TWI536975B - Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same - Google Patents
Polyelectrolyte complex gels and soft tissue augmentation implants comprising the same Download PDFInfo
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- TWI536975B TWI536975B TW100118946A TW100118946A TWI536975B TW I536975 B TWI536975 B TW I536975B TW 100118946 A TW100118946 A TW 100118946A TW 100118946 A TW100118946 A TW 100118946A TW I536975 B TWI536975 B TW I536975B
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- polyelectrolyte complex
- soft tissue
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Description
本發明係關於一種適用於軟組織植入物之聚電解質錯合物(polyelectrolyte complex,PEC)凝膠及包含該聚電解質錯合物凝膠之軟組織填補植入物。更特定而言，該聚電解質錯合物凝膠為包含幾丁聚醣及γ-聚麩胺酸(γ-PGA)之聚電解質錯合物凝膠。The present invention relates to a polyelectrolyte complex (PEC) gel suitable for soft tissue implants and a soft tissue filling implant comprising the polyelectrolyte complex gel. More specifically, the polyelectrolyte complex gel is a polyelectrolyte complex gel comprising chitosan and γ-polyglutamic acid (γ-PGA).
皮膚的填補在從受傷中恢復或於美容或支撐等目的中，可能成為填補的重要因素。例如皮膚在正常老化下可能會變得鬆散或形成如鼻唇皺摺、皺紋、坑洞及缺陷等。在臉上的皺摺或皺紋可能會影響一個人的自信心，甚至是職業生涯，因此以軟組織填補術矯正缺陷及對抗衰老的影響也變得日益重要。目前，軟組織填補術可藉由諸如蠟狀物質、膠原蛋白、脂肪、矽酮、聚乳酸、聚乙烯、聚四氟乙烯或水膠為主之聚合物組成物等材料加以填補，這些材料可根據使用的情況而有不同形式，例如濃溶液、凝膠、珠或懸浮物等，且可做為植入物或運送植入物之載體。理想的軟組織填補材料應具有足夠之耐久性並可維持於指定位置，不應從植入部位遷移。The filling of the skin may be an important factor in the recovery from injury or for cosmetic or support purposes. For example, the skin may become loose or form such as nasolabial folds, wrinkles, potholes, and defects under normal aging. Wrinkles or wrinkles on the face may affect a person's self-confidence, even a career, so it is increasingly important to use soft tissue filling to correct defects and fight aging. At present, soft tissue filling can be filled by materials such as waxy substances, collagen, fat, ketone, polylactic acid, polyethylene, polytetrafluoroethylene or water-based polymer. These materials can be There are different forms of use, such as concentrated solutions, gels, beads or suspensions, and the like, and can be used as an implant or carrier for transporting the implant. The ideal soft tissue filling material should be sufficiently durable and maintainable at the designated location and should not migrate from the implant site.
美國第4,803,075號專利揭露一種用於軟組織填補術的注射植入物組合物，其包括一種生物相容微粒(如交聯的膠原蛋白或諸如肝醣或麥芽糖等生物相容之流體潤滑劑)的水性懸浮液，以改善該生物材料懸浮液的可注射性。然而，該專利之組合物不具有足夠之耐久性，所以它們無法在體內停留足夠長的時間。US Patent No. 4,803,075 discloses an injection implant composition for soft tissue filling that includes a biocompatible particle such as cross-linked collagen or a biocompatible fluid lubricant such as glycogen or maltose. An aqueous suspension to improve the injectability of the suspension of biological material. However, the compositions of this patent do not have sufficient durability so they cannot stay in the body for a sufficient period of time.
美國第6,537,574號專利涉及一種生物相容材料，其包括由一種生物可相容性陶瓷物質之平滑、圓形、細碎的實質球體顆粒所組成之基質，其彼此鄰近或接觸，且提供一支架或結構以供自體性、三維、無定向的非瘢痕性軟組織於強化位置生長；在其中一個實施例中，在將懸浮於羧甲基維素鈉中之20至45 μm或75至125 μm的顆粒狀羥磷灰石鈣的滅菌樣本注射至組織後，羧甲基纖維素於三個月內被吸收，留下羥基磷灰石鈣於組織中。雖不難將樣本植入於軟組織內，但維持效果不易，須於三個月內補行第二次注射。US Patent No. 6,537,574 is directed to a biocompatible material comprising a matrix of smooth, round, finely divided substantial spherical particles of a biocompatible ceramic material adjacent or in contact with one another and providing a scaffold or The structure is grown in a strengthened position for autologous, three-dimensional, non-oriented non-scarring soft tissue; in one embodiment, it is suspended in sodium carboxymethyl vegas 20 to 45 μm or 75 to 125 μm After the sterilized sample of granular hydroxyapatite calcium was injected into the tissue, carboxymethylcellulose was absorbed within three months, leaving hydroxyapatite calcium in the tissue. Although it is not difficult to implant the sample in the soft tissue, the maintenance effect is not easy, and the second injection must be completed within three months.
英國第2222176號專利提供了一個用於填補凹陷性疤痕、不對稱眼眶底及表面骨缺陷等的改良微植入方法與設備。該專利採用具有約20至3000微米之經表面處理的微粒，其可經適當的生理載體和皮下注射針及注射器注射到預定之位置，諸如凹陷瘢痕的底部、凹陷的皮膚區域之下以及在骨與軟骨表面不規則處的軟骨膜與骨膜之下。在需要使用硬物質之情況下，可利用某些鈣鹽(包括羥基磷灰石或其他類似之晶體材料)、生物相容陶瓷、生物相容金屬(例如特定不銹鋼顆粒)或玻璃等生物相容材料；在某些情況下，可能需要使用完全惰性的載體，如矽油、脂肪及玻尿酸酯(例如乙基玻尿酸酯和聚乙烯吡咯烷酮等)。然而，這些載體會快速降解，因此無法長期支撐目標物。British Patent No. 2,222,176 provides an improved micro-implantation method and apparatus for filling concave scars, asymmetric eyelid bottoms, and surface bone defects. This patent employs surface treated microparticles having from about 20 to 3000 microns which can be injected into a predetermined location via a suitable physiological carrier and hypodermic needle and syringe, such as the bottom of a depressed scar, a depressed skin area, and bone. Below the perichondrium and periosteum of the cartilage surface irregularities. Biocompatibility with certain calcium salts (including hydroxyapatite or other similar crystalline materials), biocompatible ceramics, biocompatible metals (eg specific stainless steel particles) or glass, where hard materials are required Materials; in some cases, it may be necessary to use completely inert carriers such as emu oil, fat and hyaluronic acid (such as ethyl hyaluronic acid and polyvinylpyrrolidone). However, these carriers degrade rapidly and therefore do not support the target for a long time.
美國第5,344,452號專利涉及一個具組織相容性固體為主的異質性植入物，其特別適用於將皮膚之不規則處平坦化，但亦可用於其他目的的整形外科。該專利係使用被結締組織包覆或嵌入至結締組織纖維之20-40微米之聚甲基丙烯酸甲酯(PMMA)顆粒，其懸浮於人體內之膠原蛋白。然而，由於膠原蛋白係源自牛等動物，此種植入物有導致過敏之可能。U.S. Patent No. 5,344,452 is directed to a heterogeneous implant based on tissue compatible solids which is particularly useful for planarizing irregularities in the skin, but can also be used for orthopedic surgery for other purposes. This patent uses 20-40 micron polymethyl methacrylate (PMMA) particles coated or embedded in connective tissue fibers suspended in the human body. However, since collagen is derived from animals such as cattle, such implants have the potential to cause allergies.
美國專利第2008/0025950 A1號公開案揭露一種化合物及製造方法及使用該化合物於無瘢痕傷口治療、傳輸生物活性劑或活細胞及預防手術後或骨骼和軟骨的修復後沾黏之方法。該化合物可為經修飾之大分子化合物，其係藉由引進至少一個肼反應性基團和/或胺基氧基反應性基團以促進交聯。然而，形成經修飾之大分子化合物必須使用交聯反應。U.S. Patent No. 2008/0025950 A1 discloses a compound and method of manufacture and a method of using the compound for the treatment of scarless wounds, delivery of bioactive agents or living cells, and prevention of post-surgical or bone and cartilage repair. The compound can be a modified macromolecular compound that promotes crosslinking by introducing at least one hydrazine reactive group and/or an amineoxy reactive group. However, a crosslinking reaction must be used to form a modified macromolecular compound.
R.A. Appell的「人工尿道括約肌與尿道周圍之注射作用(The Artificial Urinary Sphincter and Periurethral Injections,Obstetrics and Gynecolocy Report Vol. 2,No. 3,pp. 334-342,(1990))」回顧評論中揭露各種用以治療尿道括約肌機能不全之方式，包括使用可注射物諸如尺寸約4至100微米之不規則形狀的聚四氟乙烯微聚合物顆粒以及甘油與聚山梨酸酯。另一種尿道周圍的可注射構件包括高度純化之牛真皮膠原蛋白，其係與戊二醛交聯及分散於磷酸鹽緩衝的生理食鹽水中。Kresa等人揭露一種用以治療聲門閉合不全之聲帶調整之方法，其中包括將先前經乾燥成玻璃狀、堅硬狀態之一親水性凝膠的造型植入物導入聲帶中(Kresa et al,「Hydron Gel Implants in Vocal Cords」Otolaryngolocy Head and Neck Surgery,Vol. 98. No. 3,pp. 242-245,(March 1988))。在前述兩篇文獻中，體內降解時間為評估軟組織植入物的一個重要因素。舉例來說，膠原蛋白會迅速在體內發生水解及降解並導致相對短的臨床效果，因此患者必須於通常每隔數月的時間再接受額外注射，以維持組織之支撐性。然而不斷進行的注射過程不但昂貴，亦會造成不便、不適或者疼痛及其他副作用。此外，任何包含注射等侵入性的療程都有交叉污染和感染的風險。因此，在此技術領域中對於可用於軟組織填補術且更持久之注射材料仍有需求。RA Appell's review of the "The Artificial Urinary Sphincter and Periurethral Injections, Obstetrics and Gynecolocy Report Vol. 2, No. 3, pp. 334-342, (1990)" Means for treating urethral sphincter insufficiency include the use of injectables such as irregularly shaped polytetrafluoroethylene micropolymer particles having a size of about 4 to 100 microns, and glycerin and polysorbate. Another injectable member surrounding the urethra comprises highly purified bovine dermal collagen which is cross-linked with glutaraldehyde and dispersed in phosphate-buffered physiological saline. Kresa et al. disclose a method of vocal cord adjustment for the treatment of glottic insufficiency, which involves introducing a styling implant of a hydrophilic gel that has been previously dried into a glassy, hard state into the vocal cords (Kresa et al , "Hydron" Gel Implants in Vocal Cords" Otolaryngolocy Head and Neck Surgery, Vol. 98. No. 3, pp. 242-245, (March 1988)). In both of the above documents, in vivo degradation time is an important factor in the evaluation of soft tissue implants. For example, collagen rapidly hydrolyzes and degrades in the body and results in relatively short clinical effects, so patients must receive additional injections every few months to maintain tissue support. However, the ongoing injection process is not only expensive, but also causes inconvenience, discomfort or pain and other side effects. In addition, any invasive procedure, including injections, carries the risk of cross-contamination and infection. Therefore, there is still a need in the art for injection materials that are useful for soft tissue filling and that are more durable.
本發明係關於一種聚電解質錯合物凝膠，其包含幾丁聚醣及具有分子量自約1 kDa至約400 kDa的γ-聚麩胺酸(γ-PGA)或其鹽及一種水性溶液，其中幾丁聚醣及γ-聚麩胺酸錯合物凝膠可於該水性溶液中膨潤。本發明亦提供一種軟組織填補植入物，其包含做為載體或填充材之本發明聚電解質錯合物凝膠及選用之添加劑。本發明之聚電解質錯合物凝膠及包含彼等之軟組織填補植入物具有長降解時間與更佳的支撐性，因此對軟組織可提供良好的維持性。The present invention relates to a polyelectrolyte complex gel comprising chitosan and γ-polyglutamic acid (γ-PGA) having a molecular weight of from about 1 kDa to about 400 kDa or a salt thereof and an aqueous solution, The chitosan and γ-polyglutamic acid complex gel can be swollen in the aqueous solution. The present invention also provides a soft tissue filling implant comprising the polyelectrolyte complex gel of the present invention as a carrier or filler and an additive selected. The polyelectrolyte complex gel of the present invention and soft tissue-filling implants comprising the same have long degradation time and better support, and thus provide good maintenance to soft tissues.
本發明亦提供一種軟組織填補植入物，其包括本發明之聚電解質錯合物凝膠、載體或填充材及選用之添加劑。The present invention also provides a soft tissue filling implant comprising the polyelectrolyte complex gel, carrier or filler of the present invention and optional additives.
本發明之軟組織填補物為利用電荷相反的聚電解質(如多醣與多肽)交聯形成之聚電解質錯合物凝膠。本發明係藉由混合電荷相反的聚電解質以形成聚電解質錯合物凝膠，因此無需使用化學交聯劑。在典型的真皮植入系統中，應包含至少填充材、載體及選用之添加劑，而本發明所開發的聚電解質錯合物凝膠，可依其交聯程度的不同，做為用於軟組織填補之載體或填充材。換言之，聚電解質錯合物凝膠可扮演載體或填充材之角色。本發明之電解質錯合物凝膠具有可傳輸物質的能力且無細胞潛在毒性，由於其良好之可注入性，尤其適合經由細針頭微創注射入軟組織中，加以填補。此外，該聚電解質錯合物凝膠具有較長的降解時間及更佳的支撐性，從而為軟組織提供良好的維持特性。The soft tissue filling of the present invention is a polyelectrolyte complex gel formed by crosslinking a polyelectrolyte having opposite charges, such as a polysaccharide and a polypeptide. The present invention forms a polyelectrolyte complex gel by mixing a polyelectrolyte of opposite charge, thus eliminating the need to use a chemical crosslinker. In a typical dermal implant system, at least a filler, a carrier and optional additives should be included, and the polyelectrolyte complex gel developed by the present invention can be used for soft tissue filling according to the degree of cross-linking. Carrier or filler. In other words, the polyelectrolyte complex gel can act as a carrier or filler. The electrolyte complex gel of the present invention has the ability to transport substances and has no potential toxicity to cells, and is particularly suitable for injection into soft tissues via a fine needle into a soft tissue due to its good injectability. In addition, the polyelectrolyte complex gel has a longer degradation time and better support, thereby providing good maintenance characteristics for soft tissues.
在用於本說明書及所附的請求項中時，除非文中有明確指出相反之情況，單數形式的「一(a)」、「一(an)」及「該(the)」等用語亦包含複數之情形。The terms "a", "an" and "the" are used in the singular and the singular and The case of plural.
在本文中使用「軟組織」一詞時，係指非骨骼組織。換言之，其排除骨骼、韌帶、軟骨、椎間盤和纖維組織。When the term "soft tissue" is used in this context, it refers to non-skeletal tissue. In other words, it excludes bones, ligaments, cartilage, intervertebral discs, and fibrous tissue.
在本文中使用「軟組織填補」一詞時，其包含但不限於下列內容：真皮組織填補，紋、皺褶、皺紋、輕微面部凹陷、兔唇及類似情形之填充，特別是在面部及頸部；因老化或疾病導致之輕微畸形之矯正，包括手部及腳部、手指及腳趾；為恢復聲音能力所做之聲帶或聲門擴張；睡眠紋與表情紋之真皮填充；因老化造成真皮及皮下組織流失之替換；唇部填補；魚尾紋及眼周圍眼眶溝線之填充；隆胸；口腔填補、下巴填補、頰部及/或鼻部填補；因例如過份抽脂或其他外傷導致之軟組織、真皮或皮下凹陷之填充、痤瘡或外傷性疤痕及皺紋填充；鼻唇紋、鼻眉紋及法令紋填充；以及因尿失禁(尤其是壓力性尿失禁)之尿道組織注射使用之填充。As used herein, the term "soft tissue filling" includes, but is not limited to, the following: dermal tissue filling, lines, wrinkles, wrinkles, slight facial depressions, filling of the rabbit's lips and the like, particularly on the face and neck; Correction of minor deformities caused by aging or disease, including hands and feet, fingers and toes; vocal cord or glottis dilation for restoring sound; dermal filling of sleep and expression lines; dermis and subcutaneous tissue due to aging Replacement of loss; lip filling; crow's feet and filling of the eyelid groove line around the eye; breast augmentation; oral filling, chin filling, buccal and/or nasal filling; soft tissue, dermis due to, for example, excessive liposuction or other trauma Filling of subcutaneous depressions, filling of acne or traumatic scars and wrinkles; filling of nasolabial lines, nasal eyebrows and striated lines; and filling of urethral tissue injections for urinary incontinence (especially stress urinary incontinence).
「生物吸收」一詞係指能夠被吸收並自人體排除。The term "bioabsorption" means being able to be absorbed and excluded from the body.
「生物相容」一詞係指生理上能被活組織及器官接受。The term "biocompatible" means physiologically acceptable to living tissues and organs.
「聚電解質錯合物凝膠」一詞係指由帶相反符號電荷之大分子組成之中性聚合錯合物膠，該相反符號之電荷藉由靜電相互作用造成大分子之結合。聚電解質錯合物凝膠可藉由陽離子聚合物(具有正電荷之聚電解質)及陰離子聚合物(具有負電荷之聚電解質)混合後立即形成。The term "polyelectrolyte complex gel" refers to an intermediate polymeric complex gel composed of macromolecules with opposite sign charges, the opposite sign of which causes the binding of macromolecules by electrostatic interaction. The polyelectrolyte complex gel can be formed immediately after mixing by a cationic polymer (a polyelectrolyte having a positive charge) and an anionic polymer (a polyelectrolyte having a negative charge).
「交聯」一詞係指藉由帶相反電荷之聚電解質，如多醣及多肽，形成一聚電解質錯合物凝膠之過程。The term "crosslinking" refers to the process of forming a polyelectrolyte complex gel by means of oppositely charged polyelectrolytes, such as polysaccharides and polypeptides.
本文使用之「經注入(注射)」、「注入(注射)」或「可注入性」等用語包括任何聚合物組合物之投予，如注射、浸入或或通過任何環形輸送裝置傳送至個體。注射包括通過一管狀物輸送。As used herein, terms such as "injection (injection)", "injection (injection)" or "injectability" include administration of any polymeric composition, such as injection, infusion, or delivery to an individual via any endless delivery device. Injection includes delivery through a tube.
本發明之一目的係提供一種聚電解質錯合物凝膠，其包含幾丁聚醣、具有分子量自約1 kDa至約400 kDa之γ-聚麩胺酸(γ-PGA)或其鹽及一種水性溶液，其中該幾丁聚醣及該γ-PGA形成之水膠該水性溶液中膨潤。One object of the present invention is to provide a polyelectrolyte complex gel comprising chitosan, γ-polyglutamic acid (γ-PGA) having a molecular weight of from about 1 kDa to about 400 kDa or a salt thereof and a salt thereof An aqueous solution in which the chitosan and the water gel formed by the γ-PGA are swollen in the aqueous solution.
在一個實施例中，γ-PGA分子量之範圍係自約1 kDa至約350 kDa、約1 kDa至約300 kDa、約1 kDa至約250 kDa、約1 kDa至約200 kDa、約1 kDa至約150 kDa、約1 kDa至約100 kDa、約1 kDa至約50 kDa、約5 kDa至350 kDa、約5 kDa至約300 kDa、約5 kDa至約250 kDa、約5 kDa至約200 kDa、約5 kDa至約150 kDa、約5 kDa至約100 kDa、約5 kDa至約50 kDa、約10 kDa至約400 kDa、約10 kDa至約350 kDa、約10 kDa至約300 kDa、約10 kDa至約250 kDa、約10 kDa至約200 kDa、約10 kDa至約150 kDa、約10 kDa至約100 kDa、約10 kDa至約50 kDa、約50 kDa至約400 kDa、約50 kDa至約350 kDa、約50 kDa至約300 kDa、約50 kDa至約250 kDa、約50 kDa至約200 kDa、約50 kDa至約150 kDa、約50 kDa至約100 kDa、約100 kDa至約400 kDa、約100 kDa至約350 kDa、約100 kDa至約300 kDa、約100 kDa至約250 kDa、約100 kDa至約200 kDa或約100 kDa至約150 kDa或其任何組合。In one embodiment, the gamma-PGA molecular weight ranges from about 1 kDa to about 350 kDa, from about 1 kDa to about 300 kDa, from about 1 kDa to about 250 kDa, from about 1 kDa to about 200 kDa, from about 1 kDa to About 150 kDa, about 1 kDa to about 100 kDa, about 1 kDa to about 50 kDa, about 5 kDa to 350 kDa, about 5 kDa to about 300 kDa, about 5 kDa to about 250 kDa, about 5 kDa to about 200 kDa From about 5 kDa to about 150 kDa, from about 5 kDa to about 100 kDa, from about 5 kDa to about 50 kDa, from about 10 kDa to about 400 kDa, from about 10 kDa to about 350 kDa, from about 10 kDa to about 300 kDa, about 10 kDa to about 250 kDa, about 10 kDa to about 200 kDa, about 10 kDa to about 150 kDa, about 10 kDa to about 100 kDa, about 10 kDa to about 50 kDa, about 50 kDa to about 400 kDa, about 50 kDa Up to about 350 kDa, from about 50 kDa to about 300 kDa, from about 50 kDa to about 250 kDa, from about 50 kDa to about 200 kDa, from about 50 kDa to about 150 kDa, from about 50 kDa to about 100 kDa, from about 100 kDa to about 400 kDa, from about 100 kDa to about 350 kDa, from about 100 kDa to about 300 kDa, from about 100 kDa to about 250 kDa, from about 100 kDa to about 200 kDa or from about 100 kDa to about 150 kDa, or any combination thereof.
在另一個實施例中，γ-PGA之鹽為H形式或鹽形式(例如鈉鹽、鉀鹽、鈣鹽或鎂鹽等)。In another embodiment, the salt of γ-PGA is in the H form or in the form of a salt (eg, a sodium salt, a potassium salt, a calcium salt, or a magnesium salt, etc.).
在另一個實施例中，幾丁聚醣及γ-PGA或其鹽具有自約0.1重量%至約10重量%及約0.1重量%至約20重量%之範圍的含量。較佳地，幾丁聚醣的含量為約0.5重量%至約10重量%、約1重量%至約10重量%、約2重量%至約10%、約0.5重量%至約5重量%、約1重量%至約5重量%或約2重量%至約5重量%。更佳地，γ-PGA或其鹽之含量為約0.5重量%至約20重量%、約1重量%至約20重量%、約1重量%至約15重量%、約1重量%至約10重量%或約1重量%至約5重量%。In another embodiment, the chitosan and gamma-PGA or salts thereof have a content ranging from about 0.1% to about 10% by weight and from about 0.1% to about 20% by weight. Preferably, the chitosan is present in an amount of from about 0.5% to about 10% by weight, from about 1% to about 10% by weight, from about 2% to about 10%, from about 0.5% to about 5% by weight, From about 1% by weight to about 5% by weight or from about 2% by weight to about 5% by weight. More preferably, the content of γ-PGA or a salt thereof is from about 0.5% by weight to about 20% by weight, from about 1% by weight to about 20% by weight, from about 1% by weight to about 15% by weight, from about 1% by weight to about 10% by weight % by weight or from about 1% by weight to about 5% by weight.
在另一個實施例中，幾丁聚醣可由幾丁質之N-去乙醯化獲得。幾丁聚醣是一種由隨機分佈之β-(1-4)-連結-D-葡萄胺糖(去乙醯化單元)及N-乙醯-D-葡萄胺糖(乙醯化單元)組成之線性多糖。用於本發明之組合中之幾丁聚醣係指原態幾丁聚醣或其衍生物，衍生物包括但不限於羧甲基幾丁聚醣、羧甲基幾丁聚醣、N-亞甲基亞磷酸幾丁聚醣、磺酸化幾丁聚醣、三甲基幾丁聚醣、三乙基幾丁聚醣、N-醯基幾丁聚醣、幾丁聚醣甲基丙烯酸酯、氮-異丙基丙烯醯胺幾丁聚醣及琥珀酸化幾丁聚醣。任何市售之幾丁聚醣及幾丁質(包含有去乙醯化單元)均可用於本發明。較佳地，幾丁聚醣之分子數量超過100 kDa。較佳地，幾丁聚醣的分子量範圍係自約100 kDa至約2000 kDa、約100 kDa至約1500 kDa、約100 kDa至約1000 kDa、約200 kDa至約2000 kDa、約200 kDa至約1500 kDa、約200 kDa至約1500 kDa、約100 kDa至約700 kDa、約100 kDa至約400 kDa或約400 kDa至約700 kDa，或其任何組合。In another embodiment, chitosan can be obtained by N-deacetylation of chitin. Chitosan is composed of randomly distributed β-(1-4)-linked-D-glucamine (deacetylated unit) and N-acetyl-D-glucamine (acetylated unit) Linear polysaccharide. Chitosan for use in the combination of the invention refers to the original chitosan or a derivative thereof, including but not limited to carboxymethyl chitosan, carboxymethyl chitosan, N-Asia Chitosan methyl phosphite, chitosan sulfonated, trimethyl chitosan, triethyl chitosan, N-mercapto chitosan, chitosan methacrylate, Nitro-isopropylacrylamide amine chitosan and succinicated chitosan. Any commercially available chitosan and chitin (including deacetylated units) can be used in the present invention. Preferably, the number of molecules of chitosan exceeds 100 kDa. Preferably, the chitosan has a molecular weight ranging from about 100 kDa to about 2000 kDa, from about 100 kDa to about 1500 kDa, from about 100 kDa to about 1000 kDa, from about 200 kDa to about 2000 kDa, from about 200 kDa to about 1500 kDa, from about 200 kDa to about 1500 kDa, from about 100 kDa to about 700 kDa, from about 100 kDa to about 400 kDa or from about 400 kDa to about 700 kDa, or any combination thereof.
根據本發明，聚電解質錯合物凝膠可被使用做為用於軟組織填補之載體所承載之填充材或容納填充材之載體。本發明之聚電解質錯合物凝膠藉由幾丁聚醣及具有自約1 kDa至約400 kDa分子量之γ-PGA或其鹽交聯而形成。本發明之聚電解質錯合物凝膠之流動性隨著交聯程度有所不同，當幾丁聚醣與高分子量之γ-PGA交聯時，所形成的聚電解質錯合物凝膠具有較低的流動性，而於此情形時，該聚電解質錯合物凝膠可做為用於軟組織填補之填充材；當幾丁聚醣與低分子量之γ-PGA交聯時，所形成的聚電解質錯合物凝膠具有較佳的流動性，此時該聚電解質錯合物凝膠可做為用於軟組織填補之載體。In accordance with the present invention, a polyelectrolyte complex gel can be used as a filler or a carrier for holding a filler carried by a carrier for soft tissue filling. The polyelectrolyte complex gel of the present invention is formed by crosslinking chitosan and γ-PGA having a molecular weight of from about 1 kDa to about 400 kDa or a salt thereof. The fluidity of the polyelectrolyte complex gel of the present invention varies with the degree of crosslinking. When the chitosan is crosslinked with the high molecular weight γ-PGA, the polyelectrolyte complex gel formed is more Low fluidity, and in this case, the polyelectrolyte complex gel can be used as a filler for soft tissue filling; when chitosan is crosslinked with low molecular weight γ-PGA, the formed poly The electrolyte complex gel has better fluidity, and the polyelectrolyte complex gel can be used as a carrier for soft tissue filling.
可使用任何能使本發明之聚電解質錯合物凝膠膨潤的合適水性溶液。例如，聚電解質錯合物凝膠可利用具有弱酸性pH值之水性溶液膨潤。較佳地，pH範圍為3.0到6.8。較佳地，水性溶液是水或含水酒精。水性溶液的實例包括但不限於水、甘油、異丙醇、乙醇、乙二醇或其混合物。用於凝膠載體之其他合適的溶劑對於技藝人士來說是顯而易見的。界面活性劑、穩定劑、pH緩衝液和其他添加劑等亦可使用，且對技藝人士來說為顯而易見之事。Any suitable aqueous solution which swells the polyelectrolyte complex of the present invention can be used. For example, a polyelectrolyte complex gel can be swollen with an aqueous solution having a weakly acidic pH. Preferably, the pH ranges from 3.0 to 6.8. Preferably, the aqueous solution is water or aqueous alcohol. Examples of aqueous solutions include, but are not limited to, water, glycerin, isopropanol, ethanol, ethylene glycol, or mixtures thereof. Other suitable solvents for the gel carrier will be apparent to those skilled in the art. Surfactants, stabilizers, pH buffers, and other additives can also be used, and will be apparent to those skilled in the art.
根據本發明，形成本發明之聚電解質錯合物凝膠不需使用交聯劑。本發明之聚電解質錯合物凝膠之形成係基於多電荷機制。本發明之聚電解質錯合物凝膠有足夠之耐久性，能存留在體內足夠長的時間而仍具有良好的支撐能力。較佳地，本發明之聚電解質錯合物凝膠可存留於體內至少2個月、3個月、4個月、5個月或6個月。更佳地，本發明之聚電解質錯合物凝膠可存留於體內至少6個月。較佳地，本發明之聚電解質錯合物凝膠可存留於體內2至12個月、3至12個月、4至12個月、5至12個月、6至12個月、7至12個月、8至12個月、9至12個月、10至12個月、2至6個月或4至8個月。According to the present invention, it is not necessary to use a crosslinking agent to form the polyelectrolyte complex gel of the present invention. The formation of the polyelectrolyte complex gel of the present invention is based on a multi-charge mechanism. The polyelectrolyte complex gel of the present invention has sufficient durability to remain in the body for a sufficiently long period of time while still having good supportability. Preferably, the polyelectrolyte complex gel of the present invention may remain in the body for at least 2 months, 3 months, 4 months, 5 months or 6 months. More preferably, the polyelectrolyte complex gel of the present invention may remain in the body for at least 6 months. Preferably, the polyelectrolyte complex gel of the present invention may remain in the body for 2 to 12 months, 3 to 12 months, 4 to 12 months, 5 to 12 months, 6 to 12 months, 7 to 12 months, 8 to 12 months, 9 to 12 months, 10 to 12 months, 2 to 6 months, or 4 to 8 months.
另一方面，本發明提供一種軟組織填補植入物，其包含本發明之聚電解質錯合物凝膠以做為載體或填充材，以及一選用之添加劑。In another aspect, the present invention provides a soft tissue-filling implant comprising the polyelectrolyte complex gel of the present invention as a carrier or filler, and an optional additive.
如前所述，本發明之聚電解質錯合物凝膠可做為載體或填充材。因此，本發明之聚電解質錯合物凝膠可做為載體以承載填充材及選用之添加劑。或者，本發明之聚電解質錯合物凝膠可做為承載於載體中之填充材。視本發明之聚電解質錯合物之角色不同，其可與載體或填充材及選用之添加劑相結合以構成軟組織填補植入物。As described above, the polyelectrolyte complex gel of the present invention can be used as a carrier or a filler. Therefore, the polyelectrolyte complex gel of the present invention can be used as a carrier to carry a filler and an additive selected. Alternatively, the polyelectrolyte complex gel of the present invention can be used as a filler supported in a carrier. Depending on the role of the polyelectrolyte complex of the present invention, it can be combined with a carrier or filler and optional additives to form a soft tissue filling implant.
在一實施例中，可使用各種生物相容載體以支撐本發明之聚電解質錯合物凝膠。合適載體之選擇將取決於顆粒大小、填充材量、注射針頭大小及填充材之性質。載體之實例包括但不限於：***膠、卡波姆(Carbomer)共聚物及單聚物、卡波姆互聚物、水膠、多醣、巨環多醣、寡聚醣、澱粉、乙醯澱粉、纖維素、纖維素衍生物、甲基纖維素、羧甲基纖維素鈉、羧甲基纖維素(CMC)、乙基羥乙基纖維素(EHEC)、乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素(HPMC)、乙基纖維素、烷基纖維素、烷氧基纖維素、羥基乙基纖維素、乙烯基吡咯啶酮-乙酸乙烯酯共聚物(copovidone)、聚乙烯基吡咯啶酮(povidone)、明膠、瓜爾膠、羥丙甲纖維素、羥丙甲纖維素醋酸琥珀酸酯、麥芽糊精、糖漿、洋菜、蘋果醯胺酸、單硬脂酸鋁、綠坡縷石(attapulgite)、結蘭膠、羥丙甲纖維素、麥芽糊精、果膠、藻酸丙二醇酯、藻酸鈉、藻酸鈣、膠體二氧化矽、黃蓍膠、黃原膠，卵磷脂、三碘苯衍生物、碘海醇(iohexyl)、碘帕醇(iopamidol)、，碘噴拖(iopentol)、蔗糖，鹿角菜膠、瓊脂、甘露糖醇、糖精鈉、山梨糖醇、腦磷脂、炔二醇、卡波蠟(carbowax)、聚有機磺酸、烷氧基化表面活性劑、烷基苯酚聚氧乙烯醚、乙氧基化脂肪酸、乙醇聚氧乙烯醚、乙醇聚氧烯醚、聚乙烯氧化物、聚(環氧丙烷)、聚乙二醇(PEG)、聚(丙二醇)、聚乙烯醇(PVA)聚合物或共聚物、聚丙烯醯胺、聚(乙烯羧酸)、聚甲基丙烯酸、聚丙烯酸聚合物或共聚物、聚氨基酸、白蛋白、膠原蛋白，纖維蛋白、生物膠(bioglue)、纖維素、卡波普(Carbopol)、泊洛沙姆(Poloxamer)、普朗尼克(Pluronic)、，鐵窗尼克(Tetronics)、PEO-PPO-PEO三區塊共聚物、PEO-PPO與伸乙基二胺之四官能區塊聚合物或共聚物、聚HEMA聚合物或共聚物、Hypan聚合物或共聚物、澱粉乙醇酸聚合物或共聚物鹽、聚氧基伸烷基醚、聚乙烯吡啶、聚賴氨酸、聚精氨酸、聚天門冬胺酸及聚麩氨酸、聚伸丁基氧化物、聚(羥基乙基丙烯酸酯)、聚(羥基甲基丙烯酸乙酯)、甲氧基果膠凝膠、鄰苯二甲酸醋酸纖維素、有機油、B-葡聚醣、聚山梨酯、乳酸酯、己酸酯、玻尿酸、糊精、葡聚醣、葡萄糖、及上述之混合物。In one embodiment, various biocompatible carriers can be used to support the polyelectrolyte complex gels of the present invention. The choice of a suitable carrier will depend on the particle size, the amount of filler, the size of the needle, and the nature of the filler. Examples of carriers include, but are not limited to, gum arabic, Carbomer copolymers and monomers, carbomer interpolymers, water gels, polysaccharides, macrocyclic polysaccharides, oligosaccharides, starch, acetaminophen, Cellulose, cellulose derivative, methyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose (CMC), ethyl hydroxyethyl cellulose (EHEC), ethyl cellulose, hydroxypropyl cellulose , hydroxypropyl methylcellulose (HPMC), ethyl cellulose, alkyl cellulose, alkoxy cellulose, hydroxyethyl cellulose, vinyl pyrrolidone-vinyl acetate copolymer (copovidone), poly Povidone, gelatin, guar gum, hypromellose, hypromellose acetate succinate, maltodextrin, syrup, amaranth, apple lysine, monostearic acid Aluminum, attapulgite, lanolin, hypromellose, maltodextrin, pectin, propylene glycol alginate, sodium alginate, calcium alginate, colloidal cerium oxide, tragacanth, Xanthan gum, lecithin, triiodobenzene derivatives, iohexyl, iupamidol, iopentol, cane , carrageenan, agar, mannitol, sodium saccharin, sorbitol, cephalin, acetylene glycol, carbowax, polyorganosulfonic acid, alkoxylated surfactant, alkylphenol polyoxygen Vinyl ether, ethoxylated fatty acid, ethanol polyoxyethylene ether, ethanol polyoxyalkylene ether, polyethylene oxide, poly(propylene oxide), polyethylene glycol (PEG), poly(propylene glycol), polyvinyl alcohol ( PVA) polymer or copolymer, polypropylene decylamine, poly(ethylene carboxylic acid), polymethacrylic acid, polyacrylic acid polymer or copolymer, polyamino acid, albumin, collagen, fibrin, bioglue , cellulose, Carbopol, Poloxamer, Pluronic, Tetronics, PEO-PPO-PEO three-block copolymer, PEO-PPO and B a tetrafunctional block polymer or copolymer of a diamine, a polyHEMA polymer or copolymer, a Hypan polymer or copolymer, a starch glycolic acid polymer or copolymer salt, a polyoxyalkylene ether, a polyvinyl pyridine, Polylysine, polyarginine, polyaspartic acid and polyglutamic acid, polybutylene oxide , poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), methoxyl pectin gel, cellulose acetate phthalate, organic oil, B-glucan, polysorbate, milk Acid esters, caproates, hyaluronic acid, dextrin, dextran, glucose, and mixtures thereof.
在一個實施例中，可將各種生物相容填充材承載於做為載體之本發明聚電解質錯合物凝膠中。填充材之實例包括但不限於：多醣(如玻尿酸(HA))、無機鹽、膠原蛋白、多元醇、羥基磷灰石(如羥基磷灰石鈣)、矽酮及明膠、聚甲基丙烯酸甲酯或聚左旋乳酸(PLLA)、羧甲基纖維素、交聯CMC水凝膠、脂肪及蠶絲蛋白。In one embodiment, various biocompatible filler materials can be carried in the polyelectrolyte complex gel of the present invention as a carrier. Examples of fillers include, but are not limited to, polysaccharides (such as hyaluronic acid (HA)), inorganic salts, collagen, polyols, hydroxyapatite (such as hydroxyapatite calcium), anthrone and gelatin, polymethyl methacrylate Ester or poly-L-lactic acid (PLLA), carboxymethyl cellulose, cross-linked CMC hydrogel, fat and silk fibroin.
根據本發明，顆粒形式之無機鹽包括但不限於：磷酸鈣顆粒、矽酸鈣顆粒、碳酸鈣顆粒、氧化鋁顆粒、氧化鋯顆粒、羥基磷灰石顆粒、含羥基磷灰石顆粒之氧化鋯、焦磷酸鈣顆粒、四鈣磷酸鹽顆粒、三鈣磷酸鹽顆粒、八鈣磷酸鹽顆粒、氟磷灰石(Ca10(PO4)6F2)顆粒，鈣磷灰石顆粒或其混合物。較佳地，該無機鹽為磷酸鈣顆粒、氧化鋯顆粒、羥基磷灰石顆粒、含羥基磷灰石顆粒之氧化鋯，或其混合物。較佳地，該無機鹽為羥基磷灰石顆粒、焦磷酸鈣顆粒、四鈣磷酸鹽顆粒、三鈣磷酸鹽顆粒、八鈣磷酸鹽顆粒、氟磷灰石(Ca10(PO4)6F2)顆粒、鈣磷灰石顆粒或其混合物。更佳地，該無機鹽是含羥基磷灰石顆粒之氧化鋯。更佳地，該無機鹽係羥基磷灰石顆粒。最佳地，該無機鹽係磷酸鈣顆粒。According to the present invention, inorganic salts in the form of particles include, but are not limited to, calcium phosphate particles, calcium silicate particles, calcium carbonate particles, alumina particles, zirconia particles, hydroxyapatite particles, zirconia particles containing hydroxyapatite particles. Calcium pyrophosphate particles, tetracalcium phosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluoroapatite (Ca 10 (PO 4 ) 6 F 2 ) particles, calcium apatite particles or mixtures thereof. Preferably, the inorganic salt is calcium phosphate particles, zirconia particles, hydroxyapatite particles, zirconia particles containing hydroxyapatite particles, or a mixture thereof. Preferably, the inorganic salt is hydroxyapatite particles, calcium pyrophosphate particles, tetracalcium phosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluoroapatite (Ca 10 (PO 4 ) 6 F 2 ) Granules, calcium apatite particles or mixtures thereof. More preferably, the inorganic salt is zirconia containing hydroxyapatite particles. More preferably, the inorganic salt is a hydroxyapatite particle. Most preferably, the inorganic salt is a calcium phosphate particle.
在一個實施例中，可選用於本發明之軟組織填補植入物中之添加劑可為多種材料，包括但不限於蛋白質及生物活性物質。In one embodiment, the additives useful in the soft tissue-filling implants of the present invention can be a variety of materials including, but not limited to, proteins and biologically active substances.
根據本發明，生物活性物質可具有治療性質，並且可例如促進組織生長(即生長因子)或做為抗微生物劑。較佳地，該生物活性物質為表皮生長因子(EGF)、成纖維細胞生長因子(FGF)、神經生長因子(NGF)或其混合物。較佳地，該生物活性物質為EGF。這些物質可能被嫁接到顆粒或被顆粒吸收，並可能具有隨時間釋放至周圍組織之特性。依據不同應用，技術領域中之技藝人士應可了解該等生物活性物質可併入植入物材料，及了解該等生物活性物質之醫療價值。According to the invention, the biologically active substance may have therapeutic properties and may, for example, promote tissue growth (i.e., growth factors) or act as an antimicrobial agent. Preferably, the bioactive substance is epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF) or a mixture thereof. Preferably, the biologically active substance is EGF. These materials may be grafted onto or absorbed by the particles and may have the property of releasing to surrounding tissue over time. Depending on the application, those skilled in the art will recognize that such biologically active substances can be incorporated into implant materials and to understand the medical value of such biologically active substances.
根據本發明，細胞可為脂(脂肪)細胞、胚胎幹細胞、間葉幹細胞、神經幹細胞、脂肪前驅細胞、脂肪幹細胞或牙髓幹細胞。According to the invention, the cells may be lipid (fat) cells, embryonic stem cells, mesenchymal stem cells, neural stem cells, fat precursor cells, adipose stem cells or dental pulp stem cells.
在本發明之特定實施例中，軟組織填補植入物係以例如注射器或關節鏡手術(arthroscopic)之儀器注入。這些方法因侵入性相較其他方法(例如外科手術)小，然而具有較小之感染、不適及併發症風險，且其注入量及注入位置能被輕易控制，因此為較佳之方法。一個熟悉此領域之技藝人士可了解各種注射方法。例如，在本發明之實施例中，可使用18G(gauge)之注射器將具有約500微米大小之顆粒注入，而在那些具有較小顆粒大小之實施例中，可使用更大gauge之針頭注射，例如關節注射。In a particular embodiment of the invention, the soft tissue filling implant is infused with an instrument such as a syringe or arthroscopic. These methods are preferred because they are less invasive than other methods (such as surgery), but have a lower risk of infection, discomfort, and complications, and their injection volume and injection location can be easily controlled. A person skilled in the art will be aware of various injection methods. For example, in embodiments of the invention, particles having a size of about 500 microns can be injected using an 18G (guge) syringe, while in those embodiments having smaller particle sizes, larger gauge needle injections can be used, For example joint injection.
在本發明之實施例中，軟組織填補植入物係經皮下注射至軟組織輪廓缺陷之區域。植入劑量為足夠完全消除缺陷。這種缺陷可能包括諸如口腔、***、下巴、臉頰和/或鼻子的皺紋及缺陷。In an embodiment of the invention, the soft tissue-filling implant is injected subcutaneously into the area of the soft tissue contour defect. The implant dose is sufficient to completely eliminate the defect. Such defects may include wrinkles and defects such as the mouth, breasts, chin, cheeks and/or nose.
在本發明之另一個實施例中，軟組織填補植入物可用以控制失禁，特別是壓力性尿失禁。失禁可為疾病、老化或神經肌肉病變所造成，亦可為因***手術導致控制尿道周圍之括約肌的神經受損所造成。In another embodiment of the invention, a soft tissue filling implant can be used to control incontinence, particularly stress urinary incontinence. Incontinence can be caused by disease, aging or neuromuscular disease, or by nerve damage caused by prostate surgery to control the sphincters around the urethra.
當此軟組織填補物植入軟組織時，將在植入物結構中及其周圍形成緻密、纖維化且具可撓性的組織。此將發生於植入後數天之內。植入物於身體內依然為惰性，且與新形成之組織、填補或塑形所需要的軟組織。When the soft tissue filler is implanted into the soft tissue, a dense, fibrotic, and flexible tissue will be formed in and around the implant structure. This will occur within a few days after implantation. The implant remains inert in the body and is soft tissue required for newly formed tissue, filling or shaping.
本技術領域中之技藝人士應可瞭解本發明之聚電解質錯合物凝膠、軟組織填補植入物及方法，除前述實施例外，尚可用於其他之多種用途中。本技術領域中之技藝人士亦可明瞭前述說明書之內容及所附圖式之目的為說明本發明，並非限制本發明。因此吾人應瞭解，只要不偏離本發明之精神及範圍，可對於上述內容做各種之修飾及改變。而本發明之範圍應僅為所附之申請專利範圍所限制。Those skilled in the art will appreciate that the polyelectrolyte complex gels, soft tissue filling implants, and methods of the present invention are useful in a variety of other applications, in addition to the foregoing. The above description of the present invention and the accompanying drawings are intended to illustrate the invention and not to limit the invention. Therefore, it is to be understood that various modifications and changes may be made to the above-described contents without departing from the spirit and scope of the invention. The scope of the invention should be limited only by the scope of the appended claims.
將含有30克幾丁聚醣(Mw=200 kDa)及40克聚麩胺酸(Mw=10 kDa)，加入1000克之1重量%醋酸水溶液中，於一容器中快速混合約30秒；以10N NaOH滴定至中性後，混合30分鐘。將獲得之聚電解質錯合物凝膠 靜置12小時以上。30 g of chitosan (Mw=200 kDa) and 40 g of polyglutamic acid (Mw=10 kDa) were added to 1000 g of 1% by weight aqueous acetic acid solution, and rapidly mixed in a container for about 30 seconds; After the NaOH was titrated to neutral, it was mixed for 30 minutes. The obtained polyelectrolyte complex gel was allowed to stand for 12 hours or more.
對照例為習知之凝膠。對照例1為羧甲基纖維素(CMC)載體，其係以下述方式製備：將30克CMC與150克甘油添加至裝有520毫升水性溶液之容器中並混合約30秒；慢速混合攪拌12小時以上使其混合均勻以形成CMC載體。The comparative example is a conventional gel. Comparative Example 1 is a carboxymethyl cellulose (CMC) carrier prepared by adding 30 g of CMC and 150 g of glycerin to a vessel containing 520 ml of an aqueous solution and mixing for about 30 seconds; slow mixing and stirring The mixture was uniformly mixed over 12 hours to form a CMC carrier.
將20克幾丁聚醣(Mw=2000 kDa)加入具有1000克之0.5重量%醋酸水溶液中，再添加10克γ-PGA(Mw=300 kDa)，並快速混合約30秒；以10N NaOH滴定至中性後再混合30分鐘。將所獲得之聚電解質錯合物凝膠靜置12小時以上。20 g of chitosan (Mw=2000 kDa) was added to 1000 g of 0.5% by weight aqueous acetic acid solution, and then 10 g of γ-PGA (Mw=300 kDa) was added and rapidly mixed for about 30 seconds; titrated with 10N NaOH until Mix again for 30 minutes after neutral. The obtained polyelectrolyte complex gel was allowed to stand for 12 hours or more.
將實例1所述之聚電解質錯合物凝膠及430克之羥基磷灰石顆粒(顆粒尺寸範圍為25至45微米)完全摻混，以低速混合器混合至所有顆粒均勻分布於1000毫升之凝膠懸浮液。The polyelectrolyte complex gel described in Example 1 and 430 g of hydroxyapatite particles (particle size ranging from 25 to 45 μm) were thoroughly blended and mixed in a low speed mixer until all particles were uniformly distributed in 1000 ml. Gum suspension.
此外，將對照例1之CMC載體與430克之羥基磷灰石顆粒(顆粒尺寸範圍為25至45微米)完全摻混，以低速混合器混合，直至所有顆粒均質地分布於1000毫升之載體懸浮液以形成含羥基磷灰石顆粒之CMC載體混合物(對照例2)。Further, the CMC carrier of Comparative Example 1 was thoroughly blended with 430 g of hydroxyapatite particles (particle size ranging from 25 to 45 μm), and mixed in a low speed mixer until all the particles were homogeneously distributed in 1000 ml of the carrier suspension. To form a CMC carrier mixture containing hydroxyapatite particles (Comparative Example 2) .
對照例3為市售商品微晶瓷()，其係懸浮於CMC載體中之含羥基磷灰石顆粒之微球體，由BioForm公司製造。Comparative Example 3 is a commercially available microcrystalline porcelain ( ), which is a microsphere containing hydroxyapatite particles suspended in a CMC carrier, manufactured by BioForm.
將實例1之聚電解質錯合物凝膠載體及200克聚左旋乳酸(PLLA)顆粒(顆粒尺寸範圍為40至63微米)完全摻混，以低速混合器混合直至顆粒均勻分布於1000毫升之凝膠懸浮液。The polyelectrolyte complex gel carrier of Example 1 and 200 g of poly-L-lactic acid (PLLA) particles (particle size ranging from 40 to 63 μm) were thoroughly blended and mixed in a low-speed mixer until the particles were uniformly distributed in 1000 ml of coagulation. Gum suspension.
將實例1之聚電解質錯合物凝膠與127.8克之聚甲基丙烯酸甲酯顆粒(顆粒尺寸範圍為100至180微米)完全摻混，以低速混合器混合直至所有顆粒均勻分布於1000毫升之凝膠懸浮液。The polyelectrolyte complex gel of Example 1 was thoroughly blended with 127.8 grams of polymethyl methacrylate particles (particle size ranging from 100 to 180 microns) and mixed in a low speed mixer until all particles were evenly distributed in 1000 ml of coagulum. Gum suspension.
將實例1之聚電解質錯合物凝膠與250克蠶絲微球體(顆粒尺寸範圍為20至45微米)完全摻混，以低速混合器混合，直至所有顆粒均勻分布於1000毫升之凝膠懸浮液。The polyelectrolyte complex gel of Example 1 was thoroughly blended with 250 g of silk microspheres (particle size ranging from 20 to 45 microns) and mixed in a low speed mixer until all particles were evenly distributed in 1000 ml of gel suspension. .
將1克幾丁聚醣(Mw=100 kDa)加入100毫升之1重量%醋酸水溶液中，將0.3克γ-PGA鈣(Mw=1000 kDa)及0.2克CMC加入100毫升之去離子水。將兩溶液以均質機快速混合約30秒後，即形成聚電解質錯合物之微顆粒。將實例1之聚電解質錯合物凝膠與250克聚電解質錯合物之微顆粒(顆粒尺寸範圍為100至120微米)完全摻混，以低速混合器混合直至顆粒均質分布於1000毫升之凝膠懸浮液。One gram of chitosan (Mw = 100 kDa) was added to 100 ml of a 1% by weight aqueous acetic acid solution, and 0.3 g of γ-PGA calcium (Mw = 1000 kDa) and 0.2 g of CMC were added to 100 ml of deionized water. After the two solutions were rapidly mixed in a homogenizer for about 30 seconds, microparticles of the polyelectrolyte complex were formed. The polyelectrolyte complex gel of Example 1 was thoroughly blended with 250 g of polyelectrolyte complex microparticles (particle size ranging from 100 to 120 μm) and mixed in a low speed mixer until the particles were homogeneously distributed in 1000 ml of coagulation. Gum suspension.
將實施1之聚電解質錯合物凝膠與1毫升之1×106個牙髓幹細胞完全摻混，以低速混合器混合直至所有細胞均質分布於9毫升之凝膠懸浮液。The polyelectrolyte complex gel of Example 1 was thoroughly blended with 1 ml of 1 x 10 6 dental pulp stem cells, and mixed in a low speed mixer until all cells were homogeneously distributed in 9 ml of the gel suspension.
將實施3之聚電解質錯合物凝膠及羥基磷灰石顆粒混合物與1毫升之1×106個牙髓幹細胞完全摻混，以低速混合器混合直至所有細胞均勻分布於9毫升之凝膠懸浮液。The polyelectrolyte complex gel and the hydroxyapatite particle mixture of Example 3 were thoroughly blended with 1 ml of 1×10 6 dental pulp stem cells, and mixed in a low speed mixer until all the cells were uniformly distributed in the 9 ml gel. suspension.
此外，做為對照例之含牙髓幹細胞之羥基磷灰石/CMC載體混合物(對照例4)可由下述方式製備：將對照例2之羥基磷灰石/CMC載體混合物與1毫升之1×106個牙髓幹細胞完全摻混，以低速混合器混合直至所有細胞均質分布於9毫升之凝膠懸浮液。Further, a hydroxyapatite/CMC carrier mixture containing a dental pulp stem cell as a comparative example (Comparative Example 4) can be prepared by mixing the hydroxyapatite/CMC carrier mixture of Comparative Example 2 with 1 ml of 1×. 10 6 dental pulp stem cells were thoroughly blended and mixed in a low speed mixer until all cells were homogeneously distributed in 9 ml of gel suspension.
將實例1之聚電解質錯合物凝膠及對照例1以冷凍乾燥方式處理以取得乾燥粉末；秤取0.5克之樣品，放置於含有40毫升之緩衝液體中(100 mM NaCl,45 mM NaHCO3,2 mM K2CO3)，分別於3天、1週、2週、4週、8週及12週時取出。以清水洗淨後，過濾，乾燥，秤重，並計算其樣品殘留率((原始重量-降解後重量)/原始重量)，結果如圖1所示。結果顯示實例1相較對照例1具有較長之降解時間，而對照例1於3天即降到2.5%以下，一週幾乎殆盡。The polyelectrolyte complex gel of Example 1 and Comparative Example 1 were treated by freeze-drying to obtain a dry powder; 0.5 g of the sample was weighed and placed in a buffer solution containing 40 ml (100 mM NaCl, 45 mM NaHCO 3 , 2 mM K 2 CO 3 ), taken at 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks, respectively. After washing with water, filtering, drying, weighing, and calculating the sample residual ratio ((original weight - post-degradation weight) / original weight), the results are shown in FIG. The results showed that Example 1 had a longer degradation time than Comparative Example 1, while Comparative Example 1 fell below 2.5% in 3 days, almost exhausted in one week.
將實例1及實例3之聚電解質錯合物凝膠為主的植入物移至3毫升之注射筒中，前方裝置27G之針頭，利用質地分析儀(Texture Analyzer,TA.XT Plus,Texture Technologies Corp,UK)以15公釐/分鐘之速度持續90秒推進，得到推力數據。結果如圖2所示，其顯示實例1及實例3之聚電解質錯合物凝膠為主的植入物，所需推力較低，具有良好的可注射性。The polyelectrolyte complex gel-based implants of Examples 1 and 3 were transferred to a 3 ml syringe, and the 27G needle of the front device was used, using a texture analyzer (Texture Analyzer, TA.XT Plus, Texture Technologies Corp). , UK) Propels at a speed of 15 mm/min for 90 seconds to obtain thrust data. The results are shown in Fig. 2, which shows the polyelectrolyte complex gel-based implants of Examples 1 and 3, which required lower thrust and good injectability.
以體重在25-30公斤範圍內之蘭嶼豬為實驗動物。其施以麻醉後靜躺於手術台上。於其耳朵背部之皮下各注入0.2毫升之實例1、實例3、實例8、實例9、對照例1、對照例2、對照例3及對照例4之樣本。術後餵以規則飲食，每組六隻豬。術後8週及24週後豬隻犧牲，作組織學分析，利用馬森三色染色法(Masson's trichrome stain)染色。結果如圖3、4及5所示，其組織學切片圖顯示於每個時間點，利用本發明之聚電解質錯合物凝膠之實例3均較對照例2及對照例3之支撐效果好，於兩個月後實例3之體積比相較CMC組(對照例2及對照例3)多超過20%；於六個月後實例3之高度比相較對照例2多超過40%。Lanyu pigs weighing between 25-30 kg were used as experimental animals. After being anesthetized, he lies on the operating table. 0.2 ml of the samples of Example 1, Example 3, Example 8, Example 9, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 were each injected under the skin of the back of the ear. After the operation, a regular diet was given, with six pigs in each group. Pigs sacrificed at 8 and 24 weeks postoperatively for histological analysis and stained with Masson's trichrome stain. The results are shown in Figures 3, 4 and 5, and histological sections are shown at each time point. Example 3 using the polyelectrolyte complex gel of the present invention has better support effect than Comparative Example 2 and Comparative Example 3. After two months, the volume ratio of Example 3 was more than 20% more than that of the CMC group (Control Example 2 and Comparative Example 3); after six months, the height ratio of Example 3 was more than 40% more than that of Comparative Example 2.
圖1顯示本發明之聚電解質錯合物凝膠的體外降解試驗。Figure 1 shows an in vitro degradation test of the polyelectrolyte complex gel of the present invention.
圖2顯示本發明之聚電解質錯合物凝膠的可注射性試驗。Figure 2 shows the injectability test of the polyelectrolyte complex gel of the present invention.
圖3顯示本發明之聚電解質錯合物凝膠與習知載體/植入物的組織切片圖。Figure 3 shows a histological section of a polyelectrolyte complex gel of the present invention and a conventional carrier/implant.
圖4顯示本發明之聚電解質錯合物為主之植入物及習知之植入物在植入後180天內之期間，體積維持率之變化。Figure 4 is a graph showing changes in volume maintenance rate of a polyelectrolyte complex-based implant of the present invention and a conventional implant during 180 days after implantation.
圖5顯示本發明之聚電解質錯合物為主之植入物及習知之植入物在植入後180天內之期間，高度維持率之變化。Figure 5 shows the change in height maintenance rate of the polyelectrolyte complex-based implant of the present invention and the conventional implant during the 180 days after implantation.
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| CN108078868B (en) * | 2018-02-01 | 2020-12-25 | 四川艾医生医疗科技有限公司 | Antiallergic composition for skin care products |
| EP3610853A1 (en) * | 2018-08-15 | 2020-02-19 | The Boots Company PLC | Cosmetic compositions |
| CN114652895A (en) * | 2020-12-23 | 2022-06-24 | 上海其胜生物制剂有限公司 | Preparation method of injectable tissue regeneration type chitosan composite gel scaffold |
| CN117599247A (en) * | 2023-12-14 | 2024-02-27 | 浙江来益美生物医药有限公司 | Silk fibroin microcarrier skin filling preparation, and preparation method and application thereof |
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| CN109125290B (en) * | 2018-08-28 | 2020-10-09 | 江南大学 | PH and reduction dual-response drug-loaded nanoparticle |
| CN109077983A (en) * | 2018-11-05 | 2018-12-25 | 山东福瑞达生物科技有限公司 | A kind of anti-wrinkle cosmetic of the glutamic acid containing oligomerization and preparation method thereof |
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