TWI782850B - 三維網狀水性凝膠及其製造方法 - Google Patents
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Abstract
本發明提供一種三維網狀水性凝膠及其製造方法,首先將水溶性高分子加入溶劑中均勻混合後進行水解以形成溶膠,並經由真空將溶膠轉換成凝膠,經由縮聚合反應而形成三維網狀水性凝膠。三維網狀水性凝膠係由水溶性高分子所構成,水溶性高分子包括海藻酸鈉及羧甲基纖維素鈉所組成之群組,水溶性高分子互相聯結以形成三維網狀結構。藉此,本發明三維網狀水性凝膠係為一種凝膠包覆劑型,利用高分子聚合物形成包覆藥物的三維網狀結構,能更有效的保護活性成分並達到緩釋效果,進而可增長療效並減少表皮刺激副作用的功效。
Description
本發明係關於一種三維網狀水性凝膠及其製造方法,特別是關於一種可加速各型傷口癒合及預防傷口異常癒合的三維網狀水性凝膠及其製造方。
皮膚為人體最大的器官,具有阻絕外來的細菌病毒入侵,維持體液平衡及感知外在刺激等功能。當皮膚出現傷口時,則皮膚無法達到保護的功能,若傷口處理不當可能造成感染或發炎現象。因此,需要以正確的方式來處理傷口避免傷口感染,通常需要使用具有止血、保護及防止感染等功能的敷料來覆蓋傷口。此外,敷料亦可提高皮膚修復及再生的速度,因此加速傷口癒合的手段亦為重要課題。
現今在傷口上所使用的敷料可分為乾式及濕式敷料,乾式癒合的敷料例如紗布,濕式癒合的敷料例如薄膜敷料、親水性敷料、親水性纖維敷料、泡棉性敷料、抗菌性敷料、富壓傷口敷料、先進治療敷料或主動性敷料。然而乾式敷料具有下列缺點,癒合環境差,創面局部容易脫水,形成結痂,結痂造成傷口疼痛。其此,生物活性丟失,癒合速度緩慢;滲漏快速需要頻繁更換敷料。再者,敷料與傷口新生肉芽組織黏連,更換敷料時會損傷創面,且創面與外界無阻隔性屏障,交叉感染的機會增加。
鑑於此,本發明人致力於傷口、止血及抗沾黏照護產品研發,以提升醫療品質,提供可靠又便利的生醫產品。本發明人投入眾多研發能量與精神,不斷於本領域突破及創新,盼能以新穎的技術手段解決習用之不足,除帶給社會更為良善的產品,亦促進產業發展。
本發明之主要目的係在提供一種三維網狀水性凝膠及其製造方法,具該三維網狀水性凝膠有優良的生物相容性、生物可降解性且容易合成,對低分子溶質具有良好的透過性。此外,該三維網狀水性凝膠具有抗炎性反應及傷口平整功效,進而減輕瘢痕形成、預防傷口異常癒合並達到加速傷口癒合的目的。
為達成上述目的,本發明提供一種三維網狀水性凝膠,係由一水溶性高分子所構成,該水溶性高分子包括羧甲基纖維素鈉,該水溶性高分子與一溶劑互相聯結以形成一三維網狀結構。
於本發明之三維網狀水性凝膠中,該水溶性高分子更包括海藻酸鈉,該羧甲基纖維素鈉、該海藻酸鈉與水該溶劑互相聯結以形成該三維網狀結構。
於本發明之三維網狀水性凝膠中,該水溶性高分子更包括聚乙烯吡咯烷酮,該羧甲基纖維素鈉、該海藻酸鈉、該聚乙烯吡咯烷酮與該溶劑互相聯結以形成該三維網狀結構。
於本發明之三維網狀水性凝膠中,該水溶性高分子包括10~30wt%的海藻酸鈉、10~30wt%的聚乙烯吡咯烷酮及10~40wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。
於本發明之三維網狀水性凝膠中,該三維網狀結構具有複數個膠孔形成於其中,該些膠孔的直徑係為16~18µm。
為達成上述另一目的,本發明提供一種三維網狀水性凝膠之製造方法,該方法包括:將一水溶性高分子加入一溶劑中均勻混合後形成一均質溶液,該水溶性高分子包括羧甲基纖維素鈉;將該水溶性高分子進行一水解反應生成一奈米級水溶性高分子粒子並形成一溶膠;在25~760 torr的壓力下,將該溶膠經真空轉變成一凝膠;該凝膠進行一縮聚合反應,使該奈米級水溶性高分子粒子與該溶劑間發生相互連結而形成一三維網狀結構;將該三維網狀結構經真空以形成一三維網狀水性凝膠。
於本發明之三維網狀水性凝膠之製造方法中,該水溶性高分子更包括海藻酸鈉,該羧甲基纖維素鈉、該海藻酸鈉與該溶劑互相聯結以形成該三維網狀結構。
於本發明之三維網狀水性凝膠之製造方法中,該水溶性高分子更包括聚乙烯吡咯烷酮,該羧甲基纖維素鈉、該海藻酸鈉、該聚乙烯吡咯烷酮與該溶劑互相聯結以形成該三維網狀結構。
於本發明之三維網狀水性凝膠之製造方法中,以100wt%該水溶性高分子總重量百分比計算,該水溶性高分子包括10~30wt%的海藻酸鈉、10~30wt%的聚乙烯吡咯烷酮及10~40wt%的羧甲基纖維素鈉。
於本發明之三維網狀水性凝膠之製造方法中,該三維網狀結構具有複數個膠孔形成於其中,該些膠孔的直徑係為16~18µm。
於本發明之三維網狀水性凝膠之製造方法中,將該凝膠的溫度控制於30~70度之間,壓力控制於50~70毫米汞柱之間以調控該凝膠的一溶脹度及該凝膠的結構。
於本發明之三維網狀水性凝膠之製造方法中,該溶劑係為一純水或一有機溶劑。
本發明三維網狀水性凝膠的水凝膠高聚物分子互相聯結,形成三維網狀結構,在網狀的膠孔中充滿液體;發生交聯反應的凝膠由於形成了共價交聯網路,凝膠特性表現為溶脹而不溶解。其次,由於水凝膠大量的親水基團,能夠吸收並保持大量水分。再者,該三維網狀水性凝膠具有優良的生物相容性、生物可降解性且容易合成,對低分子溶質具有良好的透過性。此外,該三維網狀水性凝膠運用技術條件的方法改變水凝膠的結構,可以調控水凝膠的溶脹度。
以下係藉由具體實施例說明本發明之實施方式,熟習此技藝之人士可由本說明書所揭示之內容輕易地瞭解本發明之其他優點與功效。此外,本發明亦可藉由其他不同具體實施例加以施行或應用,在不悖離本發明之精神下進行各種修飾與變更。
請參照圖1及圖3,圖1係為本發明三維網狀水性凝膠形成之示意圖;圖2係為本發明三維網狀水性凝膠之的SEM圖像;以及圖3係為本發明三維網狀水性凝膠形成之製造流程圖。
實施例1
如圖1至圖3所示,本發明提供一種三維網狀水性凝膠之製造方法,該方法包含:步驟S101:將一水溶性高分子加入一水或一有機溶劑中均勻混合後形成一均質溶液,其中,該水溶性高分子包括80~95wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。步驟S102:將該水溶性高分子進行一水解反應生成一奈米級水溶性高分子粒子並形成一溶膠(Sol),該溶膠是具有液體特徵的膠體體系,分散的粒子是固體或者大分子,分散的粒子大小在1~100nm之間。步驟S103:在25~760 torr的壓力下,將該溶膠經真空轉變成一凝膠(Gel),該凝膠是具有固體特徵的膠體體系,被分散的物質形成連續的網狀骨架,骨架空隙中充有液體或氣體,凝膠中分散相的含量很低,一般在1%~3%之間。步驟S104:該凝膠進行一縮聚合反應並控制加熱溫度介於30~70度之間及壓力介於50~70毫米汞柱之間,使該奈米級水溶性高分子粒子間發生相互連結而形成一三維網狀結構,特殊的該三維網狀結構賦予該凝膠很高的比表面積。步驟S105:將該三維網狀結構經真空以形成一三維網狀水性凝膠;其中,該三維網狀結構具有複數個膠孔形成於其中,該些膠孔的直徑係為16~18µm。
實施例2
實施例2與實施例1的步驟大致相同,不同處在於:在實施例2中,該水溶性高分子更包海藻酸鈉,以100wt%該水溶性高分子總重量百分比計算,該水溶性高分子包括10~30wt%的海藻酸鈉及70~90wt%的羧甲基纖維素鈉。
實施例3
實施例3與實施例1的步驟大致相同,不同處在於:在實施例3中,該水溶性高分子更包括聚乙烯吡咯烷酮,以100wt%該水溶性高分子總重量百分比計算,該水溶性高分子包括10~30wt%的海藻酸鈉、10~30wt%的聚乙烯吡咯烷酮及10~40wt%的羧甲基纖維素鈉。
溶脹度測試
藉由壓力及溫度的控制以改變該三維網狀水性凝膠的結構,以調控該三維網狀水性凝膠的溶脹度,溫度及壓力越高時則該膠孔的直徑越小且溶脹度變小,該溶脹度係經下式計算而得:{(溶脹後該三維網狀水性凝膠之重量-溶脹前該三維網狀水性凝膠之重量)/溶脹前該三維網狀水性凝膠之重量 x 100}。溶脹度測試中,該三維網狀水性凝膠的該水溶性高分子包括30wt%的海藻酸鈉、30wt%的聚乙烯吡咯烷酮及40wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算,藉由溫度及壓力改變該三維網狀水性凝膠的膠孔及溶脹度,結果如表1所示。
表1
溫度( °C) | 壓力(毫米汞柱) | 膠孔直徑(µm) | 溶脹度(%) |
30 | 50 | 17.8 | 44.03% |
35 | 50 | 17.8 | 45.07% |
40 | 50 | 17.3 | 42.05% |
45 | 50 | 16.9 | 40.12% |
50 | 70 | 16.8 | 40.01% |
55 | 70 | 16.5 | 38.57% |
60 | 70 | 16.6 | 37.23% |
65 | 70 | 16.3 | 36.11% |
70 | 70 | 16.2 | 35.74% |
緩釋試驗
該三維網狀水性凝膠的該水溶性高分子包括30wt%的海藻酸鈉、30wt%的聚乙烯吡咯烷酮及40wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算,緩釋時間可藉由調整三維網狀結構而達到緩釋效果,經由一經皮吸收測試儀來推算緩釋時間,使用的人造皮為豬皮,結果如下表2所示。
表2
溫度( °C) | 壓力(毫米汞柱) | 膠孔直徑(µm) | 緩釋時間(天) |
30 | 50 | 17.8 | 7 |
35 | 50 | 17.8 | 7 |
40 | 50 | 17.3 | 7.5 |
45 | 50 | 16.9 | 7 |
50 | 70 | 16.8 | 8 |
55 | 70 | 16.5 | 11 |
60 | 70 | 16.6 | 10.5 |
65 | 70 | 16.3 | 11 |
70 | 70 | 16.2 | 12 |
傷口癒合測試
實驗動物
實驗中所使用是8週大雄性紐西蘭大白兔,體重約為2000~2500g。所有的實驗動物被飼養於室溫維持在22
°C以及相對濕度維持在45%的獨立空調的動物房內,而且水分與飼料被充分地供給。在實驗之前,給予動物至少4週的期間去適應環境。有關實驗動物的飼養環境、處理以及一切實驗程序均符合國家衛生研究院(National Institutes of Health,NIH)的實驗動物飼養管理及使用規範(Guide for the Care and Use of Laboratory Animals)。
皮膚傷口的形成
將紐西蘭大白兔的背側部分進行剃毛,然後以碘酒以及70%酒精予以消毒後,使用手術刀於紐西蘭大白兔的背部的切出具有一約為2cm×2cm的面積大小以及約為2~3mm的深度的皮膚傷口。
水溶性高分子成分含量
實驗組1:該水溶性高分子的總重量百分比計包含:25wt%的海藻酸鈉、25wt%的聚乙烯吡咯烷酮及50wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。
實驗組2:水溶性高分子的總重量百分比計包含:30wt%的海藻酸鈉、30wt%的聚乙烯吡咯烷酮及40wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。
對照組1:該水溶性高分子的總重量百分比計包含:25wt%的海藻酸鈉、25wt%的聚乙烯吡咯烷酮及50wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。
對照組2:水溶性高分子的總重量百分比計包含:30wt%的海藻酸鈉、30wt%的聚乙烯吡咯烷酮及40wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算。
該三維網狀水性凝膠的施用
紐西蘭大白兔被隨機地分成2個實驗組以及2個對照組,其中各組的紐西蘭大白兔是依照上述的方法來形成皮膚傷口;接著,實驗組1及2的紐西蘭大白兔的皮膚傷口分別被施用以依據上述實驗組1及2該三維網狀水性凝膠,並在動物的傷口上覆蓋聚氨酯(polyurethane, PU)防水薄膜以保持溼潤。而對照組1及2的紐西蘭大白兔依照上述的方法來形成皮膚傷口;接著,對照組1及2的紐西蘭大白兔的皮膚傷口分別被施用以依據上述對照組1及2該三維網狀水性凝膠。實驗被進行總共歷時14天,在施用敷料之後的第2、7及14天之時,分別對各組紐西蘭大白兔的傷口面積進行測量,結果如下表3所示。
表3
施用後第2天 | 施用後第7天 | 施用後第14天 | |
實驗組1 | 3.74 cm 2 | 3.35 cm 2 | 3.01 cm 2 |
實驗組2 | 3.54 cm 2 | 3.09cm 2 | 2.95 cm 2 |
對照組1 | 3.96 cm 2 | 3.74cm 2 | 3.61 cm 2 |
對照組2 | 3.67 cm 2 | 3.44 cm 2 | 3.35 cm 2 |
實驗組1及實驗組2的差異在於水溶性高分子的總重量百分比,實驗組2的羧甲基纖維素鈉含量高於實驗組1,由上表可知,高羧甲基纖維素鈉含量提高了傷口閉合率。其次,實驗組1及實驗組2在動物的傷口上覆蓋聚氨酯防水薄膜以保持傷口溼潤,而對照組1及對照組2並未在動物的傷口上覆蓋聚氨酯防水薄膜,由上表可知,傷口在濕性環境下癒合速度更快。綜上所述,傷口濕性癒合具有以下優勢,首先,有利於壞死組織與纖維蛋白的溶解,濕性環境下,傷口滲出液中的組織蛋白溶解酶,可促進壞死組織的溶解與吸收。此外,保持創面恒溫,加快細胞分裂,促進創面癒合,局部濕潤、減低結痂形成,避免新生肉芽組織機械性損傷,減少更換敷料時 損傷和疼痛;保護創面神經末梢,減少疼痛。又,封閉性保濕環境,敷料形成屏障,感染機會下降,密閉狀態下的微酸環境,抑制細菌生長,有利於白細胞繁殖及發揮功能。
以本發明的高含氧水性凝膠之製造方法所製成的該該三維網狀水性凝膠具有羧甲基纖維素鈉、聚乙烯吡咯烷酮與海藻酸鈉的特性可形成高黏度的膠體,組成一種含有大量水分的網狀高分子膠體、具黏著性與良好的吸水性;膠體與體表面接觸時可發生反覆水合作用,具有向表面提供水分與吸收滲液的雙重功能,藉以控制出血或體液流失。羧甲基纖維素鈉親水基團吸收水分後變成凝膠狀附著在血管創面,膨脹後形成凝膠層,達成傷口止血。其次,該高含氧水性凝膠在傷口表面形成保護層,無色透明,高含水性;藉以維持傷口濕潤,避免摩擦、刺激傷口,不傷害新生肉芽組織,減少二次損傷。由於羧甲基纖維素鈉具有酸性的羧基與血紅蛋白中的Fe
2+結合,形成棕色黏性膠塊,以達到封閉毛細血管末端而止血。此外,凝膠體對血小板亦有黏附及聚集作用,可以加速凝血。
人體實驗
請參閱圖3A至3C,圖3A係為褥瘡病患在未施用本發明三維網狀水性凝膠時所拍攝之患部照片;圖3B係為褥瘡病患在施用本發明三維網狀水性凝膠2天後所拍攝之患部照片;以及圖3C係為褥瘡病患在施用本發明三維網狀水性凝膠7天後所拍攝之患部照片。
如圖3A至3C所示,實施例1的測試者1為一褥瘡病患,該測試者1的傷口能看到脂肪組織,並散發出惡臭,可看到肉芽組織、傷口邊緣捲邊、腐肉或痂皮,但看不見筋膜、肌肉、腱、韌帶、軟骨及骨頭。施用本發明三維網狀水性凝膠於該病患的患部並觀察0至7天傷口癒合情形,該水溶性高分子的總重量百分比計包含:25wt%的海藻酸鈉、25wt%的聚乙烯吡咯烷酮及50wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算;在使用2天後皮膚變黑的情形改善,在使用7天後傷口脂肪組織變小。
請參閱圖4A至4C,圖4A係為糖尿病足在未施用本發明三維網狀水性凝膠時所拍攝之患部照片;圖4B係為糖尿病足在施用本發明三維網狀水性凝膠2天後所拍攝之患部照片;以及圖4C係為糖尿病足在本發明施用三維網狀水性凝膠7天後所拍攝之患部照片。
如圖4A至4C所示,實施例2的測試者2為一糖尿病足,該測試者2的足肌腱韌帶組織已發生破潰,膿性分泌物及壞死組織增多。施用本發明三維網狀水性凝膠於該病患的患部並觀察0至7天傷口癒合情形,該水溶性高分子的總重量百分比計包含:25wt%的海藻酸鈉、25wt%的聚乙烯吡咯烷酮及50wt%的羧甲基纖維素鈉,以100wt%該水溶性高分子總重量百分比計算;在使用2天後潰瘍的情形改善,在使用7天後傷口慢慢癒合且傷口範圍縮小。
綜上所述,根據本發明的三維網狀水性凝膠及其製造方法,該三維網狀水性凝膠在使用後1至3分鐘內可在皮膚的表面形成一層非常薄不可見的薄膜,形成的薄膜及薄膜內的三維網狀結構能更有效地保護活性成分(API)並達到緩釋地效果,緩釋時間可藉由調整三維網狀結構,最高可達到12天。此外該三維網狀水性凝膠具有抗炎性反應、傷口平整功效及預防傷口異常癒合,進而可達到加速傷口癒合的目的以減輕換藥的疼痛。
惟以上所述僅為本發明之較佳實施例,非意欲侷限本發明的專利保護範圍,故舉凡運用本發明說明書及圖式內容所為的等效變化,均同理皆包含於本發明的權利保護範圍內,合予陳明。
10:水溶性高分子
11:溶劑
20:溶膠
30:凝膠
40:三維網狀結構
50:三維網狀水性凝膠
圖1係為本發明三維網狀水性凝膠形成之示意圖;
圖2係為本發明三維網狀水性凝膠之的SEM圖像;
圖3係為本發明三維網狀水性凝膠形成之製造流程圖;
圖4A係為褥瘡病患在未施用本發明三維網狀水性凝膠時所拍攝之患部照片;
圖4B係為褥瘡病患在施用本發明三維網狀水性凝膠2天後所拍攝之患部照片;
圖4C係為褥瘡病患在施用本發明三維網狀水性凝膠7天後所拍攝之患部照片;
圖5A係為糖尿病足在未施用本發明三維網狀水性凝膠時所拍攝之患部照片;
圖5B係為糖尿病足在施用本發明三維網狀水性凝膠2天後所拍攝之患部照片;以及
圖5C係為糖尿病足在施用本發明三維網狀水性凝膠7天後所拍攝之患部照片。
10:水溶性高分子
11:溶劑
20:溶膠
30:凝膠
40:三維網狀結構
50:三維網狀水性凝膠
Claims (5)
- 一種三維網狀水性凝膠之製造方法,該方法包括:將一水溶性高分子加入一溶劑中均勻混合後形成一均質溶液,該水溶性高分子包括羧甲基纖維素鈉;將該水溶性高分子進行一水解反應生成一奈米級水溶性高分子粒子並形成一溶膠;在25~760torr的壓力下,將該溶膠經真空轉變成一凝膠;將該凝膠的溫度控制於攝氏30~70度之間,壓力控制於50~70毫米汞柱之間以調控該凝膠的一溶脹度及該凝膠的結構;該凝膠進行一縮聚合反應,使該奈米級水溶性高分子粒子與該溶劑間發生相互連結而形成一三維網狀結構;將該三維網狀結構經真空以形成一三維網狀水性凝膠;其中,該三維網狀結構具有複數個膠孔形成於其中,該些膠孔的直徑係為16~18μm。
- 如申請專利範圍第1項所述之製造方法,其中,該水溶性高分子更包括海藻酸鈉,該羧甲基纖維素鈉、該海藻酸鈉與該溶劑互相聯結以形成該三維網狀結構。
- 如申請專利範圍第2項所述之製造方法,其中,該水溶性高分子更包括聚乙烯吡咯烷酮,該羧甲基纖維素鈉、該海藻酸鈉、該聚乙烯吡咯烷酮與該溶劑互相聯結以形成該三維網狀結構。
- 如申請專利範圍第3項所述之製造方法,其中,以100wt%該水溶性高分子總重量百分比計算,該水溶性高分子包括10~30wt%的海藻酸鈉、10~30wt%的聚乙烯吡咯烷酮及10~40wt%的羧甲基纖維素鈉。
- 一種三維網狀水性凝膠,其係藉由如申請專利範圍第1至4項所述之製造方法而製成。
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DE (1) | DE202023100113U1 (zh) |
TW (1) | TWI782850B (zh) |
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- 2023-01-11 US US18/095,538 patent/US20230218800A1/en active Pending
Non-Patent Citations (3)
Title |
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期刊 , R GHADI, et al., "Microparticulate polymers and hydrogel for wound healing", Wound Healing Biomaterials, 2, Elsevier, 2016: 203~225. * |
期刊 , RR PALEM, et al., "Physicochemical characterization, drug release, and biocompatibility evaluation of carboxymethyl cellulose-based hydrogels reinforced with sepiolite nanoclay", International Journal of Biological Macromolecules, 178, Elsevier, 2021" 464~476.; * |
期刊 , X HE, et al., "Shape memory composite hydrogel based on sodium alginate dual crosslinked network with carboxymethyl cellulose", European Polymer Journal, 156, Elsevier, 2021: 110592.; * |
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US20230218800A1 (en) | 2023-07-13 |
TW202327657A (zh) | 2023-07-16 |
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