradability and biocompatibility when used as a bone filler for being transplanted into an animal to be tested. The results of the examples and the animal test, the applicant's preparation is suitable as a composition of (4) filler, which has a long dissolution rate, and exhibits a non-segmental slow dissolution in the transplantation to facilitate the excellent regeneration of bone cells. All patents and documents cited in this specification are incorporated herein by reference in its entirety. In the event of a conflict, the detailed description (including the definition) of this case will prevail. While the invention has been described with respect to the specific embodiments of the invention, it will be understood that many modifications and changes can be made without departing from the scope and spirit of the invention. Therefore, the present invention is only limited by the one shown in the patent specification of the cap attached to the article. [Fig. 1 shows a schematic diagram of the present invention. The first embodiment shows an anhydrous calcium sulfate, calcium sulfate dihydrate according to the present invention. , the composition of the acid and the composition of the sulfuric acid 4 bow dihydrate in the dissolution test experiment, the residual weight of the composition changes over time; Figure 2 shows the composition of the anhydrous calcium sulfate, calcium sulfate hemihydrate according to the present invention The residual weight of the composition changed over time in the dissolution test experiment; Figure 3 shows the anhydrous calcium sulfate, calcium sulfate dihydrate, calcium carbonate, calcium sulfate dihydrate and phosphorus-containing calcium component according to the present invention. The composition of the vitreous body changes the composition residual weight over time in the dissolution test experiment; Figure 4 shows the anhydrous calcium sulfate, sulfuric acid|bow hemihydrate 28 1299995 anthraquinone calcium, calcium sulfate dihydrate and the like according to the present invention The composition of the hydroxyapatite is dissolved in the '4 experiment, the composition of the residual weight changes over time; Figure 5 shows that according to the invention has anhydrous calcium sulfate, calcium sulfate half Hydrated calcium glutamate, calcium sulphate dihydrate and a composition of an antibiotic in the dissolution test, the residual weight of the composition changes over time; Figure 6 shows the anhydrous calcium sulphate, calcium sulphate and semi-water according to the invention , the residual weight of the composition of the composition of the sulfur-killing self-culture dance dihydrate and the antibiotic in the dissolution test experiment;
第7圖顯不依據本發明之具有無水硫酸鈣，硫酸鈣半水合 勿蛟酸鈣，硫酸鈣二水合物、生物可分解之聚合物以及抗 生素之組成物在溶解測試實驗中隨著時間改變之組成物殘餘 ^第8圖顯示依據本發明之具有硫酸鈣半水合物之組成物在 ，解式實驗中隨著時間改變之組成物殘餘重量；Figure 7 shows the composition of anhydrous calcium sulphate, calcium sulphate hemihydrate, calcium sulphate, calcium sulphate dihydrate, biodegradable polymer and antibiotic in accordance with the present invention, which changes over time in the dissolution test. Composition Residues Figure 8 shows the residual weight of the composition having the calcium sulfate hemihydrate composition according to the present invention as a function of time in the solution test;
第9圖顯示適用做為骨骼填充物之依據本發明的組成物被 用於進行動物試驗四周後之組織學結果；以及 第10圖顯示適用做為骨骼填充物之依據本發明的組成物 破用於進行動物試驗八週後之組織學結果。 【圈式之主要元件代表符號表】 (無） 29Figure 9 shows the histological results of the composition of the present invention applied as a bone filler after four weeks of animal testing; and Figure 10 shows the composition of the composition for use as a bone filler in accordance with the present invention. Histological results after eight weeks of animal testing. [Circle type main component representative symbol table] (none) 29