TW202214267A - Method for treating oral mucositis and aqueous gel for the same - Google Patents
Method for treating oral mucositis and aqueous gel for the same Download PDFInfo
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本發明是有關一種治療口腔黏膜炎之方法，此方法包含提供一含有水溶性有機銀離子化合物的水性凝膠，以及以適當之施用方法施用於受損之口腔黏膜，主要應用在治療口腔黏膜炎(Oral Mucositis)。本發明之方法主要應用在因癌症放化療而引起之口腔黏膜炎患者上，但是也可應用在其他因素造成的口腔黏膜發炎或潰瘍的患者上，本發明同時也是有關於一種治療口腔黏膜炎之水性凝膠，其特色在於此水性凝膠之成分中含有水溶性有機銀離子化合物與高分子增稠劑，使用時會因為水性凝膠之黏稠性與剪切稀化特性使得水性凝膠在受損之口腔黏膜上得以停留較長的時間，因而讓水性凝膠中之水溶性有機銀離子化合物得以充分發揮其效用，促進因放化療治療過程中受損之口腔黏膜的復原。 The present invention relates to a method for treating oral mucositis, the method comprising providing an aqueous gel containing a water-soluble organic silver ion compound, and applying an appropriate application method to the damaged oral mucosa, mainly used in the treatment of oral mucositis (Oral Mucositis). The method of the present invention is mainly applied to patients with oral mucositis caused by cancer radiotherapy and chemotherapy, but can also be applied to patients with oral mucositis or ulcers caused by other factors. The present invention also relates to a method for treating oral mucositis. The water-based gel is characterized in that the components of the water-based gel contain water-soluble organic silver ion compounds and polymer thickeners. When used, the water-based gel will be exposed to water due to the viscosity and shear thinning properties of the water-based gel. The damaged oral mucosa can stay on the damaged oral mucosa for a long time, so that the water-soluble organic silver ion compound in the water-based gel can fully exert its effect and promote the recovery of the damaged oral mucosa during radiotherapy and chemotherapy.
口腔黏膜炎(Oral Mucositis)是發生在口腔黏膜的病變之一，口腔黏膜炎特別指癌症病患在化學藥物治療和放射線治療期間因治療所引起的口腔黏膜病變、潰瘍及發炎 反應，是一種很常見的化學藥物治療和放射線治療後引起的併發症，嚴重的口腔黏膜炎會導致癌症患者進食困難與吞嚥不易，更嚴重者會因無法進食導致營養不足無法對抗癌症而死亡。 Oral mucositis is one of the lesions that occurs in the oral mucosa. Oral mucositis especially refers to the lesions, ulcers and inflammation of the oral mucosa caused by cancer patients during chemotherapy and radiation therapy. Reaction is a very common complication caused by chemotherapy and radiation therapy. Severe oral mucositis can cause cancer patients to have difficulty eating and swallowing. In more serious cases, they may die due to inability to eat, resulting in insufficient nutrition and inability to fight cancer.
接受高劑量化學療法與造血幹細胞移植療法((hemato poietic stem cell transplantation)的癌症病患有幾乎100%的機率會得到口腔黏膜炎，80%接受放射治療的頭頸部惡性腫瘤患者會得到口腔黏膜炎，而在接受化學治療的癌症患者中有高達40-70%的比例會得到不同程度的口腔黏膜炎。 Cancer patients receiving high-dose chemotherapy and hematopoietic stem cell transplantation (hematopoietic stem cell transplantation) have an almost 100% chance of developing oral mucositis, and 80% of patients with head and neck malignancies who receive radiation therapy will develop oral mucositis. , and up to 40-70% of cancer patients receiving chemotherapy will get different degrees of oral mucositis.
當口腔黏膜炎發生時除了必須加強口腔的清潔及護理以外，通常以口腔內的局部用藥為主要的治療方法，包含了施用局部止痛劑，例如使用含***製劑(Lidocaine、Benzocaine或benzydamine)的噴劑、凝膠或漱口水，使用局部抗發炎劑，例如類固醇藥製劑(塗抹Nincort寧康口內膠、Salcoat口腔噴霧膠囊)，使用局部抗菌劑，例如含有chlorohexidine之漱口水。 When oral mucositis occurs, in addition to strengthening the cleaning and care of the oral cavity, topical medication in the oral cavity is usually the main treatment method, including the application of topical analgesics, such as the use of anesthetic preparations (Lidocaine, Benzocaine or benzydamine). Sprays, gels or mouthwashes, use topical anti-inflammatory agents such as steroid formulations (apply Nincort intraoral gel, Salcoat oral spray capsules), use topical antibacterial agents such as chlorohexidine-containing mouthwash.
以上之局部治療效果並不十分顯著，研究顯示含有chlorohexidine抗菌劑的漱口水對於口腔黏膜炎沒有太大的效果(European Journal of Cancer Care,2006,15,431-439)，當口腔黏膜炎程度嚴重時，局部塗抹藥物變得非常麻煩，以致治療效果會因而降低。 The above topical treatment effects are not very significant. Studies have shown that mouthwashes containing chlorohexidine antibacterial agents do not have much effect on oral mucositis (European Journal of Cancer Care, 2006, 15, 431-439). When the oral mucositis is severe, Topical application of the drug becomes very cumbersome, and the therapeutic effect is therefore reduced.
另外有一種用來降低口腔黏膜炎不舒適或疼痛 之水性凝膠，例如商品名為Gelclair的水性凝膠，是一種濃稠之液體，其使用方法類似漱口水，可以直接使用，也可稀釋使用，主要功能是在受損的口腔黏膜上形成一層保護層以降低口腔黏膜炎患者的不舒適與疼痛感，但是這類水性凝膠僅僅可以減緩口腔黏膜炎的不適，並無法改善口腔黏膜炎的症狀。 In addition, there is a method used to reduce the discomfort or pain of oral mucositis. Gelclair water gel, such as the water-based gel with the trade name Gelclair, is a thick liquid. Its use method is similar to mouthwash. It can be used directly or diluted. Its main function is to form a layer on the damaged oral mucosa. The protective layer can reduce the discomfort and pain of patients with oral mucositis, but this type of water-based gel can only relieve the discomfort of oral mucositis, and cannot improve the symptoms of oral mucositis.
本發明的發明者發現水溶性之有機銀離子化合物對於治療口腔黏膜炎非常有效，因而開發了一種使用水溶性有機銀離子化合物以治療口腔黏膜炎的方法以及含有水溶性有機銀離子化合物之水性凝膠。 The inventors of the present invention found that the water-soluble organic silver ion compound is very effective for the treatment of oral mucositis, and thus developed a method for treating oral mucositis using the water-soluble organic silver ion compound and an aqueous gel containing the water-soluble organic silver ion compound. glue.
本發明主要係關於一種治療口腔黏膜炎的方法，此方法包含提供一含有水溶性有機銀離子化合物的水性凝膠，以及以適當之施用方法施用於受損之口腔黏膜，主要是針對接受放化療治療之癌症病患，當然除了一般在癌症之化學藥物治療和放射線治療期間因治療而得到的口腔黏膜炎患者外，還有復發性口腔潰瘍(Recurrent aphthous Ulcer)患者、因戴牙套而引起之口腔潰瘍患者或因其他疾病(如糖尿病、手口足病)而引起之口腔潰瘍患者都可以使用本發明之方法。 The present invention mainly relates to a method for treating oral mucositis, the method comprising providing an aqueous gel containing a water-soluble organic silver ion compound, and applying an appropriate application method to the damaged oral mucosa, mainly for patients receiving radiotherapy and chemotherapy The cancer patients treated, of course, in addition to the patients with oral mucositis usually obtained during chemotherapy and radiation therapy for cancer, there are also patients with recurrent oral ulcers (Recurrent aphthous Ulcer), oral cavity caused by wearing braces Patients with ulcers or patients with oral ulcers caused by other diseases (such as diabetes, hand-mouth-foot disease) can use the method of the present invention.
口腔黏膜炎是接受化學治療及放射治療後常見的副作用之一，常出現於化學治療後4-7天、7-14天達高。而放射治療造成的口腔炎，可能在第2-3週左右開始，於治療晚期達最高峰。口腔黏膜炎症狀有口乾、口臭、發炎疼痛等， 嚴重會出現口腔或口咽部位黏膜破損或潰瘍、出血、味覺改變、吞嚥及說話困難等情形。 Oral mucositis is one of the common side effects after chemotherapy and radiation therapy, and it usually occurs 4-7 days and 7-14 days after chemotherapy. The stomatitis caused by radiation therapy may start around 2-3 weeks and reach its peak in the late stage of treatment. Oral mucositis symptoms include dry mouth, bad breath, inflammation and pain, etc. In severe cases, the mucosa of the mouth or oropharynx may be damaged or ulcerated, bleeding, changes in taste, and difficulty in swallowing and speaking.
一般受損的口腔黏膜評估主要有三種評量標準可供選擇，分別是世界衛生組織口腔黏膜評估表，口腔評估指引(OAG，Oral Assesment Guildline)以及美國國家癌症機構不良事件一般毒性標準，這些評量標準將口腔黏膜的受損程度分級以方便對癌症病人進行口腔黏膜受損程度之分析以及照護。 There are three main evaluation criteria for the evaluation of generally damaged oral mucosa, which are the World Health Organization Oral Mucosa Evaluation Form, Oral Assesment Guildline (OAG, Oral Assesment Guildline) and the United States National Cancer Institute Adverse Events General Toxicity Criteria. The quantitative standard grades the damage of the oral mucosa to facilitate the analysis and care of the damage of the oral mucosa for cancer patients.
例如世界衛生組織口腔黏膜評估表將口腔黏膜之狀況分為5個等級，第0級是口腔黏膜無變化，第1級是口腔黏膜疼痛及紅斑，第2級是口腔黏膜疼痛及紅斑而且合併潰瘍，可進食固體食物，第3級是口腔黏膜疼痛及紅斑而且合併潰瘍，僅可進食流質食物，第4級是口腔黏膜疼痛及紅斑而且合併潰瘍，無法進食。 For example, the World Health Organization Oral Mucosa Assessment Scale divides the condition of the oral mucosa into 5 grades. Grade 0 is no change in the oral mucosa, grade 1 is pain and erythema of the oral mucosa, and grade 2 is pain and erythema of the oral mucosa combined with ulcers. , can eat solid food, grade 3 is oral mucosa pain and erythema combined with ulcers, only liquid food can be eaten, and grade 4 is oral mucosa pain and erythema combined with ulcers, unable to eat.
本發明之方法可以使用在以上所述任何等級狀況的受損之口腔黏膜。 The methods of the present invention can be used with damaged oral mucosa in any of the grades described above.
本發明中的水性凝膠係一種含有水溶性有機銀離子化合物的黏稠性水性凝膠，其使用方式非常多樣化，可以類似漱口液的方式，將適量本發明之水性凝膠倒入口中，含於口中，借助口腔運動將水性凝膠均勻的分布覆蓋至口腔之受損黏膜上，之後將水性凝膠含在口腔中一段時間，然後吐掉即可。或者可以噴劑的形式，噴於口腔中受損之口腔黏膜上，也 可更深層的噴至咽喉部。也可以塗抹的方式，塗於受損之口腔黏膜上。由於此水性凝膠具有黏稠與膠剪切稀化的特性，因此可以在受損傷的口腔黏膜上停留較長的時間，讓水性凝膠中的水溶性有機銀離子化合物可以更有效的發揮其作用。 The water-based gel in the present invention is a viscous water-based gel containing water-soluble organic silver ion compounds, and its usage is very diverse. Similar to mouthwash, an appropriate amount of the water-based gel of the present invention can be poured into the mouth, In the mouth, the aqueous gel is evenly distributed and covered on the damaged mucosa of the oral cavity by means of oral movements, and then the aqueous gel is contained in the oral cavity for a period of time, and then spit out. Or it can be sprayed on the damaged oral mucosa in the oral cavity, or in the form of a spray. Can be sprayed deeper into the throat. It can also be applied to damaged oral mucosa. Because the water-based gel has the characteristics of viscosity and shear thinning, it can stay on the damaged oral mucosa for a long time, so that the water-soluble organic silver ion compound in the water-based gel can play its role more effectively .
本發明的水性凝膠含有水溶性有機銀離子化合物外還含有高分子增稠劑，其作用在於提高本發明的水性凝膠之黏度，適合的高分子增稠劑包含纖維素類、壓克力類、天然膠類、聚乙烯吡咯烷酮、聚氧乙烯以及其他水性有機增稠劑，纖維素類增稠劑包含羧甲基纖維素納(Sodium carboxylmethyl cellulose)、甲基纖維素(Methyl Cellulose)、羥丙基甲基纖維素(Hydroxypropylmethylcellulose)、羥丙基纖維素(Hydroxypropylcellulose)、羥乙基纖維素(Hydroxyethyl cellulose)、微晶纖維素(Microcrystalline cellulose)或其他水溶性具有增稠劑效能的纖維素衍生物，壓克力類包含聚丙烯酸、聚丙烯酸鈉、丙烯酸與其他壓克力單體之共聚物、丙烯酸納與其他壓克力單體之共聚物或其他水溶性具有增稠劑效能的水溶性壓克力聚合物，天然膠類包含包含瓜爾豆膠(Guar gum)，瓊脂(agar)，黃原膠(Xanthan gum)，海藻酸鈉(sodium alginate)，澱粉(starch)，殼聚醣(chitosan)，膠原蛋白(collagen)，刺槐豆膠(Locust bean gum)或***膠(gum Arabic)等，聚乙烯吡咯烷酮包含聚乙烯吡咯烷酮與乙烯吡咯烷酮和其他單體的共聚物。本發明的水性凝膠可以僅僅使用一種增稠劑，也可以兩種 以上之增稠劑合併使用。 The aqueous gel of the present invention contains a water-soluble organic silver ion compound and also contains a polymer thickener, which functions to increase the viscosity of the aqueous gel of the present invention. Suitable polymer thickeners include cellulose, acrylic cellulose, natural gum, polyvinylpyrrolidone, polyoxyethylene and other water-based organic thickeners, cellulose thickeners include sodium carboxylmethyl cellulose, methyl cellulose (Methyl Cellulose), hydroxy Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxyethyl cellulose, Microcrystalline cellulose, or other water-soluble cellulose derivatives with thickening properties Acrylics include polyacrylic acid, sodium polyacrylate, copolymers of acrylic acid and other acrylic monomers, copolymers of sodium acrylate and other acrylic monomers, or other water-soluble water-soluble thickeners Acrylic polymer, natural gums including guar gum (Guar gum), agar (agar), xanthan gum (Xanthan gum), sodium alginate (sodium alginate), starch (starch), chitosan ( chitosan), collagen (collagen), locust bean gum (Locust bean gum) or gum Arabic (gum Arabic), etc., polyvinylpyrrolidone contains polyvinylpyrrolidone and vinylpyrrolidone and other monomers copolymers. The aqueous gel of the present invention can use only one thickener, or two The above thickeners are used in combination.
以上的高分子增稠劑除了提高本發明的水性凝膠之黏度外，還會賦予本發明的水性凝膠剪切稀化(Shear thinning)的特性，這種特性使得本發明之水性凝膠在使用的過程中可以較長時間的停留在口腔黏膜，讓水性凝膠中的水溶性有機銀離子化合物可以更有效的發揮其作用。 In addition to increasing the viscosity of the aqueous gel of the present invention, the above polymer thickeners also impart shear thinning (Shear thinning) properties to the aqueous gel of the present invention, which makes the aqueous gel of the present invention in During use, it can stay on the oral mucosa for a long time, so that the water-soluble organic silver ion compound in the water-based gel can play its role more effectively.
剪切稀化的性質是一種非牛頓流體的特性，也就是流體的黏度隨著剪切力的增加而降低的特性，與牛頓牛體之黏度不隨減切力之改變而有所改變不同，有兩種流體具有這種特性，一是擬塑態流體(Pseudoplastic fluid)，另一是搖變減黏流體(Thixotropic fluid)，差異在於擬塑態流體的黏度改變不隨時間變化而有所不同，搖變減黏流體的黏度除了隨剪切力增加而降低，在剪切力降低回復的過程中黏度變化與剪切力增加時不同，也就是有時間的因素在其中，本發明的水性凝膠可以是擬塑態流體也可以是搖變減黏流體，因為二者皆具有剪切稀化的性質。 The property of shear thinning is a characteristic of non-Newtonian fluids, that is, the viscosity of the fluid decreases with the increase of shear force, which is different from the viscosity of Newtonian Newton that does not change with the change of shear force. There are two kinds of fluids with this property, one is Pseudoplastic fluid and the other is Thixotropic fluid. The difference is that the viscosity of Pseudoplastic fluid does not change with time. , the viscosity of the thixotropic viscosity-reducing fluid decreases with the increase of shear force, and the viscosity change in the process of shear force reduction and recovery is different from that when shear force increases, that is, there is a time factor in it. Glues can be either pseudoplastic fluids or thixotropic viscous fluids, both of which have shear-thinning properties.
剪切稀化的性質在本發明之水性凝膠使用時的具體優勢顯現在於讓施用方法更容易為使用者接受，以及讓水溶性有機銀高分子能更長時間的接觸受損的口腔黏膜以充分發揮其效用， The specific advantage of the shear thinning property when the aqueous gel of the present invention is used appears in that the application method is more acceptable to the user, and the water-soluble organic silver polymer can be in contact with the damaged oral mucosa for a longer time. make full use of it,
當水性凝膠以漱口液的形式使用時，被倒入口中時，口腔的運動對水性凝膠施以一剪切的力量，口腔運動的頻 率越快，此剪切力也就越大，由於本發明之水性凝膠具有剪切稀化的性質，所以其黏度會降低許多，低黏度的漱口液比高黏度的漱口液會讓使用者更能接受，也會使得水性凝膠更容易且更完全的覆蓋到口腔內每一處黏膜，不論是受損或未受損的黏膜都得以得到覆蓋，當口腔運動結束，口中的水性凝膠被吐出後，由於口腔不再運動，也就是剪切力為零，殘留在口腔黏膜上本發明的水性凝膠黏度增加而不易流動，因而得以停留在受損黏膜，而且因為黏度較高而不易為口腔中之唾液沖掉，使得水性凝膠得以較長時間的停留在受損傷的黏膜上，而水性凝膠中的水溶性有機銀離子化合物也得以更有效的發揮其作用。 When the water-based gel is used in the form of a mouthwash, when it is poured into the mouth, the movement of the mouth exerts a shearing force on the water-based gel, and the frequency of the oral movement The faster the rate is, the greater the shear force will be. Since the aqueous gel of the present invention has the property of shear thinning, its viscosity will be much lower, and the low viscosity mouthwash will be more difficult to use than the high viscosity mouthwash. It is more acceptable to the user, and it will also make the water gel easier and more complete to cover every mucous membrane in the oral cavity, whether the damaged or undamaged mucous membranes are covered. After the glue is spit out, because the oral cavity no longer moves, that is, the shear force is zero, the aqueous gel remaining on the oral mucosa has an increased viscosity and is not easy to flow, so it can stay in the damaged mucosa, and because the viscosity is high, it is not easy to flow. It is not easy to be washed out by saliva in the mouth, so that the aqueous gel can stay on the damaged mucosa for a long time, and the water-soluble organic silver ion compound in the aqueous gel can also play its role more effectively.
當以噴劑的形式使用時，同樣的在噴出的時候本發明的水性凝膠受到了噴出時噴瓶所施予的力量，以高速噴出，此時水性凝膠因剪切稀化特性而黏度降低，使得水性凝膠得以順利噴出，當噴到受損口腔黏膜上時，此時水性凝膠由於噴頭之作用力已經消失，黏度增加，因而得以較長時間的停留在受損黏膜上，水性凝膠中的水溶性有機銀離子化合物也得以更有效的發揮其作用。 When used in the form of a spray, the water-based gel of the present invention receives the force exerted by the spray bottle during spraying, and is sprayed at a high speed. At this time, the viscosity of the water-based gel is reduced due to shear thinning characteristics. When it is sprayed on the damaged oral mucosa, the water-based gel has disappeared due to the force of the nozzle, and the viscosity has increased, so it can stay on the damaged mucosa for a long time, and the water The water-soluble organic silver ion compound in the gel is also able to exert its effect more effectively.
當以塗抹的方式使用時，同樣的在塗抹的時候本發明的水性凝膠受到了塗抹時所施予的力量而黏度降低，使得水性凝膠得以順利的被塗抹到受損口腔黏膜上時，當塗抹動作停止時，此時由於塗抹之作用力已經消失，本發明之水性 凝膠黏度增加，因而得以較長時間的停留在受損黏膜上，水性凝膠中的水溶性有機銀離子化合物也得以更有效的發揮其作用。 When used by smearing, the water-based gel of the present invention is also subjected to the force applied during smearing and the viscosity is reduced, so that the aqueous gel can be smoothly smeared on the damaged oral mucosa, When the smearing action stops, because the smearing force has disappeared, the water-based The viscosity of the gel increases, so it can stay on the damaged mucosa for a longer time, and the water-soluble organic silver ion compound in the water-based gel can also play its role more effectively.
剪切稀化的性質通常是以搖變指數(Thixotropic Index)來表示，搖變指數是指在低與高兩種剪切力所量得的黏度比，搖變指數若等於1，就代表這個流體是牛頓流體，若搖變指數大於1則代表這個流體是非牛頓流體而且具有剪切稀化的性質。 The nature of shear thinning is usually expressed by the thixotropic index. The thixotropic index refers to the viscosity ratio measured at low and high shear forces. If the thixotropic index is equal to 1, it represents this The fluid is a Newtonian fluid. If the thixotropic index is greater than 1, it means that the fluid is non-Newtonian and has shear-thinning properties.
流體的量測有許多的方法，比較便利的兩種方法是Cone and Plate以及Spindle，代表性的儀器廠商是德州儀器公司(Texas Instrument)與AMETEK Brookfield公司，這兩種儀器是藉由Cone與spindle的轉動來量測流體的黏度，剪切力的大小就以cone與spindle的轉速來代表。本發明所定義的搖變指數(Thixotropic Index)是指在cone或spindle的轉速是每秒1轉(1RPM)與每秒10轉(10RPM)時所量得的黏度比。 There are many methods for measuring fluids. The two most convenient methods are Cone and Plate and Spindle. The representative instrument manufacturers are Texas Instruments and AMETEK Brookfield. These two instruments are produced by Cone and Spindle. To measure the viscosity of the fluid, the shear force is represented by the speed of the cone and the spindle. The Thixotropic Index as defined in the present invention refers to the viscosity ratio measured when the rotational speed of the cone or the spindle is 1 revolution per second (1 RPM) and 10 revolutions per second (10 RPM).
本發明水性凝膠之搖變指數必須大於1.1，更佳的是大於1.5，再更佳的是大於2。 The thixotropic index of the aqueous gel of the present invention must be greater than 1.1, more preferably greater than 1.5, and even more preferably greater than 2.
本發明中水性凝膠內所含有對治療口腔黏膜炎有效的物質是水溶性有機銀離子化合物，此水溶性有機銀離子化合物可以是小分子的有機銀離子化合物或者是大分子的有機銀離子化合物。 In the present invention, the effective substance for treating oral mucositis contained in the aqueous gel is a water-soluble organic silver ion compound, and the water-soluble organic silver ion compound can be a small molecule organic silver ion compound or a macromolecular organic silver ion compound .
本發明之小分子有機銀離子化合物是指分子量 小於1000的有機銀鹽，包含但不限於有機羧酸銀鹽、有機璜酸銀鹽與有機雜環化合物與銀離子之錯合物，這些有機銀離子化合物常溫時(25℃)在水中的溶解度必須大於0.01%，最好是大於0.1%，更佳的是大於1%。 The small molecule organic silver ion compound of the present invention refers to the molecular weight Organic silver salts less than 1000, including but not limited to organic carboxylic acid silver salts, organic sulfonic acid silver salts and complexes of organic heterocyclic compounds and silver ions, the solubility of these organic silver ion compounds in water at room temperature (25°C) Must be more than 0.01%, preferably more than 0.1%, more preferably more than 1%.
本發明之有機羧酸銀鹽可以是一般含碳數為1至10的烷基有機羧酸銀鹽，例如甲酸銀、乙酸銀、丙酸銀、丁酸銀...等，或者是含有其他水溶性官能基之烷基有機羧酸銀鹽，例如在歐洲專利EP2159270A1中所提到化學通式為CH3-O-(CH2CH2O)n-CH-COOAg的有機羧酸銀鹽，或者是其他結構之有機羧酸銀鹽。 The organic carboxylic acid silver salt of the present invention can be a general alkyl organic carboxylic acid silver salt with a carbon number of 1 to 10, such as silver formate, silver acetate, silver propionate, silver butyrate, etc., or contains other Alkyl organic carboxylic acid silver salts of water-soluble functional groups, such as organic carboxylic acid silver salts with the general chemical formula CH3 - O- ( CH2CH2O )n-CH-COOAg mentioned in European Patent EP2159270A1, Or organic carboxylic acid silver salts of other structures.
本發明之有機璜酸銀鹽可以是甲烷磺酸银、甲苯磺酸銀或其他有機磺酸銀鹽。 The organic sulfonic acid silver salt of the present invention can be silver methanesulfonate, silver toluenesulfonate or other organic sulfonate silver salt.
本發明之有機雜環化合物與銀離子之錯合物可以是咪唑化合物(imidazole compound)或***化合物(triazole compound)與銀的錯合物，例如在文獻(Dalton Trans.,2009,6985-6990)中所研究的水溶性咪唑/銀錯合物與水溶性***/銀錯合物，或者其他雜環化合物與銀的錯合物。 The complex of the organic heterocyclic compound and silver ion of the present invention can be an imidazole compound or a triazole compound and a complex of silver, for example, in the literature (Dalton Trans., 2009, 6985-6990 ), the water-soluble imidazole/silver complexes and water-soluble triazole/silver complexes studied in ), or the complexes of other heterocyclic compounds and silver.
本發明之大分子有機銀離子化合物可以是美國專利US9918478B2中所揭露之水溶性壓克力高分子銀鹽，也可以是其他分子量大於1000以上之含有銀離子之水溶性高分子。 The macromolecular organic silver ion compound of the present invention can be the water-soluble acrylic polymer silver salt disclosed in US Pat. No. 9,918,478B2, or other water-soluble polymer containing silver ions with a molecular weight greater than 1000.
本發明之水性凝膠中銀的含量必須至少大於 20ppm，最好是大於50ppm，更佳的是大於150ppm，銀離子含量愈高，對於治療口腔黏膜炎的效果也愈佳。 The silver content in the aqueous gel of the present invention must be at least greater than 20ppm, preferably more than 50ppm, more preferably more than 150ppm, the higher the silver ion content, the better the effect on the treatment of oral mucositis.
本發明之水性凝膠中除了以上的成分外，還可以加入適當的調味劑以增加使用者的接受度，例如甜味劑或涼味劑。 In addition to the above components, the aqueous gel of the present invention can also add appropriate flavoring agents to increase the user's acceptance, such as sweeteners or cooling agents.
水性凝膠之配製： Formulation of aqueous gel:
水性凝膠之原料包含用作增稠劑之聚乙烯吡咯烷酮(Polyvinylpyrrolidone，Kollidon®90F，BASF)以及羥丙基甲基纖維素(Hydroxypropylmethylcellulose，Metolose 90SH-100000SR，Shin-Etsu)，所使用之水溶性有機銀離子化合物是大分子之丙烯酸鈉-丙烯酸銀共聚物(Poly(sodium acrylate-co-silver acrylate))，由存昇泰國際有限公司所提供，其所提供的是丙烯酸鈉-丙烯酸銀共聚物水溶液(Poly(sodium acrylate-co-silver acrylate)solution)，丙烯酸鈉-丙烯酸銀共聚物水溶液中之丙烯酸鈉-丙烯酸銀共聚物含量是2.5%，銀離子含量是1%，也就是每一丙烯酸鈉-丙烯酸銀共聚物分子中含有平均約40%的銀，而丙烯酸鈉-丙烯酸銀共聚物之分子量大於5,000,000。 The raw materials of the water-based gel include polyvinylpyrrolidone (Polyvinylpyrrolidone, Kollidon® 90F, BASF) and hydroxypropylmethylcellulose (Hydroxypropylmethylcellulose, Metolose 90SH-100000SR, Shin-Etsu) used as thickeners. The organic silver ion compound is a macromolecular sodium acrylate-co-silver acrylate (Poly (sodium acrylate-co-silver acrylate)), provided by Cunshengtai International Co., Ltd., which provides sodium acrylate-silver acrylate copolymer Aqueous solution (Poly(sodium acrylate-co-silver acrylate) solution), the sodium acrylate-silver acrylate copolymer content in the sodium acrylate-silver acrylate copolymer aqueous solution is 2.5%, and the silver ion content is 1%, that is, each sodium acrylate -Silver acrylate copolymer molecules contain an average of about 40% silver, and the molecular weight of sodium acrylate-silver acrylate copolymer is greater than 5,000,000.
水性凝膠之組成如下表所示，如表所示，所配得水性凝膠中的含銀量是150ppm(0.015%)，以Brookfield DV1流變儀測得在每秒1轉時的黏度是367cps，而在每秒10轉時的黏度是298cps，此水性凝膠之搖變指數是1.23。 The composition of the aqueous gel is shown in the following table. As shown in the table, the silver content in the prepared aqueous gel is 150ppm (0.015%), and the viscosity at 1 revolution per second measured by a Brookfield DV1 rheometer is 367cps, and the viscosity at 10 revolutions per second is 298cps, the thixotropic index of this aqueous gel is 1.23.
案例1： Case 1:
男病患，59歲，罹患下咽癌，接受同步化學放射治療(CCRT,concurrent chemoradiotherapy)，在其治療開始後的第23天(T0)開始給予水性凝膠之介入，請其每日飯後以及睡前漱口使用，每次含漱至少一分鐘以上，漱完後將水性凝膠吐出即可，每週按口腔評估指引(OAG，Oral Assesment Guildline)進行口腔之檢查，共進行4週(T1至T4)如此直到其療程結束，結果如下表所示： A 59-year-old male patient, suffering from hypopharyngeal cancer, received concurrent chemoradiotherapy (CCRT, concurrent chemoradiotherapy). The intervention of aqueous gel was started on the 23rd day (T0) after the start of treatment. And gargle before going to bed, gargle for at least one minute each time, spit out the water-based gel after rinsing, and perform oral examinations every week according to the Oral Assesment Guildline (OAG, Oral Assesment Guildline) for a total of 4 weeks ( T1 to T4) until the end of the course of treatment, the results are shown in the following table:
由表中的結果可以看出，在T0時病患之狀況非常之差，在介入之第1週(T1)，其狀況即改善非常之多，在介入之第2週 (T2)以後其狀況便趨於穩定。 It can be seen from the results in the table that the patient's condition was very poor at T0, and in the first week (T1) of the intervention, his condition improved very much, and in the second week of the intervention. After (T2), the situation tends to be stable.
案例2： Case 2:
男病患，51歲，罹患咽喉癌，接受同步化學放射治療(CCRT,concurrent chemoradiotherapy)，在其治療開始後的第16天(T0)開始給予水性凝膠之介入，請其每日飯後以及睡前漱口使用，每次含漱至少一分鐘以上，漱完後將水性凝膠吐出即可，每週按口腔評估指引(OAG，Oral Assesment Guildline)進行口腔之檢查，共進行4週(T1至T4)如此直到其療程結束，結果如下表所示： A 51-year-old male patient, suffering from throat cancer, received concurrent chemoradiotherapy (CCRT, concurrent chemoradiotherapy), and was given water gel intervention on the 16th day (T0) after the start of treatment. Rinse the mouth before going to bed and use it for at least one minute each time. After rinsing, spit out the water-based gel. Perform oral examinations every week according to the Oral Assesment Guildline (OAG, Oral Assesment Guildline) for a total of 4 weeks (T1 To T4) until the end of the course of treatment, the results are shown in the following table:
由表中的結果可以看出，在T0時病患之狀況非常之差，在介入之第1週(T1)，其狀況即改善非常之多，在介入之第2週(T2)以後其狀況便趨於穩定。 From the results in the table, it can be seen that the condition of the patient was very poor at T0, and the condition improved very much in the first week (T1) of the intervention, and after the second week (T2) of the intervention. becomes stable.
案例3： Case 3:
女病患，40歲，罹患口咽癌，接受放射治療，在其治療開始後的第27天(T0)開始給予水性凝膠之介入，請其每日飯後以及睡前漱口使用，每次含漱至少一分鐘以上，漱完後 將水性凝膠吐出即可，每週按口腔評估指引(OAG，Oral Assesment Guildline)進行口腔之檢查，共進行4週(T1至T4)如此直到其療程結束，結果如下表所示： A 40-year-old female patient, suffering from oropharyngeal cancer, received radiotherapy, and began to intervene with water-based gel on the 27th day (T0) after the start of treatment. Please rinse your mouth every day after meals and before bedtime. Rinse each time for at least one minute, after rinsing Just spit out the water-based gel, and perform oral examinations according to the Oral Assessment Guidelines (OAG, Oral Assesment Guildline) every week for 4 weeks (T1 to T4) until the end of the course of treatment. The results are shown in the following table:
由表中的結果可以看出，在T0時病患之狀況尚未發展至非常糟的狀況，在介入之第1週及第2週(T1&T2)，其狀況並未惡化甚至有些改善，在介入之第3週(T3)以後其狀況已有改善進步直到療程結束(T4)。 From the results in the table, it can be seen that the condition of the patient has not developed to a very bad condition at T0, and in the first and second weeks of the intervention (T1 & T2), the condition did not worsen or even improved somewhat. After the 3rd week (T3), his condition has improved and progressed until the end of the course of treatment (T4).
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